## 1. Preamble

This document is a shallow investigation, as described here. As we noted in the civil conflict investigation we shared earlier this year, we have not shared many shallow investigations in the last few years but are moving towards sharing more of our early stage work.

This is a shallow on telecommunications infrastructure in low- and middle-income countries (LMICs). I spent about three weeks on it, during which I read major papers in the field and spoke to about ten experts. This document has been read and discussed by Open Philanthropy’s Global Health and Wellbeing cause prioritization team.

We’re continuing to look at the robustness of the social scientific evidence on telecommunications. Many of the papers are quite new and remain unpublished, which limits our ability to review the data behind them in detail. However, we think that the initial evidence is quite positive, and we think that someone looking to launch an impactful organization might want to examine this space more closely. We think there may be both nonprofit and for-profit ideas worth pursuing (the latter could still have large social returns, and provide benefits from an earn-to-give perspective). We see Wave as an interesting model for the latter.

We welcome comments either posted to the Effective Altruism forum, emailed to me at [email protected], or shared via this Google Form.

#### 1.1 Major sources of uncertainty

It seems worth flagging two major uncertainties that this shallow does not resolve:

1. I am quite unsure what the expansion path for telecommunications technologies looks like. Technologies often spread much faster than expected; it is possible that philanthropic investment is less needed/marginally useful here than I think it is.
2. The literature on telecommunications access and income is still quite limited; there are really only two randomized controlled trials (RCTs), both of which have relatively small sample sizes. In addition, there’s only one RCT on cellphone coverage and the other studies in this literature use difference-in-differences with two-way fixed effects, which may yield misleading results. We’d like to have more evidence and are currently considering funding more research in this area.

## 2. Summary

#### 2.1 Why telecoms?

For the purposes of this document, “telecoms” includes internet access, fixed-line telecommunications infrastructure, and cellular phone access.

We did some initial work on infrastructure in general.  Investment in telecoms looked unusually promising in catalyzing income growth.  Two RCTs find that access to a form of telecommunications increased incomes by 20% in the first year.  Therefore, we decided to look into the topic further.

This shallow seeks to answer the following questions:

• What is the current status of information and communication technology (ICT) infrastructure? Where is ICT infrastructure worst?
• What are the best tactics to improve ICT infrastructure?
• Should Open Phil fund any of those tactics?

#### 2.2 Who is already working on it?

Mostly, the market is solving access to at least some telephony and internet – in 20 years, mobile phone usage has increased approximately 85 percentage points. In sub-Saharan Africa, where mobile phone usage has lagged much of the rest of the world, access to 3G networks increased 55 percentage points in the six years through 2020.[1]In 2014, Steve Song gave a talk noting that 20% of Africans had access to 3G. By 2020, GSMA said that 75% of Africans have access to 3G. This increase has happened without particular effort from philanthropists, and with significant barriers to usage. However, neither access nor usage of telecoms are universal, growth is beginning to slow, and there are still large gaps to fill.  This is not uncommon for new technologies; initial adoption is generally much faster than rollout to the last 10-15% of users.

ICT is relatively light on philanthropic investment, likely because it is an active area of commercial investment. I’m somewhat uncertain on total funding, as several entities either don’t report their spending or don’t clearly separate it from other spending, but I am fairly certain that it is not a central focus area for any major foundations.

There are four major areas where there is at least some ICT funding, none of which I have managed to come up with a good total investment figure for.

1. The Gates Foundation seems to be the only large foundation that is very active in this area. Much of their funding is targeted specifically towards women and/or financial services; they are less interested in ICT as a category than ICT as a catalyst for other things. I’ve had difficulty figuring out what their total ICT spend is, because ICT-centric projects are not necessarily categorized as being such. They funded the original Phillip Roessler RCTs on cellphone provision (targeting women in particular).
2. There are a handful of ICT-specific foundations – e.g. the Internet Society Foundation (~$50M a year), the Web Foundation (~$4M a year), the Association for Progressive Communications (~$4M a year), ISIF Asia (~$2M a year). This might be 100M per year if you add up all the small foundations (though that’s potentially high/optimistic).
3. Commercial entities also do some amount of philanthropic work – e.g. Google.org’s technology and innovation arm, the Ericsson for Good initiative, Meta’s Connectivity, and Data for Good.

While their overall footprint is relatively large — Google.org gives about $100M per year, and Meta is obviously a large company — their ICT-specific spending appears to be a relatively small percentage of that. If I were to guess, I’d say the companies spend perhaps 50M together on more or less philanthropic ICT work — but this is a highly uncertain estimate. 1. Commercial non-philanthropic spending is potentially very large, but the overlap with our interests (work that makes cell phones/internet access available to new users) is very unclear. However, there’s clearly a lot of commercial capital overall. Orange Telecom is currently building (pg. 41) 2000 towers in the DRC to (ostensibly) cover 10M additional people in rural areas. Likewise, Google just made first landing of the Equiano cable, their third private international cable, which connects Portugal to West and South Africa (with 20x the capacity of previous cables to the region), which probably cost around$400M. Safaricom is spending $500M expanding to Ethiopia, and Africell is spending$200M on an Angola expansion. Capital spending per year on telecoms in sub-Saharan Africa is ~$10B. I would guess that total philanthropic spending on telecoms access is probably less than$150M a year, but I am (again) highly uncertain. Adding in relevant commercial spending could vastly increase that number.

#### 2.3 What could a new philanthropist do?

Since most interests in the space are commercial entities, they are by definition interested in commercially viable products, and somewhat less interested in the social returns to ICT infrastructure. This means that rural and/or very poor communities are less likely to receive ICT infrastructure.

We could target grants towards these communities – where there might be a large percentage increase in income, but from an extremely low base. These communities might not be commercially viable for telecoms, but investing in them could be above our cost-effectiveness bar. There is pretty good evidence that there are large economic gains to be had in going from no connectivity to some connectivity. (This is discussed further in the importance section.)

The completely unserved populations are now quite small – perhaps 3%-9% of the world’s population.[2]It’s possible that this number is much larger — see my notes on the global coverage gap. These ~250-750 million people are (somewhat by definition) difficult to reach, but we could invest in some of the companies working on reaching them. One example is Africa Mobile Networks, which is building “network-as-a-service” for mobile operators (pg. 40).

It may be more promising to not only focus only on strictly increasing coverage, but also on decreasing the cost to use mobile devices in areas that already have (at least some) coverage. Most of the ways to drive down cost (competition, deregulation, additional infrastructure) will also likely do something to expand coverage or improve the quality of coverage where it exists now.

These include:

## 3. Importance

The limited existing literature suggests that improving communications technology is a surprisingly good way to improve incomes. This appears to be true both when expanding coverage and expanding access, and for both adding cell coverage and internet coverage.[3]Indeed, I am sometimes a little sloppy in distinguishing between the two. The results are remarkably consistent and large.

When expanding coverage, the economics literature has found:

• In the Philippines, an RCT showed that gaining access to a community network increased incomes 17%, with those who could actually place calls from home increasing their incomes 28% in fourteen months. This would be a 7000x return in our units given their per-tower costs.
• In Senegal and Tanzania, a quasi-experimental study found that access to 3G increased incomes 14% and 7% in a year. This would be equivalent to a 3500x-7000x return if building a tower costs roughly the same as it does in the US.
• A similar quasi-experimental study in Nigeria found that access to mobile broadband increased incomes 5.8% in a year, 7.8% in two years, and 9.2% in three years. Based on these numbers, a tower would meet our cost-effectiveness bar if it covered ~2200 people.
• In sub-Saharan Africa, a quasi-experimental study exploiting the rollout of subsea cables showed that gaining access to improved internet raised employment by 7% and GDP/capita by 2%.

When expanding access:

• An RCT in Tanzania showed providing people with phones boosted incomes 7%, and providing people with smartphones boosted incomes 20% in a year. Note that this was true even though 88% of households already had access to a feature phone before the RCT.

Another way of looking at impacts is to look at studies of products enabled by mobile expansions, such as mobile money. Suri and Jack find that MPESA lifted 2% of Kenyan households out of extreme poverty – I think a naive back-of-the-envelope calculation (BOTEC) based on that analysis would imply that MPESA increased average consumption by 3.4%.[4]They say that 2% of Kenyan HHs exit extreme poverty based on MPESA overall. The coefficient on “leave extreme poverty” w.r.t. “agent density” is -0.007, so 0.02/0.007 ~ 2.9x multiplier on that coefficient. The coefficient on “log(per capita consumption)” is 0.012, so 0.012*2.9 ~ 0.034. Having this large of an effect from mobile money alone is another credible signal of large total impacts.

I think these results are positive and consistent enough to suggest that telecoms access gives at least a 5% income boost, and more likely a >10% income boost. That is an extremely “big if true” result.

For instance, a very rough estimate suggests if this is true, perhaps 9% of Africa’s growth in the last two decades has been from increased cell coverage, and an additional 2%-8% came from growth in internet usage. Thus, expanded access to telecommunications alone could explain ~⅙ of the growth Africa has experienced from 2000 to 2020.

A similar macro BOTEC suggests that increasing usage of mobile broadband in sub-Saharan Africa to South Asian levels (28% usage → 34% usage – which is only a modest change compared to high-income country levels of usage) would be worth $171 –$342 billion[5]Depending on whether you expect a 5% income increase or a 10% income increase to Open Philanthropy, using our framework for valuing income increases.

## 4. Neglectedness

Mobile communications is not the most neglected of topics when viewed in terms of total spending, as global telecoms spending is somewhere around 1.6 trillion dollars a year. But this is obviously not spent evenly around the globe; US telecom providers spend about $226/person/year on capex, while African ones spend about$13/person/year.

I found it more helpful to separately consider the number of people who have no coverage (the coverage gap) and the number of people who do not use mobile devices (the usage gap).

The coverage gap is closing fairly rapidly over time. GSMA claims that 93% of the world’s population currently has access to 3G or better mobile data; the International Telecommunications Union claims it is 94%, with an additional 3% having access to 2G data. This would leave about 600 million people without access to coverage.[6]Note that for the above I am considering mobile internet only. In the near future, satellites in low orbit will make it possible to access broadband in almost all parts of the world in the near future. However, satellite internet is quite pricey. Starlink terminals are currently $500 loss-leaders … Continue reading This is down from 750 million just two years before; if coverage continued to increase at that rate, it would take just eight years to reach global coverage. However, this data is likely to be optimistic; it is based on self-reported data by telecoms, who are likely to have incentives to overstate how good their networks are. As I noted above, I am uncertain about this data, and it is possible that the number of people with no cell phone coverage is substantially greater than 600 million. I do think it’s likely that >90% of the world has access to cell service, but I’m not willing to swear to any exact percentage. I’d estimate the true coverage gap is somewhere between 3% (the number claimed by GSMA) and 9% (3x what GSMA claims). This would mean ~240M-710M people lack coverage globally. #### 4.2 Usage Gap If defined like the coverage gap, the usage gap would be the percentage of people who have access to any kind of cell phone coverage, but don’t use it. But for reasons I frankly don’t understand, this is almost never what people actually mean by the usage gap. Indeed, finding that number is fairly difficult; since SIM swapping and sharing phones is common in low and middle income countries, good estimates of the percentage of the population with access to a cell phone are thin on the ground. My guess is that most but not all residents of L&MICs have access to a feature phone, as surveys in several sub-Saharan Africa countries suggest that about 80% of people have access to a phone and the number of subscriptions is over 100 per 100 people. This is likely less true the poorer the country you consider; the number of subscriptions / 100 people in LICs is nearly 50% lower than it is in MICs. Instead, the “usage gap” generally actually means the percentage of people who have theoretical access to mobile internet but do not use it. This is now about 6x the percentage that don’t have any access, or about 43% of the global population. Usage is lower among the groups you would expect – rural residents (37% less likely to use mobile broadband),[7]Rural coverage can be 40X the cost of urban coverage. lower income people, women (20% less likely to use mobile broadband), speakers of minority languages, etc. Like the coverage gap, the size of usage gap is decreasing over time – but the experts we spoke to were less than convinced that usage will ever be universal. The most common reason for people not to use telecom services is the cost of both the device and the coverage. Per the GSMA, an internet-enabled device costs an average of 44% of monthly income in a low or middle income country. Philanthropic investment is unlikely to change device costs, but we might be able to reduce tariffs (often 7-10% of the purchase price) through policy work. Even if you have a phone, though, the cost of using data can be prohibitive in developing countries. In sub-Saharan Africa, for instance, 2 GB of data can cost 10-20% of monthly income, and it is fairly obvious why internet penetration in Nigeria is 2x that of Togo (see image below). Prices are dropping over time — GSMA reports that the price of a marginal GB of data has dropped 40% in four years – but I think we could speed this process along. It’s not clear that telecoms companies have the incentives to lower their prices as much as possible – many are monopolies or duopolies – but we could advocate for changes. As physical infrastructure improves, regulatory costs decrease, or competition increases, the marginal GB becomes cheaper, and the marginal consumer becomes more likely to be able to afford to use mobile internet. ## 5. Tractability Possible “Grant Ideas” All of these are somewhat more nebulous than I would like; I am not sure what organization you would literally write a check to in order to make these things happen. In many cases, the ideal organization would be a company doing this work to which we could potentially provide low-cost capital, which has different costs than a typical grant. I split these into two sections — possible grants that would address the coverage gap, and possible grants that would address the usage gap. #### 5.1 Coverage Gap #### 5.1.1 White-Label Tower Companies In the US, many cell phone towers are owned by companies that are not the telecoms that run services through them. This is not true elsewhere, where towers are largely built, owned and maintained by the telecoms. This is less than efficient – if a new carrier wants to expand into an area, they have to build a new set of towers, since they cannot use their competitors’ existing towers. The Tribune Express cites (without a source) that “[in Pakistan] a dismal reality is that 40% of the 34,000 towers are just 300 metres apart,[8]Cell phone towers should be 1-2 km apart. which results in wastage of$1 billion worth of capital due to the existence of parallel towers at close distances.” In many places, this can make coverage expansion unviable. The population density might be enough to support one company and one infrastructure buildout, but certainly not three or four.

This might also allow telecom companies to lower prices. If each company must complete a full build-out, they must also pay for said full build-out. If companies are sharing towers, the cost per company is lower, and the amount that the company must recoup from their customers is also lower. Thus, this intervention might be able to address both the coverage gap (by making expansion into new areas more economical) and the usage gap (by lowering the cost of service in all areas).

There is at least one group working on this in Pakistan. It appears to be an incumbent telecom company, so it’s not clear if they need funding. African Mobile Networks and BRCK are working on related issues in Africa (though BRCK is building a wifi rather than mobile solution).

#### Right-of-Way Fees

It is cost-prohibitive in some countries to put down more land-based fiber. In some municipalities in Nigeria, there are policies that require companies to pay extremely high fees to put down cable. These towns are often just skipped during buildout.

If we are interested in subsidizing capital for land-based fiber, I think we would have to fund advocacy for reducing these fees as well; it’s not that helpful to lower interest rates if it is still extremely costly to build cable.[11]This effort could be compared to our work on land use reform, which often involves funding advocates for reduced housing regulation.

#### Competition

Almost all telecoms markets have only a few entrants, and some remain monopolies. As long as there is no competition in the market, there are few incentives for telecom companies to improve or increase their coverage.

One of the most obvious examples of this is EthioTelecom. EthioTelecom is the only telecommunications provider in Ethiopia, and while it claims to cover 88% of the country with at least 2G service (and 66% with 3G), it is unusably bad. South Africa’s average internet speed is about 10,000x faster than Ethiopia’s. Unsurprisingly, Ethiopia has low internet penetration and essentially no digital economy.

By comparison, when Cambodia introduced competition into the mobile market, the cost per gigabyte of data dropped from $4.56 in 2013 to$0.13 in 2019 (pg. 166 of the World Development Report) and mobile usage spiked to 6.9 gigabytes per capita per month.

However, introducing competition without improving infrastructure has its own challenges. When pricing pressure is substantial, the infrastructure can’t keep up. This has been most notable in India, but also has happened elsewhere in southeast Asia. Carriers are not making enough money to upgrade their infrastructure, and so service is somewhat worse.

#### Spectrum Costs

Spectrum licensing fees can be 20-30% of buildout costs. When you buy spectrum in most countries, you have exclusive use of that part of the spectrum.

This allows incumbent carriers to essentially block new entrants (by licensing the part of the spectrum they would use) — but does not require the incumbent to use it. A licensing regime that does not allow you to license spectrum unless you plan to use it could be helpful, and allow more entrants into the market.

This might be more effective than pushing for competition more generally.

#### Tariffs

Handset costs are a significant barrier for many people in low and middle income countries (LMICs). The phone supply chain is relatively efficient, so we are unlikely to be able to reduce the cost of the actual device, but we could reduce the effective cost to consumers by reducing tariffs.

Tariffs of 7-10% are common on imported electronics in LMICs. This is pretty substantial, and makes electronics more expensive to purchase in poor countries than in rich ones. We could advocate for tariffs on these devices to be reduced, so that more people could afford handsets.

## 1. Editorial note

This document is a “shallow” investigation, as described here. Over the last few years, we’ve moved towards trying to do more shallows quickly for internal audiences.  We wanted to experiment with sharing more again to see how much work it takes and whether it generates informative feedback or leads, so this is the first shallow we’ve published in a number of years.

This is a shallow on reducing civil conflict.  It took me about two weeks to write.  During this time, I read major papers in the field and spoke to about five experts, but did not fully critique their assumptions.  I have tried to flag my major sources of uncertainty in the document.

This document has been read and discussed by the cause prioritization team.  At this point, we do not plan to proceed to a medium investigation, but that could change if we substantially update our estimates of either the financial costs of civil war or the tractability of the problem.

We welcome comments either posted to the EA Forum, emailed to me at [email protected], or shared to this Google Form (can be submitted anonymously).

## 2. Major sources of uncertainty

My major sources of uncertainty after writing this are the following:

• What is the best way to model the economic impact of civil war?  I tended to make fairly conservative (in the sense of total size of the problem) assumptions – e.g. economies that experience civil war recover fully within ten years – but I am not sure how reasonable those assumptions are. We’re currently hiring some academics to investigate these questions further.
• Am I fully capturing the health impacts of civil war on civilians?  There is relatively little data about the social or economic consequences of being displaced within the Global South, and I am not sure my estimates of off-battle-field DALYs are particularly good.
• Fundamentally, I am quite uncertain how much of a difference micro-scale interventions like cognitive behavioral therapy will make on macro-scale events like war.

## 3. Summary

#### 3.1 What is the problem?

Living through a civil war is very bad for your health.  The direct cost of civil conflict is about 10M DALYs per year, but the indirect cost probably quadruples that figure.[1]The GBD estimate includes only direct DALYs, so war injuries/war deaths but not deaths caused from disrupted access to healthcare, etc.  (This is a fairly conservative estimate; one paper argues that there are 25x as many indirect deaths as there are direct deaths.)  Infant mortality and malnutrition rates are twice as high in states either experiencing or recovering from civil conflict as in stable ones.  Life expectancy is about a decade lower than would be expected in a peaceful state.

Per my BOTEC, civil wars cause a loss approx. ⅔ as many DALYs per year as malaria and NTDs (combined).  A civil war costs about $14,000 OP value per country resident per year, or 0.14 life years. (Malaria, by contrast, has a DALY burden of 0.038 life years / resident of sub-Saharan Africa – so civil wars are not as significant a burden on life as malaria, but not insubstantial either, at least in countries where they are ongoing.) But war’s impacts are not limited to health. War impoverishes the populations that experience it, such that poverty is increasingly concentrated in and around states experiencing civil conflict. By 2030, about ½ of the global extreme poor will live in such states. This is not simply because poverty is declining elsewhere; an increasing percentage and an increasing number of the global poor live in countries either at war or at high risk of descending into war. Most of these wars are not wars of global importance; no major power has any particular investment in settling them. (Indeed, for the purposes of this shallow, I am choosing to focus on civil wars where great powers did not intervene – thus excluding Iraq, Afghanistan, Ukraine, Yemen, Israel/Palestine, as reducing conflict there is likely to involve different processes than reducing conflict in more local wars.) War is bad for growth; unlike other emerging markets, states at war generally have zero or negative growth. The residents of fragile states are particularly unable to bear a recession or depression, as civil wars essentially exclusively happen in low income countries. #### 3.2 Who is already working on it? 30% of overseas development aid goes to fragile states, totaling about$76 billion in 2018.  However, most of that is targeted toward poverty reduction and alleviation rather than reducing conflict.  The UN estimates that about $6.8B was spent on peacebuilding projects in 2013, with another$8B spent on peacekeeping operations.

The US government is and has been the largest single contributor to peacebuilding budgets.  Particularly during the Iraq and Afghanistan Wars, the US spent copiously on stabilizing these two countries to dubious effect.  In 2013, spending on peacebuilding in these two countries alone was over 100 billion.  For the purposes of this shallow, I ignore those conflicts and attempts at peacebuilding, and focus only on conflicts where a great power is not involved.

In 2020, the US spent $4.1B a year in peacebuilding in countries where it was not actively involved. Nonetheless, even$4.1B makes the US the largest single contributor to peacebuilding efforts.  The majority of this is in the form of UN peacekeeping missions ($1.45B) and general international organization funding ($1.5B), with the Department of State funding an additional $650M a year in peacebuilding and democracy promotion programs. Private spending is likely considerably smaller than government spending. According to one source, 2020 grants were only$150M, $50M of which comes from USAID. This is likely somewhat of an underestimate, as the 990 for a single NGO – Search for Common Ground – reveals yearly funding of about$25M, but I would not expect private spending to be more than $300M total. #### 3.3 What could a new philanthropist do? Open Philanthropy might be interested in funding a) more research on particular interventions (see potential grants), b) lobbying for more effective interventions rather than less effective ones (e.g. CBT for ex-combatants instead of community-driven development programs). Open Philanthropy could also fund lobbying for more engagement with international peace processes (for instance, lobbying for funding UN peacekeeping to the level requested by the UN, rather than the smaller amount currently provided by the US government). ## 4. Importance Global poverty reduction will likely stall out without improvements in states with civil conflict (or that are recently post-conflict). While extreme poverty in east Asia and south Asia will approach zero by 2030, poverty in fragile states (mainly but not exclusively in Africa) will increase over the same period. The economies in fragile states barely grew during the period 1970-2008, and the living standards of the people living in those states are unlikely to improve unless governance improves. Stabilizing existing fragile states and preventing other states from becoming fragile is thus of potentially very high importance – indeed, eradicating poverty likely requires it. Estimates of how badly a civil war affects a host economy vary widely; Imai and Weinstein 2007 estimate that a civil war costs an economy 1.25% of growth a year, Collier 1999 estimates a 2.2% decrease due to war, the IGC roughly estimates 4-5%, UNDP puts the reduction in GDP at 12.3%/year for civil wars after 1990. (Though an extreme example, GDP/capita in Syria is 11% of what it was before the war.) I’ve chosen to use a 5% annual hit to GDP/capita in the BOTEC. (I assume LICs would otherwise grow at 3%, so in the BOTEC, countries at war shrink at 2%.) With this input, the financial cost substantially outweighs the cost in health; I find that a 5% hit to growth for four years and full recovery by year 10 will cost individuals about$1000 in income, for a total financial cost of about $21B in an average LIC.[2]Paul Collier finds the financial cost of the average civil war is$64B 2008 USD in The Bottom Billion, though he doesn’t specify in any detail how he reaches this figure. A rough estimate of the financial cost of all civil wars that occurred in 2017 was 290B.[3]This is greater than the cost of the number of civil wars that started in 2017 * the cost of a civil war, because more civil wars start than resolve, so the number of civil wars is increasing over time. Note that this is a relatively optimistic assumption – it implies that these countries grow at >7% for the six years following the end of the civil war.

Civil wars also cost lives.  IMHE estimates that 10.1 million DALYs are lost per year directly due to “conflict and terrorism”.  This is about 0.25% of all DALYs, but that estimate does not include any deaths or disability incurred through displacement[4]On average,  ~100 people are displaced per battle death. or disrupted access to healthcare.  I am highly uncertain how many DALYs this adds (see mortality cost), but it seems that the indirect deaths due to conflict substantially outnumber direct deaths on the battlefield.  (I take total DALYs to be 4x the number of direct DALYs, but I’d be willing to believe anything from 2-20x.)

Between deaths and lost income, preventing an average civil war would have OP value of around 1.2 trillion,[5]The true value obviously varies substantially by the size of the country and the severity of the civil war; even small countries can have particularly deadly civil wars (Liberia), while India is a large country that has had several small civil conflicts. of which 20% is from DALYs and 80% is from lost income.

Unfortunately, it seems relatively few civil wars are currently averted.  After a relative lull in interstate and intrastate violence in the 2000s, the number of civil wars and the number of people killed in civil wars has increased in the last decade.  There are also now more refugees than any previous point in history.  While data on poverty among refugee populations is scant, it is likely that they are experiencing considerably more poverty than either the native population of their host country or that they would have if not forcibly displaced.

#### 4.1 Sources of Uncertainty

Most of the above figures are fairly conservative; I could be substantially underestimating both the mortality cost and the financial cost of civil war.

Mortality Cost

In terms of mortality cost, I’ve estimated that about 25% of deaths from civil war occur on the battlefield.  Papers range from suggesting that there are as many deaths off the battlefield as on the battlefield, to suggesting that only 4% of war deaths occur on the battlefield.  Sources attempting to determine the percentage of battlefield deaths by war vary by nearly as much.

I am not sure I have strong thoughts on which end of this range is more likely to be right; I would be willing to believe that the total number of DALYs caused by war is >> 4x the number of reported battlefield DALYs.

Further complicating estimates of the total number of DALYs from civil war, one expert mentioned that battlefield death counts are often a severe underestimate, by >3x.  I am willing to believe I’m probably order of magnitude correct on DALYs, but that’s about it.

Financial Cost

There is substantial heterogeneity in how badly civil wars affect the economy of the country experiencing one; in some cases, rebel groups stay in the hinterland and life in the major cities is able to keep ticking along much as usual, while in others, the economy completely collapses.  Given this, it’s difficult to figure out what the counterfactual is for the economy of countries experiencing civil war.

The best single paper is probably Costelli, Moretti and Pischedda 2017, which does attempt to estimate a counterfactual with a synthetic control rather than just doing a cross-country regression.  Costelli, Moretti and Pischedda 2017 finds a total effect of -17.5%, which is relatively similar to the BOTEC simulation I use (-5%/year for four years).

It is also unclear how much a civil war in one country affects its neighbors.  I do not model spillover effects at all; Paul Collier claims that modeling spillovers doubles the cost of civil wars.  I could fairly easily be convinced into a substantial increase here too.

## 5. Neglectedness

Per DALY, civil wars do not seem particularly neglected.

International spending on averting and settling civil wars seems to be in the range of 10-15B (not including governments also spend money trying to pacify restive areas).[6]Estimating government military and policing spending to reduce the chance of civil war seems difficult, so I’m not doing it.  OECD countries spend about $5B on peacebuilding, the UN spends about$6.5B on peacekeeping, and presumably non-OECD countries spend at least some amount (though likely not a lot)

This means that the world spends about $330-$495 per DALY from civil wars, about 1.5-2.5x what is spent per DALY on HIV/AIDS.

However, the financial cost of civil war substantially outweighs the DALY cost.  About $15B is spent preventing civil wars, but civil wars cost$290B in 2017.  If one adjusts for the greater consumption value for LIC residents – civil wars almost exclusively happen in very poor countries – OP’s valuation of for loss of income is $14T. This gives a current OP-valued cost/current non-OP spending ratio of 966 versus 497 for HIV/AIDs — which means we could view conflict prevention as relatively underfunded. ## 6. Tractability I am reasonably convinced this area is both important and neglected relative to its importance. However, its tractability seems questionable. In the below, I review some possible interventions to prevent civil conflict. #### 6.1 Tractability and Speed Several experts have mentioned that speed matters a lot in reducing the severity of conflict. Once things have started to spiral, there is a very limited time in which one can bring down the temperature of the situation. It is helpful if a particular intervention already has people on the ground, or can get them there very quickly. Peacekeepers are often useful for this, as they are on site and neutral.[8]Once they are deployed; the process of getting peacekeepers deployed is notoriously long. For example, an expert told us a story about a town in a country that had recently ended a civil war where a girl had been murdered and her body dumped outside a mosque. Tensions escalated quickly, the local imam was beaten up, and there were threats of further attacks on the Muslim community to happen the next day. The local peacekeeping mission had Muslim and Christian leaders make a broadcast on local radio together, and this kept the situation from escalating further. Even a limited delay likely would have made such an intervention impossible; de-escalation would have been much more difficult after further violence. This suggests that we should focus particularly on organizations that can react quickly. #### 6.2 Possible Interventions #### 6.2.1 Predicting Civil War The first step to preventing civil war is to determine where a civil war is likely to be in the future. Nearly every party interested in knowing about future conflicts has a project designed to provide information about where future conflicts will occur – the USthe EU, ECOWAS, the OSCE, etc. The Integrated Crisis Early Warning System (ICEWS) claims to have a forecast accuracy of 80% (though I am skeptical that this means an 80% accuracy for predicting exactly when conflict escalation is likely to happen). At the macro level, it is relatively easy to tell which countries are at risk of future conflict. Countries that have had prior civil conflict are quite likely to have civil conflict in the future, and poor countries are also more likely to have insurgencies and civil conflict. The riskiest countries therefore are both poor and have current conflicts: the DRC, Yemen, Nigeria, Sudan/South Sudan, Somalia. However, it is difficult to predict exactly when a recurrence will occur, no matter how fine-grained the data. Bazzi et al find that predicting conflict over space is fairly straightforward, but adding time-varying information provides little additional information. Indeed, the within-location-but-time-varying model has an R2 of only 0.01. I think this is likely to be a problem not easily solved with additional research or funding, but I don’t know how well superforecasters do on this problem. My inclination is that if the Pentagon has an incentive to solve a problem, and has failed to do so, I suspect the sticking point is not resource constraints, but I may be wrong here. If it is possible to predict which situations will escalate, that could be enormously valuable. #### 6.2.2 UN Peacekeeping Despite the perceptions of peacekeepers as largely useless, the empirical evidence suggests peacekeepers really do keep the peace; indeed, of interventions to reduce the risk of return to conflict in a fragile state, peacekeeping is probably the most promising of the bunch. The experts we have spoken to have universally agreed that peacekeeping works. Peacekeepers may also help support the rule of law and a functioning justice system in the difficult reconstruction period. Reducing The Likelihood Of A Return To War Even when parties to a civil war come to the negotiating table, talks often break down, and even signed agreements are often ignored in favor of rearming and returning to war. With a third party willing to enforce a signed agreement, warring parties are much more likely to make a bargain (5% vs. 50%) and the settlement is much more likely to hold (0.4% vs. 20%) (per Walter 2002). Peacekeeping is the most common tool used to enforce such an agreement, or at least give all parties substantial warning if one party violates the agreement. A cross-sectional logit by Page Fortna finds that peacekeepers reduced the likelihood of further war by 75% through the mid-2000s. However, I am not sure that I believe that past peacekeeping successes necessarily imply future peacekeeping successes. Per Krasner and Eikenberry, “[peacekeepers] work best when there are a limited number of national parties, when there are no hostile neighbors, when there are no national spoilers, and when there is [still] a functioning state”. It is not clear to me that this describes that many modern civil wars. Many modern civil wars happen in places where the state is very weak to non-existent – Somalia, CAR – and there are many national parties. Furthermore, it is often difficult to get enough peacekeepers. In a place like Liberia (population 5M), a force of 15,000 will suffice; should you wish to deploy a similar density of peacekeepers to the DRC (population 89M) or Ethiopia (population 115M), you would likely need more peacekeepers than currently exist in the world. I took a 30% haircut on Fortna’s number. Even with this haircut, peacekeeping has decent returns of up to ~152x; BOTEC here. If we have some leverage here, such that the cost of one lobbyist returns >7x in funding for peacekeeping, this seems possibly worth keeping on the radar and/or considering as part of a larger advocacy portfolio. Rule of Law Support UN peacekeepers also often have a mandate to support rule of law reform. While it is not their primary mission, UN missions have “assumed responsibility for drafting laws and lobbying for their passage, revis[ed] constitutions, train[ed] judges, prosecutors, and police officers, [built] courthouses, police stations and prisons, monitor[ed] extrajudicial punishments, arbitrary arrests and indefinite detentions, assist[ed] with criminal investigations and prosecutions, improv[ed] coordination both between and among state and non-state authorities and more generally elevating the role of the state as a purveyor of security and justice” (Blair 2021, 17). By providing an interim rule of law during the transition from war to peace, peacekeepers show governments and citizens a demonstration of how rule of law should work. In his 2021 book, Robert Blair finds that this is remarkably effective. Spending time with a UN peacekeeping mission increased individuals’ trust in formal institutions by 30 percentage points. This seems like a valuable contribution by peacekeeping. It is unclear if this is contributing to the increased likelihood of peace holding, but it does seem useful. What Could Funding Do? As noted above, it is relatively unlikely that additional funding for peacekeeping would increase the number of missions. If the Security Council has not yet agreed to a mission, there is likely a reason for that; that reason will not vanish with more funds. However, simply increasing the funding for existing missions seems to be useful; Collier and Hoeffler find that doubling mission funding reduces conflict by 25%. In particular, additional funding could be used for one of two purposes: increasing the number of peacekeepers or increasing the quality of peacekeepers. The first seems to be effective in reducing conflict; the larger the mission, the more combatants are deterred from returning to conflict (Hultman, Kathman and Shannon 2014Kreps 2010, Kathman and Wood 2016). The second is also useful as better-trained (more expensive) peacekeepers are more effective at keeping the peace. Current peacekeepers are poorly trained and poorly paid,[9]The UN reimburses at$1400/month/peacekeeper.  This is cost-effective for Egypt (2812 peacekeepers), where the average soldier costs $672/month, but means that even South Africa is effectively subsidizing the UN when it contributes peacekeepers (average South African expenditure/soldier/month = … Continue reading often from armies not known for their efficacy. Given existing variation in peacekeeper troop quality, it may be possible to use additional funding to rely more on the higher quality peacekeeping troops,[10]This might also serve to reduce the number of bad PR incidents involving peacekeeping troops. Well-trained soldiers are hopefully less likely to be involved in sexual abuse of minors. and less on cheap troops from countries with histories of major human rights violations from their armed forces. Alternatively, it might be possible to spend some additional funding on better training peacekeeping troops. Training for peacekeeping is currently two weeks long due to the “limited time available for professionals” and the need “to pay staff while enrolled in long-term training programmes.” This does not seem like enough time to train people to operate in a foreign country, under high stress conditions, especially if they are going to serve as an example of the rule of law.[11]By contrast, the US Peace Corps has 10-12 weeks of training, and explicitly does not operate in conflict zones.[12]Most peacekeepers come from countries that aren’t well known for their strong rule of law; the top contributors are Bangladesh, Nepal, India, Rwanda, Ethiopia, and Pakistan. #### 6.2.3 Disarmament, Demobilization, and Reintegration (DDR) Programs There are relatively few evaluations of programs to reintegrate ex-combatants. This is unfortunate, as they are nearly universal and would seem to be a key to maintaining peace – it is not uncommon for former combatants to join other conflicts or start their own, new conflicts.[13]This can be within the same country – for instance, Ahmad Shah Massoud clearly never stopped rebelling – or in another country – for instance, Paul Kagame, who would lead the RPF in the Rwandan Civil War, began his career as soldier in Musevini’s army in the Ugandan Bush War. In order to encourage fighters to truly put their weapons down, DDR programs often have multiple goals – both combatant reintegration into the economy (increasing the opportunity cost of rejoining the war) but also convincing fighters to support the peace process (so that they would not want to rejoin anyway). The very limited literature (a JPAL/IPA review includes only two papers) shows limited support for the former and no support for the latter. The program Gilligan, Mvukiyehe, and Samii 2012 evaluates – in Burundi – increased employment, but the program evaluated in Humphreys and Weinstein 2007 – in Sierra Leone – did not. Neither GMS 2012 nor Humphreys and Weinstein 2007 find any impact of the DDR programs they evaluate in breaking social linkages from rebel groups or increasing support for peace. A friend running a survey on ex-FARC rebels was also quite skeptical of the efficacy of the DDR program in Colombia. The empirical results here don’t accord terribly well with my priors; I’d expected that DDR programs would be well-defined and effective. Nonetheless, it doesn’t seem like there’s much to fund here; DDR programs are often run by either the government (as in Colombia) or by a UN mission if there is one (El Salvador, Cambodia, Mozambique, Angola, Liberia, Sierra Leone, Guatemala, Tajikistan). The lack of evaluations and reports suggests that there has been relatively little NGO input in the process. #### 6.2.4 Community-Driven Development Community-driven development has been a very popular form of intervention since the 1990s. In a typical CDD program, an NGO provides funding for development projects provided that the local community plans how that development money should be spent. There is usually an area of development that the funding is earmarked for (e.g. health, education), but the community can choose what to implement within that broad category. In theory, this encourages the local community to take ownership of the project, allows them to choose what they need, and the resulting project will provide services in contexts where the government is generally absent. In a setting where the economy is growing and the government is providing a useful service, locals are less likely to choose to support rebel groups and conflict will be reduced. In practice, this does not appear to be the case. Across a large sample set (not necessarily in conflict areas), Rao and Mansuri 2013 finds no evidence that CDD projects improve social cohesion. JPAL has evaluated a handful of CDD projects in post-conflict societies, and also found little evidence of change in governance. There is even some evidence that CDD projects become rebel targets, and are likely to increase rather than decrease conflict (Crost, Felter, and Johnson 2014). Due to their dubious efficacy, CDD programs are somewhat falling out of favor as development interventions, and given the evidence, I see no reason Open Philanthropy should try to change that. When we advocate for more global aid, this should likely not be one of the kinds of aid we advocate for. #### 6.2.5 Cognitive Behavioral Therapy Most pre-civil war countries are not at peace; rather, they have some background level of conflict that does not rise to the level of a civil war. Perhaps a murder goes unsolved and a community is blamed (see tractability and speed); perhaps some tourists are kidnapped, perhaps two allied political parties fall out, perhaps police kill a few civilians. Some percentage of these low-level conflicts – events where a few people are killed, but not dozens – are likely to escalate to further violence. (In the above linked cases, they did, but not all tourist kidnappings or cases of extrajudicial killings lead to rebellions.) The experts we spoke to suggested it is almost a stochastic process which conflicts escalate and which do not. While it’s difficult to predict which particular violent event will spiral into wider conflict, probably one of them will eventually. If there are fewer low-level violent events, the number of opportunities for things to spiral out of control is also reduced. Ex-combatants are often a source of this low-level violence, as they previously used violence to resolve disputes. Small studies show that giving ex-combatants cognitive behavioral therapy can make them less likely to use violence in future (Blattman, Jamison, and Sheridan 2019; Heller, Shah, Guryan, Ludwig, Mullainathan, and Pollack 2016). In one study, even therapy with non-licensed professionals with minimal training (Dinarte and Egana-delSol 2019) was successful at reducing violent activity and improved participants’ level of emotional regulation. CBT may have contributed to Liberian men choosing not to join the Ivorian civil war, but it’s equally likely job training increased their opportunity costs such that being a mercenary was less attractive. CBT seems to be most effective when combined with other forms of intervention – that is, CBT and cash are more effective than either cash or CBT alone (though notably CBT plus cash also costs more) – and the effects fade with time, so it is possible ongoing interventions would be required. It is worth noting CBT seems less effective for the “hard cases”; Dinarte and Egana-delSol 2019 finds that the positive results are driven by people who were committing less violence to start with. This may limit the efficacy of CBT if the majority of violence is committed by a small number of individuals.[14]I don’t know if post-war violence is evenly distributed across the violence, or mostly comes from a small number of individuals. It is also not clear how this would scale. CBT tends to be quite resource (and people) intensive, and requires direct contact with every individual. (The Blattman study involved 999 men; Dinarte and Egana-delSol 1000 children.) While it is promising that such programs may not require trained professionals as facilitators, there is only one study that shows that. I would thus put this firmly in the bucket of “promising, but needs more research to determine how implementation would work at scale”. If OP was interested in this, we would want to invest in more research. I would be particularly interested to see more research on training facilitators for therapy; there is a fairly limited supply of trained psychologists to conduct interventions; I really only think this has legs if it’s fairly easy to train people to teach CBT. #### 6.2.6 Cash Transfers and/or Job Training Per Paul Collier, civil wars are not a problem of grievances, but of greed. Combatants choose to participate in rebellion because E[participation] > E[not participating]. For combatants to choose to lay down their arms, and continue to not participate in the war, E[not participating] must be greater than E[participating]. This is challenging because ex-combatants often have limited non-martial skills and little ability to support themselves in a post-civil war economy. Cash transfers and job training make the non-martial world more appealing and increase the opportunity cost to participating in the war. In theory, this will also serve to win hearts and minds – that given better opportunities, youths will be less interested in the war and more interested in their economic prospects. They will hopefully also be more supportive of the government that provided said economic prospects. The theory here is not dissimilar to that of most DDR programs. As DDR programs have also found, encouraging young people to work is considerably easier than changing their minds about politics. Most – but not all – employment programs do seem to increase wages and employment outside of illicit activities. Programs in LiberiaUganda, the Ivory Coast and the USA have all been relatively successful (though one in Afghanistan was not). The record on conflict prevention and social cohesion is more mixed. There is at least one success – a job training program in Liberia kept men from joining the nearby Ivorian civil war, though there was no impact on social cohesion within Liberia. In Afghanistan, cash transfers increased support for the Taliban and job training increased support for the government; in Uganda, there was no impact on social cohesion or protest. A review article shows “few sustained positive impacts of programs on stability, even in the face of economic gains”. As a development intervention, job training appears to show some promise. As a way to reintegrate fighters, job training seems to have little impact. #### 6.2.7 Alternative Dispute Resolution (ADR) Cognitive behavioral therapy is probably the best studied way to reduce the number of low-level violent events, but it is not the only way. Since the desired outcome is a behavior change rather than a mindset change, it is plausible that changing social norms would suffice to reduce using violence to resolve disputes. In Liberia, Hartman, Blair and Blattman find reasonably large effects from a training program on resolving disputes peacefully. Over three years, the number of violent disputes declined 9%, at a cost of about$14,000 per village.  How cost effective this is depends heavily on the assumptions you use; if a national program of ADR reduced the chance of a civil war as brutal as the Liberian Civil War by 4.5%, it would be near a 1000x return, but if it reduced the chance of a less severe civil war by 4.5%, the return would be nearer to 100x[15]The Liberian Civil War involved considerably more deaths than would have been expected for a country of Liberia’s size. (BOTEC here).

Mercy Corps finds a giant effect from an ADR program in Nigeria – a 43% (!) reduction in reported violence.  Even if the effect is considerably smaller than that (likely), it likely had an effect of >1000x.

However, all the caveats about cognitive behavioral therapy also apply here.  Alternative dispute resolution is hard to scale, relatively expensive (possibly cheaper than CBT at scale, but it’s not clear), and it’s unclear how many civil wars reducing low-level violence would really avert.  Still, given there’s at least one paper that suggests the return could be >1000x, this is where I would spend research money first.

#### 6.2.8 Contact Interventions and Mass Media

Violence is often fueled by a fear or hatred of the “other”.  This is often but is not exclusively a racial or ethnic other; it can be a class/occupation other, such as in farmer/herder conflicts in the Sahel.

There is good evidence that the more one interacts with the othered group, the less likely one is to hold prejudiced views.  A number of programs therefore have tried to promote intergroup cooperation through promoting direct interaction (for instance, through mixed soccer teams or mixed vocational training) or by broadcasting mass media showcasing cooperation.

Direct Contact

In general, direct contact interventions reduce reported prejudice, though this is not a universal finding. This is probably one of the more reliable and replicated findings in the conflict literature – that increased contact with an outgroup leads to reduced negative feeling towards that group.

There is somewhat less good evidence that this affects one’s behavior toward the othered group.  It’s possible this is simply because the interventions are generally quite small in scale, and are swamped by the political context in which people are living.  However, it’s also not clear that a change in reported prejudice will always map to a change in discriminatory behavior.

Interestingly, there is a recent exception to the relative lack of impact on behavior.  Mercy Corps recently did an impact evaluation on a peacebuilding program in the Middle Belt in Nigeria[16]Not generally considered a civil war, but has often exceeded 1000 deaths per year. and found positive effects on economic behavior.  As the conflict worsened elsewhere, and herders were less inclined to come to the market to do business with farmers in control communities, interactions in the treated communities were stable.

This seems like the most promising intervention studied, because it shows a clear theory of change for blunting the economic impact of civil war.  Per my BOTEC, most of the cost of civil war comes from a loss of income rather than a loss of life, and the severity of the economic contraction varies widely across civil conflicts.

I do not know how to map a decrease in contact to a decline in GDP but a return of >1000x seems within the range of possibility.  This intervention ($60/person in Nigeria) prevented a 13%-19% decline in pastoralists selling products at the market. If this could shift a village from a path of a 7% economic contraction to a 2% economic contraction during the war,[17]A 5% shift is essentially made up here, but it seems plausible enough – pastoralists selling at the market isn’t the only economic activity in a village, but it’s probably a significant part of the economy. this would avert losses of approx.$1000 USD ($50K OP value) in income/person, for a return of 833x. Mass Media Rather than relying on direct contact, some interventions use mass media to show cooperation between groups. Multiple experts mentioned one NGO – Search for Common Ground – as being particularly good at this type of intervention (they reach 51M people currently). The evidence for this is somewhat less strong than for direct contact. In Nigeria, a broadcast from religious leaders led to higher acceptance of ex-combatants, and one intervention in Rwanda made ethnicity less salient. However, a different mass media intervention in Rwanda did not change attitudes towards outgroups. A talk show in the DRC designed to reduce prejudice actually increased it. Mass media is substantially cheaper than a direct contact intervention, though, and avoids difficulty scaling. I would be interested to see what results come from a Search for Common Ground mass media intervention in Nigeria (funded 2020, PIs Dube and Robinson). #### 6.2.9 Investigative Journalism Two of the experts we spoke to expressed skepticism of the effectiveness of journalism for journalism’s sake. However, both seemed to think that journalism can provide information for targeted sanctions. Both government and rebel leaders often become very wealthy, and most of that money is not kept in-country. International sanctions have the potential to put pressure on individuals to come to the table by freezing access to their money. Country-wide sanctions do seem to end conflicts somewhat sooner (Letzkian and Regan 2016Escriba-Folch 2010), but these results are not strong. Lezkian and Regan find sanctions alone are not terribly effective – military intervention is also required – and Escriba-Folch finds that total economic sanctions for the country are required, which can have major humanitarian implications. The theory for country-wide sanctions thus seems not great – this requires journalism to get sufficient traction to change policy, and then the policy may or may not actually work. There is some anecdotal evidence that individual sanctions can be more effective than country-wide, though I can find no systematic work on this. One person we spoke with mentioned further conflict was averted in Kenya in 2007 by threatening the leaders’ children’s visa statuses in the west. I am still very uncertain how this would actually work, though. Funding journalism to reduce conflict requires quite a lot of things to happen after the production of a story. Policy-makers must read the story, decide to act, apply (hopefully individual-level sanctions), and if all that happens, it is possible that rebels will be incentivized to make peace. I also think too much international attention risks drawing a major power directly into the conflict. This requires a sweet spot where the major powers care enough to apply sanctions but not get involved directly. If the civil war is too important, a major power may decide to back one side and the conflict will become much more complicated. For instance, the Syrian Civil War is probably the most documented conflict everthe country remains sanctioned, and yet the war continues, because of a major power intervention. #### 6.2.10 Mediation and Diplomacy Multiple people mentioned that quality mediation can make a difference in getting a peace deal. The difficulty is figuring out what “quality” mediation is; it’s not clear to me how we would evaluate the quality of high-level mediation. The academic literature on mediation has varied conclusions – possibly it works, possibly it doesn’t. However, mediation is definitely cheap; even a small probability of success would make mediation cost effective. For instance, the Center for Humanitarian Dialogue is one of the larger such organizations. Their annual budget is about$42M/yearly, and they are active in 23 conflict zones, for an average cost of $2M per country. If a marginal Center for Humanitarian Dialogue mediation-year has a 0.52% chance of ending a war one year sooner, it would reach an OP return of 1000x. #### 6.3 Sources of Uncertainty #### 6.3.1 Individual-Level Measures My most significant source of uncertainty is how much we can rely on individual measures to tell us about a country-wide event. Much of the post-2010 literature on conflict has focused on micro-level interventions with strong causal identification. In general, the treatment is applied to individuals or communities; outcomes are measured at the individual level. Unfortunately, civil war is not an individual action, and it is not clear how changing individual actions map to 1) meso-scale rebel group organization, 2) macro-scale war. Attitudes exist within a context of political institutions; do we believe that changing attitudes without changing institutions will change the likelihood of civil war? I think the answer to that depends on one’s theory of civil war escalation. Most of the experts we spoke to model civil war escalation as a stochastic process, where some events end up escalating but it is not clear ex-ante which ones will do so. In this case, reducing the number of conflict events should reduce the number of events that spiral out of control (see alternative dispute resolution). #### 6.3.2 The Changing Nature of Civil War This shallow discusses prevention of civil wars where there is not extensive international intervention. For much of the 1990s and 2000s, this has been most civil wars (see below) However, there has been a recent uptick in proxy wars or wars where at least one side is substantially backed by a great power. The interventions described below are unlikely to be as successful in Syria or Ukraine, or even Yemen, as they are in Nigeria or Liberia. I do not have a good sense of how likely future civil wars are to have major international intervention. I am concerned that the universe of civil wars in which such interventions may work is shrinking. On the other hand, civil wars don’t start as internationalized conflicts; if events are de-escalated before major powers are interested, perhaps the interventions themselves could prevent civil wars from becoming internationalized. Footnotes ↑1 The GBD estimate includes only direct DALYs, so war injuries/war deaths but not deaths caused from disrupted access to healthcare, etc. Paul Collier finds the financial cost of the average civil war is$64B 2008 USD in The Bottom Billion, though he doesn’t specify in any detail how he reaches this figure. This is greater than the cost of the number of civil wars that started in 2017 * the cost of a civil war, because more civil wars start than resolve, so the number of civil wars is increasing over time. On average,  ~100 people are displaced per battle death. The true value obviously varies substantially by the size of the country and the severity of the civil war; even small countries can have particularly deadly civil wars (Liberia), while India is a large country that has had several small civil conflicts. Estimating government military and policing spending to reduce the chance of civil war seems difficult, so I’m not doing it. Note: This section describes how OP might support an intervention if it chose to do so, rather than describing a recommendation for what OP should do. If an intervention doesn’t work, OP would not fund it or advocate for it. Once they are deployed; the process of getting peacekeepers deployed is notoriously long. The UN reimburses at $1400/month/peacekeeper. This is cost-effective for Egypt (2812 peacekeepers), where the average soldier costs$672/month, but means that even South Africa is effectively subsidizing the UN when it contributes peacekeepers (average South African expenditure/soldier/month = $2700). France (618 peacekeepers), Germany (563 peacekeepers), and the UK (605 peacekeepers) are unlikely to want to contribute more personnel at that reimbursement rate. This might also serve to reduce the number of bad PR incidents involving peacekeeping troops. Well-trained soldiers are hopefully less likely to be involved in sexual abuse of minors. By contrast, the US Peace Corps has 10-12 weeks of training, and explicitly does not operate in conflict zones. Most peacekeepers come from countries that aren’t well known for their strong rule of law; the top contributors are Bangladesh, Nepal, India, Rwanda, Ethiopia, and Pakistan. This can be within the same country – for instance, Ahmad Shah Massoud clearly never stopped rebelling – or in another country – for instance, Paul Kagame, who would lead the RPF in the Rwandan Civil War, began his career as soldier in Musevini’s army in the Ugandan Bush War. I don’t know if post-war violence is evenly distributed across the violence, or mostly comes from a small number of individuals. The Liberian Civil War involved considerably more deaths than would have been expected for a country of Liberia’s size. Not generally considered a civil war, but has often exceeded 1000 deaths per year. A 5% shift is essentially made up here, but it seems plausible enough – pastoralists selling at the market isn’t the only economic activity in a village, but it’s probably a significant part of the economy. ## South Asian Air Quality This is a writeup of a medium investigation, a brief look at an area that we use to decide how to prioritize further research. ## In a nutshell • What is the problem? South Asia experiences some of the world’s highest levels of population-weighted PM2.5 air pollution. Our understanding is that poor air quality contributes significantly to negative health outcomes for the more than 1.8 billion people in the region, and that reducing the levels of particulate matter present in the air could save millions of lives. • What are possible interventions? Possible interventions, many of which require coordinated state action, include improving air quality monitoring programs and crafting and implementing sector-specific policies to reduce emissions. A philanthropist interested in reducing South Asia’s air pollution levels could support efforts to inform the design, implementation, and enforcement of more effective air pollution abatement policies, such as funding monitoring programs, research, and technical assistance. • Who else is working on this? Philanthropic interest in South Asian air quality appears to be limited but growing rapidly, although many major philanthropic actors seem to address air pollution as a climate concern rather than as a health issue. Outside of the philanthropic sector, we think it’s likely that governments are the biggest spenders on improving air quality. We remain substantially uncertain about the exact levels of funding South Asian governments are directing toward the issue. ## 1. The problem South Asia – and in particular the Indo-Gangetic Plain that covers parts or all of India, Pakistan, Bangladesh, and Nepal – experiences some of the world’s highest population-weighted air pollution levels.1 Our understanding is that poor air quality contributes significantly to negative health outcomes for the more than 1.8 billion people in this area.2 Of the pollutants present in South Asia’s air, we focus on PM2.5 – particulate matter no larger than 2.5 micrometers in diameter – which we understand to be associated with the greatest health costs.3 In total, the State of Global Air report – a collaboration between the Health Effects Institute and the Institute for Health Metrics and Evaluation’s Global Burden of Disease project – attributes approximately 71.4 million disability-adjusted life years (DALYs) across South Asia annually to air pollution.4 According to the Institute for Health Metrics and Evaluation, air pollution in South Asia accounts for nearly 3% of all DALYs worldwide – i.e. eliminating dangerous levels of air pollution in South Asia alone would reduce the number of prematurely lost years of healthy life by 3% each year.5 Exposure to PM2.5 air pollution can occur outdoors or within households, with the two settings associated with different concentrations, health outcomes, and interventions. Sources of outdoor, or ambient, air pollution in South Asia include brick kilns, vehicles, coal power plants, and crop burning.6 According to the State of Global Air report, South Asia’s average experienced ambient air pollution in 2019 was 78.2 µg/m3, a concentration higher than both the World Health Organization’s recommended standard of 10 µg/m3 and its intermediate standard of 35 µg/m3.7 While we have not investigated the overall evidence base thoroughly, we have encountered widespread agreement that long-term exposure to ambient PM2.5 pollution can result in significant negative health effects, such as chronic respiratory and cardiovascular diseases, that reduce life expectancy. The State of Global Air report, for example, estimates that, in 2019, almost 40 million DALYs in South Asia were attributable to ambient PM2.5 air pollution.8 This number appears to be stable in some South Asian countries and increasing in others.9 While we have not independently vetted this or other mortality and morbidity estimates, it seems reasonably plausible to us based on South Asia’s population-weighted air pollution levels and what the literature we’ve reviewed says about air pollution’s role in chronic illnesses.10 Concentrations of household (as opposed to ambient) air pollution in South Asia appear to be far more difficult to measure, with estimates we found ranging from 35 µg/m3 to over 2,000 µg/m3.11 We found more certainty, however, that household air pollution is widespread: one source estimates that roughly 60% of people in South Asia use solid cooking fuels, the primary source of household air pollution.12 This percentage is apparently decreasing as people switch to cleaner energy sources.13 The lack of reliable household PM2.5 concentration data makes it difficult to confidently discern health effects. The available evidence indicates that negative health outcomes of household air pollution in South Asia may include low birth weight, preterm birth, and other conditions that are correlated with an increased risk of infant death.14 The State of Global Air report, for example, attributed approximately 95,000 infant deaths within the first month of life to household air pollution in South Asia in 2019, estimating an overall impact of approximately 30 million DALYs within the region for that year.15 Of the nations comprising South Asia, India appears to experience among the highest average annual population-weighted ambient air pollution levels – 83.2 µg/m3 – and to contain the greatest number of DALYs attributable to both ambient and household air pollution – 31.1 million and 20.9 million, respectively.16 South Asia’s growing and aging population means that the burden from air quality – all else equal – is rising. In the case of household air pollution, this appears to be more than offset by people switching to cleaner cooking fuels, reducing the burden over time.17 However, the number of DALYs attributable to ambient air pollution appears to be increasing as outdoor air quality is worsening, accentuating demographic trends.18 The outsize impact of air pollution in India relative to other South Asian nations suggests to us that improving India’s air quality could greatly reduce South Asia’s population-weighted annual PM2.5 concentrations and DALYs resulting from air pollution.19 #### 1.1 Why believe these estimated harms We often have concerns about the quality and reliability of non-experimental social scientific evidence, and prefer to be able to replicate key inputs to our calculations ourselves. That is not possible with the State of Global Air report, which does not have open data and code. So we start with some skepticism that these large DALY estimates should be taken at face value. However, we did a review of the underlying literature and – while, as with all social science literatures, we think there could be room for improvement – we came away thinking that we would probably not want to adjust the State of Global Air burden estimates downward by more than a factor of two. More specifically, biological mechanisms appear to support the conclusion that exposure to air pollution results in significant negative health effects, including mortality, in humans. Both the American Heart Association and the Lancet Commission on pollution and health, as well as epidemiologists we have spoken with, state that breathing particulate matter generates inflammation and vascular damage. These effects in turn are linked to conditions such as atherosclerosis and high blood pressure, which are known to cause life-threatening diseases such as ischemic heart disease and ischemic stroke.20 In infants, the proposed pathway seems to be that particulate pollution causes lower transmission of nutrients to fetuses, resulting in lower birth weight and nutrient deficiencies associated with higher infant mortality and lifelong health complications.21 There are various animal and human RCTs and studies on these biological mechanisms. The studies generally find that particulate pollution causes vascular inflammation, atherosclerosis, and low birth weight.22 More recent animal studies, however, do not seem to use mortality as an outcome of interest, and some much older studies found null effects of air pollution exposure on mortality.23 According to Open Philanthropy’s scientific research team, the null mortality results in animal models in the older studies are not necessarily evidence against mortality effects in humans, largely due to innate differences in biology and lifespans, though we do take them to be a mild negative update. Outside of studies on the relevant biological mechanisms, we have found various natural experiments conducted by economists that attempt to isolate the causal effect of particulate pollution on mortality. Ebenstein et al., 2017 in particular examines the health effects of air pollution in conditions similar to those in South Asia, although we’re skeptical of this paper’s headline mortality effects.24 Other quasi-experimental papers, many of which focus on short-term exposure to particulates, generally find meaningful effects on mortality on both infants and adults.25 These papers have reassured us that the non-experimental social science literature we have found is likely not detecting the mortality effects of a confounding variable. We have not found any meta-analyses that look for publication bias in the quasi-experimental evidence mentioned above. There is an epidemiological literature, however, that contains funnel plots that aim to identify publication bias. In a literature with no publication bias, one would expect to see a symmetric, triangle-shaped pattern of dots in the scatter, with the lower-powered analyses equally likely to fall on the right or left of the high-powered analyses. The plots within Pope et al., 2020 (specifically Figure 4), which examines epidemiological papers on the causal effect of air pollution on mortality in cohort studies, appear to have some asymmetry in the middle of the funnels.26 We very tentatively believe that a publication-bias adjustment based on these charts would reduce the mortality effect size to a number slightly to moderately below the consensus in the epidemiological literature.27 ## 2. Possible Interventions #### 2.1 Government action Many potential air quality improvements require coordinated state action. The following abatement policies are some of the ones that we thought had a mix of potentially addressing a large portion of the pollution problem and were likely administratively feasible.28 #### 2.1.1 Retrofitting and building efficient brick kilns 20% of clay bricks are produced in South Asia, although PM2.5 emissions attributable to the sector seem to vary by country and be concentrated in urban areas.29 A report by the World Bank estimates that the brick sector is the second-largest PM2.5 contributor in Bangladesh and Nepal, responsible for 11% and 3% of PM2.5 emissions, respectively.30 In India, meanwhile, the share of PM2.5 emissions attributable to brick kilns appears to be comparatively lower, although we have encountered substantial uncertainty around this point. The Health Effects Institute offers one of the lower estimates we found, tracing approximately 2% of India’s PM2.5 pollution and 2 to 3% of its PM2.5-related deaths to brick kilns.31 The World Bank’s report has the highest estimate of the sources we gathered, attributing 8% of India’s PM2.5 emissions to the brick sector.32 The World Bank estimates that retrofitting existing kilns could reduce PM2.5 by 30-50%, as well as improving energy efficiency.33 Despite the uncertainties around emission levels, we think it is plausible (but by no means decisive) that a government-championed effort (e.g., regulations and/or subsidies) to retrofit and build efficient brick kilns would be administratively feasible and could meaningfully reduce PM2.5 pollution from the brick sector.34 #### 2.1.2 Implementing and enforcing a ban on older vehicles At least since 2015, government bodies in India have indicated an interest in limiting the use of older vehicles.35 There are some regional bans, but it’s unclear to us to what extent they have been implemented or enforced.36 This existing – if inconsistent – interest in banning older vehicles, along with what appears to be a low number of vehicles over 10 years old (meaning political/economic costs of a ban are smaller), suggests that this is a potentially promising area for further government action.37 We’re uncertain about the percentage of the population-weighted PM2.5 pollution in South Asia that is vehicular, although it appears fairly significant. A report by India’s Ministry of Environment, Forest and Climate Change estimates that vehicles contribute approximately 28% of population-weighted PM2.5 emissions in Delhi during the winter and 4% nationally when accounting for all modes of transportation.38 The Energy and Resources Institute attributes 50% of Bangalore’s PM2.5 load to automobile emissions.39 A source apportionment study of Mangalore attributed 70% of particulate pollution to vehicles.40 Older vehicles in particular appear to be a significant contributor to vehicle emissions, with one estimate we found claiming that vehicles older than 15 years account for 15% of total vehicular pollution, and tend to pollute 10 to 25 times as much as newer vehicles.41 Based on these numbers, we think it is likely that a ban on older vehicles could reduce total PM2.5 pollution, although we’re very uncertain about the total reduction we could reasonably expect and how enforceable (and beneficial) a ban would realistically be. #### 2.1.3 Mandating and enforcing coal scrubbers Most of the estimates we found attribute approximately 15% of India’s PM2.5 emissions to coal power generation.42 It seems plausible to us that coal is a significant source of PM2.5 emissions, given the prominence of coal in India’s electricity generation and CO2 emissions.43 One report we saw claims that installing wet coal scrubbers in power plants could reduce PM2.5 emissions by as much as 98% and newer fabric filters can reach efficiencies as high as 99.7%.44 While we have not independently vetted this estimate, if accurate, it indicates to us that coal scrubbers could significantly improve India’s air quality.45 The Indian government has already mandated that plants install coal scrubbers to limit emissions, although compliance appears to be limited.46 Given the apparent magnitude of coal power emissions and the government’s existing interest in pursuing mitigation measures, additional efforts to install coal scrubbers might be a promising intervention. Below, we share our rough back-of-the-envelope calculations (BOTECs) on the potential cost-effectiveness of philanthropic support for the installation of coal scrubbers. #### 2.1.4 Reducing crop burning with better targeted tractor subsidies Our impression is that crop burning is a relatively minor source of emissions in India; one article claims that it constitutes an average of 5% of annual PM2.5 pollution in Delhi, although it reaches up to 40% at certain points in the year.47 The vast majority of farmers appear to burn their crops, with only an estimated 20% using tractors to till their fields.48 It seems plausible that better targeting tractor subsidies to increase the percentage of farmers using tractors, while decreasing the percentage of those who burn stubble, could moderately improve Delhi’s air quality.49 We are unsure of the potential impact tractor subsidies might have on air quality across the broader South Asian region. #### 2.1.5 Better targeting liquified petroleum gas subsidies From what we have found, solid cooking fuels – still used by approximately 60% of households – account for roughly 40% of the health burden from PM2.5 pollution in South Asia.50 We tentatively assume that substantial reductions in solid cooking fuel use could lead to large reductions in health impacts. The main replacement for solid cooking fuel (e.g. wood, agricultural refuse, charcoal, etc.) is liquified petroleum gas (LPG). The Indian government already subsidizes LPG use, currently entitling each household to 12 LPG cylinders per year.51 The subsidies, however, do not provide significant discounts to the market price, suggesting that LPG cylinder prices may remain too high for many poor households to afford.52 As a means of increasing the subsidies available to the poor, the government has unsuccessfully attempted to convince wealthier households to voluntarily pay for unsubsidized LPG.53 Better targeting the subsidies by increasing availability and subsidy size for poorer households could plausibly help reduce the number of households that use solid cooking fuels. #### 2.2 What could a philanthropist support? We have encountered widespread uncertainty around the share total and population-weighted PM2.5 that is attributable to different sources in India and across South Asia. Addressing this information deficiency seems to be crucial to appropriately targeting abatement strategies. As such, it seems likely that philanthropic efforts may be able to productively focus on 1) improving the information ecosystem for local decision makers and other stakeholders and 2) increasing the technical capacity of key governmental agencies to address air quality. A philanthropist interested in supporting either of these two outcomes might pursue any of a variety of activities, some of which we’ve listed below. #### 2.2.1 Source apportionment studies As we mentioned previously, we have found that the deficiency in pollution source apportionment data has made it difficult to gauge the potential impacts of available interventions. Source apportionment studies are scientific studies that attempt to measure what share of the total PM2.5 concentration in a given city or region can be attributed to different sources, e.g. transportation, power generation, other industrial sources, etc.54 Source apportionment studies could be conducted in partnership with interested cities needing technical assistance.55 Such localized studies, in providing governments with rough estimates of their cities’ largest sources of air pollution, could potentially improve governments’ (and philanthropists’) abatement strategies. Below, we share our rough back-of-the-envelope calculations on the potential cost-effectiveness of philanthropist support for source apportionment studies. #### 2.2.2 Air quality monitoring A philanthropist might fund either low-cost sensors or advanced monitoring stations. Low-cost sensors, which we have already supported, can be installed locally and could contribute data to real-time air quality maps that report shifts in pollution amounts. We assume that these maps could help improve public awareness of local pollution levels and precipitate minor behavior change, as well as enable governments and other entities to track the impacts of abatement methods. The limited accuracy of low-cost sensors may impede pollution measurements, however, as individual sensors may not be able to detect small changes in concentrations.56 Advanced monitoring stations are much more accurate – also significantly more expensive – and could be installed in each of India’s airsheds. Potentially combining the stations with sun photometers to measure the atmospheric column could allow for significantly more accurate and frequent satellite measurements of air pollution sources and concentrations.57 These measurements could, in turn, provide governments with more precise pollution targets, enable the effects of abatement policies to be tracked, and contribute to general air quality reporting. We think that air quality monitoring could be a fairly large source of philanthropic spending in the short term, with smaller ongoing costs after the initial implementation. From our conversations, we also received the impression that Indian air monitoring is comparatively well-funded, and that supporting monitoring in other South Asian regions might generate more impact on the margin. We have not independently vetted these claims. #### 2.2.3 Research on the abatement curve and air pollution health effects in India We perceive research on the abatement curve (the graph describing the financial costs and volumes of PM2.5 reductions by intervention pursued) and air pollution health effects in India as having a variety of benefits. A better defined abatement curve data could serve as a menu of options for interested philanthropists or policymakers. Research on health effects could provide more targeted data on the health effects of PM2.5 pollution, including potentially distinguishing between the health effects of different types of pollutants. In addition, such research could help drive awareness among governments and the public of the extent of the problem and accordingly encourage the adoption of targeted abatement measures (particularly if this research identifies a more narrow set of lower cost policy changes that could solve a large share of the total problem). We have heard that this may be more effective if the research is based at national institutions that also provide expertise to local governments or non-governmental organizations working on this issue. #### 2.2.4 Technical assistance Providing technical assistance to government entities could improve the outcomes of pollution abatement measures by increasing governmental capacity to implement, enforce, and monitor air pollution abatement measures. A funder interested in this outcome could, for example, work with outside consultants to provide technical assistance to India’s pollution control boards, which, for a number of reasons, have struggled to enforce air quality regulations.58 We have found conflicting estimates of the pollution control boards’ current spending, although it seems to be between$100 million to $300 million a year, split between air pollution, water pollution, noise pollution, and waste management.59 #### 2.2.5 Policy outreach The interventions outlined in the section above are largely under the purview of the government. As such, philanthropic efforts might focus on providing decision makers with data and resources to craft effective air pollution abatement policies. Potential funding areas could include source apportionment and concentration research, real-time air quality maps, and reporting on air quality in local news outlets. Other means of increasing the salience of air quality might include funding programs like the Clean Air Fund’s Doctors for Clean Air, which raises awareness of the health impacts of air pollution, or supporting air quality programs at universities. #### 2.3 How cost effective could spending in this area be? If air pollution costs 71.4 million DALYs annually in South Asia, and we were spending$20 million per year, we would need to be pulling forward solutions to approximately 0.06% of the problem by 10 years for every year of our spending in order to clear our 1,000x bar.60 It is difficult to reason about small numbers like that but given the relatively limited scale of other philanthropy in this space, we do not think that would be an unreasonable bar for us to clear.

We do not have a specific plan for how to spend money cost-effectively on this problem at that level, but we’ve done a few back-of-the-envelope calculations on promising-seeming potential projects, described in more detail below, that also make us think they could clear the 1,000x bar.

We have already recommended funding, totalling $3 million, to install a network of low-cost air quality sensors in India. We have removed our current BOTEC since it’s related to our hiring process for a South Asian air quality program officer. #### 2.3.2 Source apportionment studies By our rough calculations, a source apportionment study would need to accelerate a reduction of 0.8 µg/m3 in pollution by 10 years for a city of 5 million to reach our 1,000x bar.61 This calculation assumes that: • The cost of a source apportionment study would scale as a function of population size. We roughly estimate that a study in a city of 5 million would cost$500,000.
• Source apportionment studies would only measure, and thus impact, ambient air pollution levels.
• The PM2.5 concentration in cities is proportional to the national concentration. The average annual population-weighted concentration of ambient air pollution in India is 83.2 µg/m3. Approximately 31,140,452 DALYs in India are due to ambient air pollution, and every DALY is valued at $50,000.62 • India’s population is 1,366,000,000.63 #### 2.3.3 Coal scrubbers According to a report by the Disease Control Priorities Network, installing coal scrubbers in all power plants would cost approximately$1.7 billion.64 The same report estimates that to retrofit the plants with the lowest cost per life saved would cost $615 million, although other sources we’ve encountered estimate costs that are more than an order of magnitude higher.65 If the$615 million figure were correct, paying to install coal scrubbers could reach and perhaps surpass our 1,000x bar, assuming the following conditions are true:

• As we discussed above, coal power generation contributes approximately 15% of India’s PM2.5 emissions.
• Installing scrubbers reduces PM2.5 emissions by at least 80%.66
• The selected coal power plants are responsible for 75% of the sector’s DALY costs.67
• The health effects of air pollution in India cost approximately $2.68 trillion/year.68 • Given that the government is already mandating the installation of coal scrubbers, our funding speeds installation up by five years. Under these conditions, we would estimate an ROI of$2.68 trillion (total cost of ambient air pollution) × .15 (power sector share of total PM2.5) × .75 (selected plants’ share of power sector DALYs) × .8 (reduction in PM2.5 from scrubbers) × 5 (years of speed-up) / $615 million (cost of scrubbers) = ~1,960x, though again we do not know these assumptions to be correct and have seen much higher cost estimates in the literature. #### 2.4 What scale could a program in this area possibly reach? Based on our understanding of the available funding opportunities, we think there is a high likelihood that a program in this area could spend at least$25 million per year on activities such as air quality monitoring, abatement and source apportionment studies, technical assistance, scaling existing organizations working on air quality, and policy outreach, at a cost-effectiveness level comparable to other funding opportunities we pursue. We think there is a lower likelihood of significantly more than $25M/year of capacity in opportunities we would consider quite cost-effective. ## 3. Who else is working on this? #### 3.1 Philanthropic organizations Philanthropic interest in South Asian air quality appears to be limited but growing rapidly: an estimate by the Clean Air Fund, which was cited to us in multiple conversations, puts the philanthropic spending in this area at roughly$7 million in 2019, up from $1 million in 2015.69 We have not vetted the report’s estimates and would guess there are structural underestimates because the report is based on self-reported data from foundations, some of whom may not participate in data sharing, but the estimates are broadly consistent with what we heard in conversations. The international philanthropic actors working on South Asian air quality that we have heard mentioned most frequently are Bloomberg Philanthropies, the Children’s Investment Fund Foundation, ClimateWorks, the IKEA Foundation, the MacArthur Foundation, the Oak Foundation, Pisces Foundation, and the William and Flora Hewlett Foundation. Some major Indian funders, such as Ashish Dhawan, have also come up in our conversations with experts and funders in the field. We do not believe that this is an exhaustive list: we would guess that we have accounted for the largest philanthropic funders working in this area, but we are certainly missing smaller investments from non-profits and activists. Many of these major philanthropic actors appear to address air pollution as a contributor to climate change rather than in terms of direct negative health effects from particulates. Climate-focused philanthropic spending on air quality is part of a broader effort to mitigate emissions in India, with philanthropic annual spending on emissions reductions that we think is on the order of$100M-$350M.70 It is unclear to us to what extent treating air quality as a climate concern versus as a health issue would result in significantly different funding strategies. There is definite potential for overlap between climate and air quality spending, as many interventions that reduce greenhouse gasses tend to reduce PM2.5 emissions as well (e.g., limiting reliance on coal for electricity generation). But the two goals can also come apart (e.g., flue-gas desulphurization units on coal plants help improve air quality for health, but as far as we know do not mitigate climate impacts). Overall, we do not think that the presence of significant climate funders mitigates the need for more focused work to improve air quality from a health perspective.71 #### 3.2 Government We found it difficult to find reliable estimates of governmental spending on air quality. According to one source we found, in the 2019-2020 budget cycle, the Indian government created and allocated a fund of Rs 44 billion (approximately$609 million at the time of conversion) to address air pollution in large cities.72 Additionally, a 2020 report released by the Council on Energy, Environment and Water and UrbanEmissions notes that the National Clean Air Plan, which directs cities to create action plans to reduce particulate matter concentrations by 20-30% by 2024, receives Rs 4.6 billion (approximately $63 million at the time of conversion). However, the report also noted that there are no penalties for non-achievement or “legal mandate for reviewing and updating plans.”73 In fact, only nine cities seem to have noted the costs of execution, which ranged from Rs 890 million to Rs 160 billion (approximately$11.9 million to $2 billion at the time of conversion, respectively).74 We remain substantially uncertain of the accuracy of these estimates and recognize that it’s plausible that there may be additional state funds we do not know about. Overall, we think it’s likely that the government is the biggest spender on improving air quality, but that the current spending is substantially lower than the amount required to adequately reduce air pollution. ## 4. What have we done so far? Air quality monitoring stood out to us as a particularly tractable abatement strategy that has the capacity to absorb immediate funding. We have accordingly recommended grants totalling$3 million to support a three-year collaboration between Professor Joshua Apte of UC Berkeley, the Indian Institute of Technology Delhi (IIT Delhi), and the Council on Energy, Environment, and Water (CEEW) to install a network of low-cost air quality sensors in South Asia.

The aim of the collaboration is that the data from the sensors will inform the design, implementation, and enforcement of more effective air pollution abatement policies. Additionally, we also see this project as an early learning opportunity for the testing and deployment of low-cost sensors across South Asia; if successful, we predict that the sensors could have spillover effects on the speed at which other low-cost sensors are deployed, although we have not consulted experts on this point. Both of these outcomes could plausibly result in significant reductions to South Asian air pollution levels.

For our back-of-the-envelope calculations on the potential cost-effectiveness of these grants, see above.

## 5. Potential risks and downsides

We have identified a number of potential risks and downsides to funding air quality improvements efforts in South Asia, including:

• Immediate spending capacity appears to be limited. We have identified a few abatement activities – such as air quality monitoring and certain forms of technical assistance – that could benefit from immediate funding. We have otherwise struggled, however, to identify areas that have the capacity for large-scale recurring support, and we expect that a philanthropist hoping to make South Asian air quality a long-term funding area may need to consistently find novel grantmaking opportunities.75
• Air quality interventions largely depend on government regulation and enforcement. Accordingly, most philanthropic efforts in South Asian air quality would be limited to activities that inform government policies but that may not directly impact air quality (for example, funding air quality monitoring stations that in turn provide decision makers with data to craft effective abatement measures). It will likely be difficult to predict what the likely impact of these efforts might be.
• There are risks and restrictions specific to funding work in India. The Indian government has historically regulated foreign grantmaking within India and recently implemented additional restrictions on foreign funding to Indian NGOs.76 It is our impression that all of the potential philanthropic efforts listed in this writeup are permissible under current laws, but there is a risk that the Indian government could implement additional restrictions that would change that.
• Philanthropic efforts could lead to overly restrictive policies in some domains, which in turn could create space for corruption or potentially slow economic growth. While this writeup does not take into account risks from air pollution beyond mortality, we recognize that some abatement strategies may not be economically feasible or desirable after accounting for their costs.
• Philanthropic interest in South Asian air quality appears to be growing, so additional funding now could risk crowding out other funders who would otherwise enter.

## 6. Our process and next steps

We talked to a number of experts and major funders in the field in the process of researching South Asian air quality. The following individuals agreed to being named as sources for this report, though this should not be interpreted to mean that any experts named here endorse our conclusions in part or in total:

• Aaron Van Donkelaar
• Ambuj Sagar
• Amita Ramachandran
• Arden Pope
• Avijit Michael
• Brikesh Singh
• Dan Kass
• Ishwar Gawande
• Jarnail Singh
• Josh Apte
• Kanchi Gupta
• Matt Whitney
• Melanie Hammer
• Michael Greenstone
• Pallavi Pant
• Randall Martin
• Rohini Pande
• Sam Ori
• Sangita Vyas
• Santosh Harish
• Siddarthan Balasubramania
• Vinuta Gopal

We continue to be open to learning about more opportunities in this space and may make additional grants in the future.

## 7. Sources

 Air Quality Life Index, “India Fact Sheet” Source Anderson et al. (2005) Source Apte et al. (2018) Source Arceo et al. (2016) Source Belis et al. (2014) Source Berger (2020) Source BreatheLife, “Cities at the Centre of India’s New National Clean Air Programme” Source Brook et al. (2009) Source Brook et al. (2010) Source Burnett et al. (2018) Source Business Insider, “Indian Government Will No Longer Pay Out Direct Benefit Transfer for Cooking Gas — Subsidy Eliminated as Oil Prices Fall” Source Centre for Science and Environment, “What Will India Do With Its Old Vehicles?” Source Chay and Greenstone (2003) Source Chen et al. (2013) Source Clancy et al. (2002) Source Clean Air Fund, “The State of Global Air Quality Funding” Source Correia et al. (2013) Source Council on Foundations, “New Indian FCRA Amendments Impact Foreign Grants to Indian NGOs” Source Cropper (2016) Source Cropper et al. (2017) Source Currie (2013) Source Deryugina et al. (2019) Source Doctors for Clean Air, “Homepage” Source DW, “India Pollution: How a Farming Revolution Could Solve Stubble Burning” Source Ebenstein et al. (2017) Source Eil et al. (2020) Source EPA, “Particulate Matter (PM) Basics” Source Ganguly et al. (2020) Source Gao et al. (2018) Source Gardener (1966) Source Ghosh (2021) Source GiveWell, “Interpreting the Disability-Adjusted Life-Year (DALY) Metric” Source Goel et al. (2013) Source Greenstone et al. (2015) Source Haryana State Pollution Control Board, “Budget Estimate” Source Health Effects Institute, “Burden of Disease Attributable to Major Air Pollution Sources in India” Source Health Effects Institute, “Household Air Pollution and Noncommunicable Disease | Summary for Policy Makers” Source Heft-Neal et al. (2020) Source Hindustani Times (2021) Source Johnson et al. (2020) Source Kalaiarasan et al. (2018) Source Koshy (2019) Source Landrigan et al. (2017) Source Maharashtra Pollution Control Board, “Budget 2019-2020” Source Martin et al. (2019) Source McCormick (1985) Source Menon (2016) Source Mohan (2020) Source Myllyvirta et al. (2016) Source Narayan (2020) Source National Clean Air Programme, “Final Proposal” Source Open Philanthropy, “Scientific Research” Source Peng et al. (2020) Source Police et al. (2018) Source Pope et al. (2009) Source Pope et al. (2016) Source Pope et al. (2020) Source Rakshit (2020) Source Roeyer et al. (2020) Source Sharma and Dikshit (2016) Source Sharma and Kumar (2016) Source Sharma and Nagpure (2019) Source Snider et al. (2015) Source SS Rana & Co (2020) Source State of Global Air 2020, “Explore the Data” Source State of Global Air 2020, “Homepage” Source Task Force on Hemispheric Transport of Air Polution, “Questions and Answers” Source The Financial Express, “To Curb Stubble Burning, Pay Attention to EPCA on Making Straw Management Machines Affordable” Source The New Indian Express, “Three Years on, Not Many Willing to Give Up LPG Subsidy” Source The World Bank, “Population, Total — India” Source Times of India, “Centre Cuts Pollution Control Budget, Draws Flak From Experts” Source Times of India, “Foreign Contribution Regulation Act” Source Tripathi (2020a) Source Tripathi (2020b) Source Tuli (2020) Source Varadhan (2019) Source Veras et al. (2008) Source Zhang (2016) Source

## Research and Development to Decrease Biosecurity Risks from Viral Pathogens

This is a writeup of a medium investigation, a relatively brief look at an area that we use to decide how to prioritize further research.

## In a nutshell

What is the problem? We think natural, and to a greater extent engineered, pathogens have the potential to cause global catastrophes. We expect that as biotechnology advances, the risk of dangerous outbreaks will increase. Our impression is that viral pathogens seem especially likely to contribute to catastrophic pandemics because they have the potential to be highly virulent and transmissible compared to other pathogen types, and there are very few broad-spectrum therapeutics for use against pathogenic viral outbreaks and they have undesirable side effects. This report focuses primarily on reducing the risk from viral pathogens through scientific research and development, especially on vaccines and therapeutics.

How could the problem eventually be solved or substantially alleviated? We believe that if a subset of the following abilities/resources were developed, the risk of a globally catastrophic pandemic would be substantially reduced:

• A better selection of well-stocked, broad-spectrum antiviral compounds with low potential for development of resistance
• Ability to confer immunity against a novel pathogen in fewer than 100 days
• Widespread implementation of intrinsic biocontainment technologies that can reliably contain viral pathogens in the lab without impairing research
• Improved countermeasures for non-viral conventional pathogens
• Rapid, inexpensive, point-of-care diagnostics for all known pathogens
• Inexpensive, ubiquitous metagenomic sequencing
• Targeted countermeasures for the most dangerous viral pathogens

A deeper understanding of the immune system also seem useful for its potential to expose new potential threats and countermeasures, though we see this as a source of potential important “unknown unknown” considerations rather than having a specific vision for how the research will lead to alleviating the problem.

This report focused on vaccines and antivirals because we investigated them in relatively greater depth. We did that because they seemed like broad and important areas where we guessed that we might be able to uncover particularly promising projects related to averting catastrophic viral pandemics. We didn’t look as deeply into the other areas listed above because our briefer investigations indicated to us that a deep investigation was relatively less likely to be fruitful, generally because the areas seemed less important and/or less neglected.

spreadsheet we drafted summarizes our overall views on this subject.

What are the possible research interventions? There are a wide variety of methods of conferring passive and active immunity to pathogens. As computational models and gene editing techniques have become more advanced, new strategies involving these technologies have become increasingly feasible. Research into novel and technologically advanced vaccine and passive immunoprophylaxis (which we here categorize with vaccines) development methods, such as ab initio antigen and antibody design, and vectored immunoprophylaxis, currently appear especially promising for their potential to expand the range of pathogens against which immunity can be conferred. Thus far, we have identified only a few specific promising projects in this space, and many of the most promising-seeming lines of research may be fully funded already.

Within research and development related to antivirals, host-directed antiviral compounds (i.e. antivirals that target part of the hosts’ cellular machinery, rather than targeting the virus) appear promising to us since some inhibit machinery used by a large number of viruses, making them likely to be relatively broad-spectrum, and making it seem less likely that individual pathogens will develop resistance to them. We think these compounds are unlikely to prove fully efficacious against all viruses in humans, but that they merit further investigation, and note that more extensive research on their antiviral effects in vitro, in animals, or on humans could be funded.

Who else is working on it? Our Scientific Research Program Officers’ general impression is that there are many academics and companies working on vaccine and diagnostics research and development. We are unsure how much of this work is relevant to understanding and mitigating the risk of globally catastrophic pandemics (as opposed to developing improved vaccines for known pathogens with less pandemic potential). We speculate and have seen anecdotal evidence that companies may not be incentivized to focus on work related to rare but potentially catastrophic outbreaks, because those areas generally provide weaker and less reliable revenue streams than work related to chronic conditions (e.g. HIV, hepatitis). However, we encountered several efforts that appear especially relevant to the effort to develop vaccines and therapeutics specifically for the purpose of countering novel and/or potentially pandemic viral outbreaks.

Of the areas discussed above, our impression based on our research is that:

• Broad-spectrum antivirals are receiving limited attention. We’re planning to fund work in this area.
• Vaccine R&D is generally a crowded space, though it seems possible to us that a deeper investigation into more of the specific subtopics would reveal additional opportunities.
• Diagnostics R&D seems highly crowded.

## 1. Our process

We decided to investigate scientific research and development that could assist with our Biosecurity and Pandemic Preparedness Program. Much of the research was conducted by our Scientific Research Program Officers, Chris Somerville and Heather Youngs (“Chris” and “Heather” throughout the rest of this writeup), who are biochemists and scientific generalists with no prior expertise in this topic. Former Open Phil scientific advisor Daniel Martin-Alarcon also contributed to this research. We asked them to survey the fields of vaccine and antiviral research and development, identify promising projects that were not being pursued, and help us understand how much progress is being and seemingly could be made on the development of rapid vaccines and broad-spectrum antivirals if various potential research projects were successful. Chris wrote an analysis of what steps could be taken to create a vaccine (or multiple vaccines) against a novel pathogen in approximately 100 days or fewer, and what scientific advances this would require (this may already be possible in some cases). They also briefly investigated the topic of the development of diagnostics for potential pandemic pathogens. We chose those topics because we thought they had the potential to be most relevant to preventing or reducing harm from pathogens with the potential to be globally catastrophic.

Chris, Heather, and Daniel conducted literature reviews and collectively wrote about 150 pages of rough material on this area, which was shared internally. Topics investigated included viral zoonosis, identification of new human pathogens, antigen discovery, candidate vaccine development and testing, animal models, systemic scientific issues, clinical trials, and technologies for scale-up and distribution. They declined to publish these materials without doing a significant amount of work to clarify and refine them, and Open Phil decided it would not be a worthwhile use of their time. In aggregate, Chris and Heather spent about 7 weeks each researching the topics in this report, and Daniel Martin-Alarcon spent approximately 2 weeks.

Claims not cited are generally based on the internal report produced by, and subsequent conversations with, Chris and Heather. In some cases throughout this text, citations are provided as examples of support for the associated claims, but may not be the primary or original reason we believe the claims to be true (often, our belief is based on information and impressions conveyed to us by Chris and Heather, which stems from both their general understanding of many of these topics and their speculation based on a wide range of readings, which we expect would be unduly time-consuming and ultimately unsatisfying to attempt to cite fully). We may continue and extend this investigation in the future.

Nick Beckstead and Claire Zabel reviewed the materials produced by Chris and Heather.

I, Claire Zabel, drafted this page, and it was reviewed by Chris and Heather and some other Open Phil staff before it was published.

Note that this report does not constitute a comprehensive overview of our thoughts on this area. We omitted information when we thought the public discussion of the topic (either of particular types of risks or countermeasures we find promising because they might address those risks) could contribute substantially to the risks while not offering commensurate benefits.

## 2. What is the problem?

Our shallow investigation into biosecurity describes the broader problem as we see it.1 In brief, we think natural and engineered pathogens have the potential to cause global catastrophes.

We expect that as biotechnology advances, the risk of deliberate attacks or accidental releases of dangerous pathogens will increase. If scientists and health professionals had the capacity to quickly and accurately identify pathogens, had access to reliable broad-spectrum therapeutics, and could rapidly develop effective vaccines against novel pathogens, it seems like many of the biosecurity risks we are most concerned about would be substantially smaller. We’re particularly concerned about pandemic risk from viruses because of (i) their potential for high transmissibility and virulence, and (ii) the lack of effective therapeutics for many viral diseases.

Because of this, we’re interested in research interventions that could be useful against a variety of potentially dangerous pathogens (especially viral pathogens), and could make medical countermeasure development faster and more effective.

## 3. How could the problem eventually be solved or substantially alleviated?

This section focuses on imagining how scientific advances could eventually make it possible to prevent or substantially reduce the risk of a catastrophic pandemic. A spreadsheet we drafted summarizes our overall views on this subject. We go into greater detail on the subjects which seemed most promising to us once the initial research review was completed.

Those subjects include:

• Establishing a portfolio of strategies to rapidly and reliably develop efficacious and safe vaccines. If researchers had many different ways to stimulate immunity to novel viral pathogens, and thus develop vaccine candidates within months, that seems likely to substantially reduce the chances that pathogen could cause a globally catastrophic event, compared to worlds in which it takes many years to develop a vaccine or researchers are unable to develop vaccines against some pathogen types.
• Investigating and developing efficacious broad-spectrum antivirals against which it is unlikely that a virus could evolve resistance. If these antivirals were successfully developed, they could be deployed in the event of a dangerous viral outbreak, possibly as soon as the outbreak was announced. We speculate that government offices such as the Biomedical Advanced Research and Development Authority (BARDA) might stockpile the antivirals in advance for this purpose, if the antivirals were available.

It seems plausible to us that substantial scientific progress could be made in the two areas listed above within years or a few decades.

Research in the following areas might lead to the recognition of additional risks or strategies for reducing risks. Because these areas are more exploratory, we have found it more difficult to anticipate which concrete positive outcomes they might lead to and timelines on which those might be realistic, and we don’t have particular concrete visions for how this could happen. We see these areas as sources of unknown unknown considerations with the potential to change our understanding of the risk landscape in important but unpredictable ways.

• Basic research in immunology: greater knowledge of how the immune system works might aid in the design of more effective and safe immunogens (molecules that stimulate an immune response in the host), as well as open up new lines of research into other potential countermeasures. Chris and Heather’s impression was that scientists still lack understanding of many aspects of the human immune system, and thus they have limited ability to predict which methods stimulate immunity to different pathogens (i.e. it is very difficult to generate a good vaccine). Further research could lead to insights into the human immune system, which we imagine could enable scientists to identify new sources of risk and better predict which strategies for creating new therapeutics and vaccines are likely to succeed.

We focused on topics where we thought it was most likely we could identify neglected but broadly significant research areas related to averting viral pandemics. However, some other themes we did not investigate and report on as thoroughly are listed below:

• Preventing accidental release and making deliberate misuse more difficult with biosafety measures that don’t interfere with research. This is based mainly on our speculation about the possibility of altering pathogens to make them usable and safe for research in the lab but inviable outside it. For example, Benjamin tenOever and his colleagues at the Mount Sinai Medical Center devised a method for engineering flu viruses to “carry a 21-base-pair-long sequence that complements miR-192, a microRNA found in human and mouse lung cells but not in the respiratory tract of ferrets….” This microRNA binds with influenza RNA transcripts, flagging them for destruction within the cell. Viruses engineered with this method caused symptoms in ferrets but not mice and, by extension, presumably not humans. This method, which they call “molecular biocontainment” could potentially be used to create viruses that could be studied realistically in model organisms but would be unable to harm humans if they were released from a lab.2Further work in this area could test whether strategies that have already been proposed would interfere with research, or lead to the development of new molecular biocontainment strategies. We speculate that if molecular biocontainment tools were robust and in widespread use, the risk of accidental release of dangerous pathogens would be substantially reduced. However, it seems plausible that uptake would in fact be low and some or many labs might continue to engage in more dangerous practices. More experiments could be done to determine whether this technique could interfere with experimental results.3
• Platform technology for diagnostics: Research and development of diagnostics could help healthcare workers reliably and cheaply identify common, rare, or novel pathogens. This could be valuable for quickly identifying the presence and spread of outbreaks, and ensuring that infected individuals receive appropriate treatment, if it’s available. Chris and Heather’s impression is that:
• A wide variety of rapid diagnostics are currently available or under development and the field is well funded at the moment.
• Many companies are already working in this space to improve on current technology and reduce costs.

But they also note the following limitations:

• Some diseases that don’t provoke a strong immune response and/or reside in certain relatively inaccessible tissues (e.g. brain tissue) remain difficult to diagnose. However, our Scientific Research Program Officers suspect that highly infectious pathogens will be relatively more straightforward to find with a diagnostic because those pathogens will likely be shedding large amounts of virus into bodily fluids.
• Some diagnostics are relatively imprecise (e.g. it might be possible to identify that a patient suffers from influenza, but not to easily identify the strain).
• Some diagnostics require a relatively long time (days) to yield results, which can make treating individuals and identifying potentially pandemic viral outbreaks at the outset of the outbreak more difficult.
• Some diagnostics require access to equipment that is expensive and/or hard to use in the field.

It seems to us that work on this area is likely to be broadly useful for diagnosing more common pathogens as well as those that might cause dangerous pandemics, and so we would guess this area is less likely to be neglected than research and development in areas that have fewer common applications. So, we have tentatively decided against prioritizing this area as highly as the ones listed above for conventional grantmaking. This line of reasoning suggests, however, that if there are types of diagnostics that are mainly useful for identifying pathogens likely to be involved in potentially catastrophic pandemics (for example, novel ones), those types of diagnostics might be relatively neglected.

• Non-viral therapeutics (antibiotics, fungicides, etc.): Work on therapeutics for non-viral pathogens could also lead to the development of new countermeasures. Focusing on antivirals seems in expectation more impactful to us because (i) it’s our impression that conventional non-viral pathogens are less likely to be responsible for catastrophic pandemics and (ii) broad-spectrum therapeutics exist for many non-viral pathogens (e.g. antibiotics are effective against many types of bacteria), though resistance to existing therapeutics sometimes renders them ineffective.4 However, we have not investigated this area deeply, and we otherwise restricted this writeup to R&D related to viral pathogens only.
• Medical countermeasures aimed at addressing specific pathogens: Research and development using known techniques could expand the range of medical countermeasures available to target specific pathogens of concern. Examples of this kind of work might include creating influenza vaccines that are effective against the most virulent forms of influenza. Our understanding is that certain projects along these lines, if they are aimed at providing fairly robust defenses against some of the pathogens that seem most dangerous, may be highly impactful, but that projects aimed at pathogens that seem less concerning are lower-priority for funders with our focus.
• Metagenomic sequencing for enhanced surveillance: The cost of metagenomic sequencing (sequencing from environmental samples which may contain genetic material from diverse organisms) might fall and systematic sampling, e.g. at airports, might be established such that it becomes feasible to rapidly and reliably identify pathogens with pandemic potential. We anticipate that that would make it substantially easier to contain dangerous outbreaks, but have deprioritized the area because our strong impression has been that there are many actors focused on the goal of reducing the cost and difficulty of metagenomic sequencing. Establishing a system for detecting outbreaks early and reliably is an area of interest to us, but does not seem directly related to the focus of this report (scientific research and development related to potentially catastrophic viral outbreaks).

## 4. What are the possible research interventions?

Additional research could be pursued on all of the topics listed above. However, we focus below on impressions about and future research directions that seem promising related to:

• Platform technologies and strategies for the rapid development of vaccines (i.e. technologies and strategies that might be useful for developing many potential vaccines quickly, not only ones directed against one or a few existing pathogens).

We focused on those because they seemed the most likely to be useful against a globally catastrophic biothreat in the near future, and we thought a systematic review of the literature might turn up promising giving opportunities for a new funder. However, we also think additional research in the other areas described above could prove valuable, and we have sufficient uncertainty that it would not surprise us if research on those topics proves as or more valuable.

## 5. Platform research and development related to vaccines

#### 5.1 Background on vaccine development

Developing and using vaccines has several established advantages over other types of medical countermeasures; namely, vaccines often only need to be used once or relatively rarely to protect an individual from a disease, and (partly because of this) vaccines are often cheap enough to be widely deployed in the developing world. In addition, once a vaccine is developed a population can often be preemptively vaccinated, meaning there is a relatively large window of time in which this intervention can be usefully deployed if the threat can be identified in advance.

These advantages, while substantial, seem relatively less important for addressing the biosecurity threats we are most concerned about (which may involve novel threats that are only likely to arise once or rarely, and which are difficult to predict with sufficient specificity to immunize the general population in advance), than they are in the context of most work on public health. Nonetheless, if it were possible to create new vaccines rapidly, it seems likely that they’d prove invaluable tools against potential viral pandemics, because they can be customized to provoke the immune system to provide strong protection against specific pathogens of concern. This is in contrast to therapeutics like antivirals (which seems likely to be less efficacious and accompanied by more severe side effects, based on our general understanding of the track record of these types of medical countermeasures). Chris and Heather believe that eventually immunization is likely to be possible against many or all dangerous pathogens, and that rapid vaccine development against most pathogens of concern is slightly more likely than not to become possible in the next 20 years.

Chris and Heather broke the process of vaccine development for a novel pathogen into four steps:

1. Sequencing the pathogen’s genome: Chris and Heather report that sequencing the pathogen is likely to be straightforward and rapid (though working with dangerous pathogens often requires substantial protective gear and specialized facilities), and there are already significant extraneous pressures to reduce the cost and increase the speed of sequencing, so we did not think searching for giving opportunities at the sequencing stage of the process was likely to be as impactful as work on the next two stages. They noted that during the 2014 Ebola outbreak, in-field sequencing of the samples was completed within 24 hours.5
2. Antigen discovery and design: The process of identifying antigens, molecules that stimulate the production of antibodies and other components of an immune response against the relevant pathogen, and possibly designing antigens that provoke a strong immune response that neutralizes the pathogen. This step may be unnecessary if conventional vaccine development methods, such as injecting deactivated or weakened forms of the pathogen, are effective and safe.
3. Vaccine candidate formulation: The process of developing candidate vaccines. Generally, vaccine development involves delivering the relevant antigens in some form to the relevant population so that the patient’s immune system produces the necessary antibodies. However, short-term immunity may in some cases be achieved by delivering antibodies produced in a lab in cells from another organism instead (this is called passive immunization, and sometimes is not counted as a type of vaccine development, though we group it here for simplicity). Multiple vaccine development strategies could be deployed simultaneously.
4. Testing: The process of testing a vaccine candidate for safety and efficacy, generally first in animals and then in humans. We expect that this process might be substantially abbreviated in the event of a sufficiently severe outbreak.

Steps two and three seemed the most likely to have neglected-yet-impactful opportunities for improvement from a scientific R&D perspective. Below we enumerate some parts of the antigen discovery and vaccine candidate formulation process that we investigated.

#### 5.1.1 Antigen discovery

This is the process of discovering a pathogen’s antigens, the molecules on the pathogen that stimulate an immune response in the host. This step is primarily used in the development of vaccine design in cases in which conventional vaccine development methods, such as using an attenuated (weakened) or deactivated pathogen, is infeasible or ineffective. Below are some areas of research related to this process that could improve or hasten vaccine development.

• Biosensor platforms: Researchers could develop better biosensor6 platforms for detecting the binding of antibodies to an antigen. This might allow them to better distinguish the immunogenicities of different antigens. Chris and Heather report that many platforms are already available and we think this is unlikely to be the bottleneck on the development of effective vaccines and prophylactics, though there may be room to incrementally improve the data quality of high-throughput devices.
• Structural/computational protein design: Research in this area could advance vaccine development in a few different ways:
• Once the amino acid sequence of an antigen is known, it is not necessarily the case that if it is synthesized separately from the rest of the original pathogen, it will form the same shape as the antigens in the virus and continue to bind to the relevant antibodies. This increases the difficulty of creating effective vaccines using methods of vaccine development that don’t involve the entire virus (either deactivated or attenuated). Computational tools could be used to predict protein interactions and design delivery platforms (e.g. nanoparticles or virions) for proper antigen display.
• Chris and Heather speculate that those tools could help researchers design antigens ab initio that are better at stimulating the appropriate immune response than the antigens in the original pathogen.7 Artificial antigen design might be worthwhile because some diseases, such as influenza, do not naturally present antigens to the body that are capable of stimulating a strong immune response (instead, the antigens they present mutate rapidly, so immunity to influenza is usually fleeting and restricted to only some strains of the disease). These tools are being applied in the lab, but the research is still at the relatively preliminary stage and they have not yet led to vaccines which are approved for use in humans.
• Alternatively, Chris and Heather theorize that in the future researchers may be able to use information about antigen-antibody interactions and computational tools to predict the optimal antibodies for binding to the antigen.8 In that scenario, those antibodies could then be tested, synthesized (if successful), and injected to deliver passive immunity (discussed in more detail below). This could be useful in a scenario in which there have not been instances of successful immune responses clearing the pathogen outside the lab.

However, Chris and Heather are uncertain about whether computational models have advanced sufficiently to be able to routinely achieve these goals.

Overall, it seems like further research into the development of methods for identifying and presenting antigens that will lead to the synthesis of improved antibodies has the potential to be useful in the event of the release of a dangerous pathogen, especially one engineered to escape the natural immune response. Funding work on improving computational models seems like a promising opportunity for a philanthropist interested in this area, and we have funded one project in this space.9

#### 5.1.2 Vaccine candidate formulation

There are several well-established methods of developing new vaccines, including using live attenuated or inactivated versions of the pathogen, among others.10 We don’t focus on these in this writeup, because it was our impression that additional research on these methods would be less likely to have substantial impact. We made this judgment because we believe that there is likely to be more low-hanging fruit related to new strategies and because we believe the new strategies are more likely to expand the range of pathogens that can be vaccinated against. However, some ideas involving the application of new gene-editing technology to older methods also seem promising to us.11

Our Scientific Research Program Officers looked at some less-established (partially overlapping) strategies for vaccine (and passive immunoprophylaxis) candidate development. These include:

• Nucleic acid vaccines: Nucleic acid vaccines involve delivering nucleic acids (DNA or RNA) coding for the antigens to cells, not the antigens themselves (as is the case with conventional vaccines). Once the antigens are produced by the patient’s cellular machinery, their immune system (hopefully) produces antibodies, generating immunity to the disease. No vaccines of this type have been approved for use in humans, though several DNA vaccines are in use to prevent diseases in nonhuman animals12 and trials on many nucleic acid vaccines are ongoing.13 There are many DNA vaccines in development, including the recently approved vaccines for Zika, however, the effectiveness has been lackluster in clinical trials.14 Improvements in delivery and adjuvant activation are ongoing and may result in effective DNA vaccines. RNA vaccines may be more efficacious because they don’t need to be delivered to the cell nucleus. Our Scientific Research Program Officers’ overall impression is that RNA vaccine testing thus far indicates good results in animals and appears promising in humans.
• Viral vector delivery: DNA or RNA coding for the antigens of viral pathogens (but not the other, harmful parts of the virus) could be integrated into a virus that is generally not pathogenic in humans, or encapsulated in a viral coat so that it can deliver the nucleic acid into human cells with high efficiency. Then people could be infected with that (non-pathogenic) virus and the viral machinery could induce the infected people to create the antigens, and subsequent immune response, conferring immunity.15 If effective, this could address some of the delivery problems with nucleic acid vaccines raised above. Adeno-associated viruses (AAVs) are among the most-studied candidates for this method of delivery, though there are others.16 While this strategy involves risks such as not working in the fraction of the population that had already been exposed to the relevant virus, it nonetheless seems possible to us that it would be one of several useful strategies to pursue in the event of the emergence of a potentially catastrophic disease outbreak.
• Passive immunoprophylaxis: Instead of delivering antigens and thus stimulating a full immune response, researchers could inject the relevant antibodies (which the immune system produces in response to the antigens). These antibodies might be delivered in the form of antisera (human or nonhuman blood serum containing antibodies from a survivor of the pathogen), or produced in a recombinant cell line or organism (e.g., plant). Once the antibodies have been delivered and if the process is effective, the host will have short-term immunity against the pathogen of concern but the immunity will be limited because no memory B cells (cells which produce the relevant antibodies and which are indirectly stimulated by the antigens) will be produced. Another limitation of this strategy is that some diseases require T-cell immunity or other aspects of immune response, in addition to the production of neutralizing antibodies, which this approach doesn’t deliver. However, this strategy has the following advantages: 1) it could be used to rapidly immunize people who are incapable of producing effective antibodies 2) in the future it’s possible that this strategy could be used to administer artificial antibodies that are superior to the ones human produce naturally.
• Vectored immunoprophylaxis: Researchers could engineer DNA or RNA that codes for the creation of antibodies, then integrate that DNA or RNA into a (relatively safe) virus (for example, an AAV), as is described in the case of viral vector nucleic acid vaccines (above), except with antibodies instead of antigens. Susceptible groups could then be deliberately infected with the non-pathogenic virus. If effective, this would cause the body to produce the antibodies, temporarily protecting the vaccinated person against the pathogen of concern if he or she becomes infected.17 Similar limitations to the ones described above for passive immunity (e.g. impermanence) apply, though it may be substantially easier to immunize large numbers of people this way. This is because we expect it to be substantially easier and cheaper to produce the nucleic acid sequence coding for an antibody and insert it into a virus than it would be to produce and administer the antibody protein itself en masse.

There are several other lines of research on vaccines that seem like they could plausibly be impactful, including the ones listed below (though, none of the below both strongly attracted our interest and were not already being pursued). We note them here only briefly with the purpose of representing more of the breadth of possible research topics:

• Adjuvants: vaccines that stimulate an insufficient immune response alone are sometimes accompanied by compounds called adjuvants that increase the immune response to the vaccine. Further research on adjuvants could lead to stronger responses to vaccines with otherwise low efficacy.
• Vaccine production platforms: different vaccines are produced using different platforms. For example, whole animals, eggs and cell lines can be used to generate whole (live, attenuated, or killed) vaccines, whereas cell lines or plants are more appropriate for recombinant vaccines and/or virus-like particles. Not all systems are suitable for all pathogens. New platforms could facilitate more rapid production of vaccines.
• Effective surrogates for safety and immunity. In order to make more effective or new vaccines, it would be useful to have a non-human organism that has an identical immune response to humans and similar sensitivities for toxicity in which to test the safety and efficacy. Because of the development of new genome editing technologies it is is now theoretically possible to strongly modify the immune systems and other biochemical pathways of animals to more closely resemble that of humans.
• Polysaccharide antigens: Like other antigens, polysaccharides and glycosylated protein antigens can elicit part of innate immune responses, in addition to stimulating the production of neutralizing antibodies. And, Chris and Heather note that mutations that alter glycosylation may alter presentation of classical antigens, reducing vaccine efficacy. However, most of the new approaches to vaccine design, such as producing nucleic acid vaccines, are not expected to be useful for this, and the immune responses to polysaccharides or protein glycans are poorly understood and difficult to study, and tools for artificial synthesis are lacking.

#### 5.2 Vaccine R&D in preparation for a potentially catastrophic pandemic

In the event of an outbreak of a highly virulent and transmissible pathogen, we would guess that multiple lines of research might be pursued simultaneously. For example, researchers might in parallel attempt to:

1. Identify antigens that can be used to prepare a nucleic acid vaccine
2. Use computational methods to produce recombinant vaccines in cell cultures
3. Clone antibodies that might be useful for generating passive immunity sera
4. Create a live attenuated vaccine

Chris and Heather report that in some cases it’s possible to develop an initial vaccine candidate within six months or faster (although in most circumstances completing and evaluating the clinical trials necessary for the vaccine to be approved by the FDA takes years). We know of several examples of this, although they are importantly disanalogous to the likely situation we’d expect would occur with a novel viral outbreak:

• Flu vaccines are prepared twice annually in preparation for seasonal flu,18 although our understanding is that the development processes depend on the vaccine backbones and organizational infrastructure developed in previous years (facilitating accelerated development).
• Related to the above, Dormitzer et al. (2013) reports that “[w]ithin 6 months of the [2009 H1N1 outbreak] pandemic declaration, vaccine companies had developed, produced, and distributed hundreds of millions of doses of licensed pandemic vaccines.” although it also notes that these vaccines were for the most part not ready until after the pandemic had already entered a natural decline.19
• The World Health Organization (WHO) announced the Zika outbreak in February of 2016, and by August 2016 several Zika vaccine candidates were in clinical trials.20 We do not know when development of those vaccine candidates began, and the WHO announcement may not be a good indicator of when vaccine development began.

This space seemed fairly crowded to our Scientific Research Program Officers, and they did not encounter many gaps in the research being pursued. Their overall impression is that there are not substantial obstacles remaining to developing vaccines in under 100 days, depending on the pathogen type,21 although to the best of our knowledge it has never been done and both (potentially severe) scientific obstacle we haven’t identified and logistical issues could arise. However, this would not include testing for safety and efficacy.

They commented that, based on the level of sophistication of the science, they were surprised that relatively few new and effective vaccines have been developed in recent years, and they did not know why that was the case. They are reasonably confident that further advances in vaccine development will result in novel useful vaccines in the coming years, and that emergency scenarios would (if they occurred) spur more rapid development of relevant vaccines, as evidenced by the recent responses to Zika and Ebola. However, we are uncertain about whether this would substantially increase investment and progress in platform technology related to vaccine development.

Overall, our impression is that the following seem particularly likely to be valuable to prepare in advance of the emergence of a potentially globally catastrophic pathogen:

• Ab initio protein design for improved antigens and antibodies
• Vectored immunoprophylaxis

But thus far, we have identified only a few specific promising projects in this space.

More generally, our Scientific Research Program Officers think developing a more mechanistic (i.e. coming from an understanding of the mechanisms involved in stimulating immunity) rather than empirical (i.e. trying out different approaches and checking if they succeed) process for developing vaccines is likely to result in more reliable and rapid production of new vaccines.

## 6. Antivirals for pandemic preparedness

#### 6.1 Background on antivirals

In contrast to vaccines, it’s our impression that relatively little work has gone into antiviral research and development in recent years. And, it seems to us that the majority of antivirals currently available are not likely to be useful countermeasures in the event of a potentially globally catastrophic pandemic. That’s because:

• Many of them are not broad-spectrum; most only treat one or a few different viral diseases.22
• Existing antivirals have variable effectiveness, and over time viruses have been evolving resistance to them.23

#### 6.1.1 Host-directed antivirals

Some compounds which exhibit antiviral activity are host-directed, meaning that they target proteins in the host that the virus depends on rather than the virus itself. The ones we know of are inhibitors of chaperone proteins, proteins which assist in the folding of other proteins, including viral proteins. Our Scientific Research Program Officers’ reading of the literature suggests that these types of antivirals may be unsuitable for long-term use, since their mechanism of action relies on interfering with host-cell machinery, and thus they may cause relatively severe side effects.24

However, some of them (Hsp90 inhibitors) have been tested for medium-term use as therapeutics for cancer patients, and have been tolerated.25 Hsp90s are “chaperone” proteins. It appears that dependence on Hsp90s among viruses is widespread, and may be universal.26 Hsp90 inhibitors appear particularly promising to us because the ones we know of seem likely to be relatively broad-spectrum and difficult for viruses to evolve resistance against (because the antivirals target relatively conserved virus-host interactions). Hsp70s are also chaperone proteins with inhibitors which we think may be promising, although Chris and Heather report that there is some weaker evidence of broad-spectrum antiviral activity among Hsp70 inhibitors and less evidence indicating that they may be safe for human use.

Overall, we think these compounds merit further investigation, though we think they’re unlikely to prove fully efficacious and safe against viruses in humans due to the low overall base rate of discovery of new, highly effective pharmaceuticals. If these compounds were effective against highly virulent viruses at similar doses to those used for treating cancer patients, it seems likely to us that these side effects would be considered acceptable. Chris and Heather speculate that these antivirals would only be employed for short-term (i.e. on the scale of days or weeks) use against a virus; the idea would be to use them to mitigate the effects of the virus and “buy time” for the immune system to launch an immune response and clear the virus.

Chris and Heather thought it was unlikely that viruses could evolve or be easily engineered to have resistance to host-directed antivirals, because the pathway of protein folding is both complex and very fundamental, and so they said that many mutations would be required obviate the requirement for a given chaperone protein.

There are other proteins involved in the chaperone protein complex with inhibitors that may also prove useful as broad-spectrum antivirals, but the Hsp90 inhibitors seem the most promising because those are the only chaperone protein inhibitors that have been studied extensively in humans and have been found to be relatively safe.

A funder could fund studies on these antivirals’ efficacy against different viruses in vitro or in animal models or humans, for viral pathogens against which they have not yet been tested. We are in the process of investigating funding opportunities in this space.

## 7. Who else is working on it?

Our Scientific Research Program Officers’ overall impression is that there is a lot of commercial activity related to infectious disease vaccine and therapeutic development, and there are many companies working on the development of vaccines and diagnostics for use against viruses with greater economic potential in the developed world (e.g. influenza, hepatitis). However, we found it challenging to evaluate what proportion of the work is likely to be relevant to addressing pathogens with the potential to cause globally catastrophic pandemics. We did not look deeply into this topic because we thought it would be more useful to first identify more specific research topics that seemed most promising in this space, then investigate those. Thus, this section is relatively perfunctory compared to similar sections in other cause reports of ours.

It seemed plausible to us that this area might be neglected relative to its importance because the relevant people and groups might not see work on it as their responsibility or in their best interest; for example, we speculated that pharmaceutical companies might not be incentivized to develop vaccines and therapeutics designed specifically for use in a catastrophic pandemic, especially if they have side effects that make them unsuitable for use against less severe diseases, or diseases for which less dangerous alternative treatments exist. That’s because developing pharmaceuticals is generally very expensive,27 and we think that the relevant opportunities are relatively unlikely to deliver continual and reliable revenue streams (because the risks are rare and disproportionately associated with societal disruption), compared to e.g. treatments for chronic and common diseases.

We did encounter some potentially relevant efforts in this space that we thought were worth highlighting:

• The National Institutes of Health (NIH) allocated an estimated $1.7B for “biodefense” research in 2016,$1.4B of which went through the National Institute of Allergy and Infectious Disease (NIAID).28
• The Coalition for Epidemic Preparedness Innovations (CEPI), a group formed in 2016, states that it intends to develop vaccines against known pathogens that may have epidemic potential.29 In January 2017, it was reported that approximately $500M in funding had been committed to CEPI.30 • In 2013, The Joint Science and Technology Office for Chemical and Biological Defense worked on post-infection antivirals including antibodies and FDA-approved drugs.31 • In February 2017, the Defense Advanced Research Projects Agency (DARPA) announced a four-year initiative called the Pandemic Prevention Platform (P3) program to prepare nucleic acid vaccines within 60 days of the identification of a novel pathogen.32 Other information that seemed relevant to us: • The NIH does not report spending on antivirals as a distinct category.33 However, 55 grants related to “broad-spectrum antivirals,” representing ~$17M, were reported by Grantome in 2015.34
• Chris and Heather’s impression during this investigation was that there are a variety of funders and other actors involved in platform tools for vaccine development, such that the topics they investigated did not seem highly neglected.
• Chris and Heather contacted companies and researchers that had previously been involved in the development of Hsp90 and Hsp70 inhibitors, as well as some other groups in the field we thought might have insight into this, and did not find evidence of ongoing research on the development of these inhibitors as broad-spectrum antivirals.
• If countermeasures were developed, the Biomedical Advanced Research and Development Authority (BARDA) might stockpile them. BARDA’s stated mission is to develop and procure medical countermeasures that address public health threats, including pandemic influenza and other infectious diseases.35 The Department of Defence may also manufacture relevant medical countermeasures.36
• There may also be non-public governmental research related to pandemic pathogen countermeasure R&D

## 8. Questions for further investigation

• How neglected are the various themes discussed in this document that relate to vaccine development (e.g. “computational protein design,” “vectored immunoprophylaxis,” etc.)? What are the most promising unfunded projects related to these themes?
• On what timescales could we expect to achieve advances in vaccine production such that vaccines against the most dangerous pathogens can reliably be developed in 100 days or fewer? What would the likely positive consequences be in a pandemic if vaccines could be produced that much earlier?
• What types of viral pathogens with the potential to produce globally catastrophic pandemics could not be addressed with the advances discussed in this writeup? What research would help address the risks posed by those?
• Are host-directed antivirals relatively safe and effective in humans? What viral pathogens would they not be sufficiently effective against, if any?
• What types of research into immunology would be most likely to yield insights that prove useful for preventing catastrophic disease outbreaks?

## 9. Sources

 BARDA: BARDA unveils path forward in the BARDA Strategic Plan 2011-2016 Source (archive) Carolson, 2016 Source (archive) CEPI: Approach Source (archive) Clinicaltrials.gov keyword “DNA vaccine” Source (archive) Clinicaltrials.gov keyword “hsp90” Source (archive) Clinicaltrials.gov keyword “RNA vaccine” Source (archive) Cohen 2017 Source (archive) Correia et al. 2014 Source (archive) DARPA: “Removing the Viral Threat” 2017 Source (archive) De Clercq and Li 2016 Source (archive) Department of Defense Chemical and Biological Defense Annual Report to Congress, 2014 Source (archive) Devitt 2013 Source (archive) Dormitzer et al. 2013 Source (archive) Geller, Taguwa, and Frydman 2012 Source Grantome.com “broad spectrum antivirals” Source Hasson, Al-Busaidi, and Sallam, 2015 Source Howe and Haystead, 2015 Source Kutzler and Weiner, 2008: Table 2 Source (archive) Morrison 2016 Source (archive) NIAID Fiscal Year 2017 Congressional Budget Justification Source (archive) NIH Categorical Spending 2017 Source (archive) Overview of the Department of Defense’s (DoD) Advanced Development and Manufacturing (ADM) Facility and Capabilities, 2017 Source (archive) Quick et al. 2016 Source (archive) The Open Philanthropy Project’s grant to the University of Washington for “Universal Flu Vaccine and Improved Methods for Computational Design of Proteins” November 2017 Source The Open Philanthropy Project’s non-verbatim summary of a conversation with Gigi Gronvall, October 6, 2014 Source The Open Philanthropy Project’s non-verbatim summary of a conversation with Wendy Barclay, October 2, 2014 Source Shaw 2017 Source (archive) Tripp and Tompkins 2014 Source (archive) Tufts Center for the Study of Drug Development, 2014 Source Sanders and Ponzio 2017 Source (archive) Vaccines.gov “Types of Vaccines” Source (archive) Willis et al. 2013 Source (archive) World Health Organization: Vaccines Against Influenza, 2012 Source (archive)

## Mechanisms of Aging

This is a writeup of a medium investigation, a relatively brief look at an area that we use to decide how to prioritize further research.

## In a nutshell

• What is the problem? Aging is a major contributor to cardiovascular disease, cancer, diabetes, neurodegenerative diseases, and other causes of death and impairment. Better understanding, and being able to mitigate, the basic mechanisms of aging could therefore contribute to reduced age-related mortality and impairment for a very large number of people.
• How could the problem eventually be solved or substantially alleviated? We think it’s plausible that age-related diseases and impairments could be alleviated if scientists achieved specific research objectives in a number of areas (prevention/correction of epigenetic errors, senescent cell removal/prevention/reprogramming, reversing/addressing stem cell exhaustion, and organ/tissue regeneration and replacement). This list is not exhaustive and is populated with areas that seem to us to be especially fundamental and/or dynamic and potentially broadly applicable, and therefore seem like plausibly useful areas for subsequent research.We are highly uncertain how large the potential gains might be if the above objectives were achieved, but think several years of healthy life extension (and possibly more) could plausibly be made in the next 10-20 years in some areas (such as senescent cell removal), while areas that could yield substantially greater gains will likely require multiple decades of progress in enabling areas like neuroscience, selective delivery of agents to cells and/or organelles, and epigenetics. However, we don’t have a strong opinion about whether supporting the nearer-term or longer-term objectives is likely to have greater expected benefits per unit cost.
• Who else is working on it? The NIH reports spending $2.7 billion per year on aging-related research. We are unsure how much of this is relevant to understanding, preventing, and mitigating the basic mechanisms of aging. We are aware of several foundations and nonprofits focused on aging research with collective expenditure around$80 million per year (likely an underestimate of philanthropy in the area). During this investigation, we became aware of several companies explicitly focused on aging with about $1 billion in investment collectively. Open questions include: which themes are neglected; what levels of healthy life extension might be realized if the different research goals are accomplished; and which long-term research directions are most promising and neglected. ## 1. Our process Our scientific advisors, Chris Somerville and Heather Youngs, are biochemists and scientific generalists with no prior expertise in aging research. We asked them to survey the field of aging, divide it into subfields, identify promising projects that were not being pursued, and help us understand the potential impact on healthy lifespan if various potential long-term research projects were successful. The latter question was not discussed in the literature, and we had to approach it very speculatively. We excluded investigation of science mainly relevant only to one specific age-related disease (e.g. research on cancer, cardiovascular disease, and Alzheimer’s) but included some topics relevant to many age-related diseases (e.g. developing the ability to grow organs from induced pluripotent stem cells). Our advisors conducted literature reviews, spoke with several people in the field, and wrote rough internal memos for other staff to review. This was their main priority for roughly one and a half months.1 Nick Beckstead drafted this page and it was reviewed by our scientific advisors and a few other Open Philanthropy Project staff before it was published. ## 2. What is the problem? Aging is a major contributor to cardiovascular disease, cancer, diabetes, neurodegenerative diseases, and other causes of death and impairment (some of which, such as muscular atrophy, loss of teeth, and damage to joints, are so common that they are not generally considered “diseases”).2 Proposed basic mechanisms are various and have disputed levels of comparative importance, but include “genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.”3 Additional potential mechanisms are presented below. #### 2.1 What currently available interventions can address this problem? There are a large number of symptoms associated with aging. Some are widely recognized as diseases and are subject to a variety of treatments (e.g., neurodegenerative disorders; heart disease); others are not considered “diseases,” and there are generally few if any treatments targeting them (e.g., normal muscular atrophy). While it is conceivable that there could be treatments addressing aging “in general” (e.g., addressing all or a large proportion of associated symptoms via a single mechanism), such treatments have not been conclusively demonstrated and may not be possible. There are approaches that have been hypothesized to fit in this category, such as caloric restriction. While some of these have been tested in model systems, they have not been tested in humans for the purpose of extending healthy lifespan, and we would guess that they would not have radical effects on healthy lifespan if they were tested (but plausibly could be substantially positive). We did not carefully consider nutrition and lifestyle interventions (except for caloric restriction) because we have a strong prior that available data is inconclusive and our science team’s expertise is more in the direction of molecular biology and biochemistry than nutrition. ## 3. How could the problem be substantially alleviated? This section focuses on imagining, very speculatively, how scientific advances could eventually make it possible to prevent or substantially alleviate some problems associated with aging. Claims not cited are generally based on the internal memos produced by, and subsequent conversations with, our advisors (along the lines of the process described above). This list highlights some imaginable scientific advances that attracted the interest of our scientific advisors because of their potential to extend healthy lifespan. The first three attracted the interest of our scientific advisors because they appear to address “basic mechanisms” of aging that might account for a large proportion of aging-related symptoms, whereas the last is less basic in this sense but seems especially dynamic and potentially broadly significant. The list is not exhaustive. With those caveats and clarifications in mind, we would guess that healthy lifespan might be extended if scientists eventually were able to: • Prevent the accumulation of epigenetic errors associated with aging, or restore more youthful epigenetic states in cells. Various alterations of epigenetic state4 are correlated with both chronological age and symptoms of aging, and there are theoretical reasons to expect that these alterations would cause symptoms of aging.5 Interventions on the epigenetic state of mice have shown results consistent with the points previously stated6 but we anticipate that multiple aspects of inducing “epigenetic rejuvenation” would be challenging.7 • Solve the problem of senescent cell accumulation. As animals age, senescent cells (i.e., cells which neither grow and divide nor apoptose) accumulate. Research suggests that senescent cells contribute to damaging inflammation and may also suppress tissue regeneration by stem cells. In lab experiments, mice who had a portion of their senescent cells removed lived about 25% longer than mice in the control group that were born at the same time.8 We imagine that selectively killing senescent cells might become possible through a number of generic strategies.9 We have a less specific sense of how reprogramming senescent cells or preventing them from becoming senescent in the first place might work, but imagine that advances related to epigenetics (discussed above) or advances related to several of the other directions discussed in this document could be helpful. We mean to raise the above generic strategies only as plausible possibilities and do not have confidence in the feasibility or timeline for success of particular approaches. • Reverse stem cell exhaustion. Somatic stem cells are induced by factors such as growth, normal senescence, and tissue damage to divide and replenish other cells. As adult humans age, their stem cells appear to become depleted or increasingly less active, which is thought to decrease the body’s capacity to replace and repair damaged tissue.10 It’s unclear how much of what we call aging is attributable to decreased stem cell activity, and what causes the apparent decrease in stem cell activity, but numerous factors have been implicated.11 Additionally, as noted above, cytokines released by senescent cells may play a role. We see a few (speculative) possibilities for addressing stem cell exhaustion, and we discuss three of them in a footnote.12 • Learn how to use induced pluripotent stem cells (IPSCs) to regenerate and/or replace tissues and organs damaged by aging and aging-related diseases Progress in getting IPSCs to differentiate into other cell types and organoids may allow repair or replacement of organs such as liver, pancreas (islet cells), lungs, kidneys, spinal cords, eye, and heart, and also some cell types in the brain, and could contribute to management of aging-related diseases affecting these cells/tissues/organs/organoids, including heart disease, diabetes, liver disease, vision loss, ALS, and Huntington’s disease.13 We are highly uncertain about, and do not have internal consensus regarding, the potential extension in healthy lifespan that might result if 1-2 of the above objectives were accomplished. Some of us see several years of healthy life extension as the plausible potential upside and others see larger possible gains, but all of us involved in creating this report expect that any increase in healthy lifespan would keep average lifespan within the range of natural lifespans observed in humans today (barring a historically exceptional increase in the rate of scientific progress). We would guess that much more radical life extension would likely require a larger number of successes like these and likely multiple successes that are not listed here, and we accordingly assign it much lower probability in the next few decades (with some caveats). We held this view about the difficulty of radical life extension prior to this investigation. Our findings fit with this prior view, and the investigation did not strongly affect our views on the matter. Some other themes are also potentially important to aging, but they are covered in this write-up in less detail because we have focused on topics that seemed more basic, dynamic, and/or potentially broadly significant to us. The themes covered in less detail here include: genomic instability, telomere attrition, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, altered intercellular communication, decline of the immune system, inflammation, neurodegeneration, the microbiome, and damage to individual cells (e.g. antioxidants and DNA repair). We may investigate inflammation and decline of the immune system more thoroughly in the future because these topics caught the interest of our scientific advisors. We compare our list of highlighted topics with a plan proposed by researchers at the SENS Foundation in a footnote.14 ## 4. What are the possible research interventions? Common obstacles to achieving the goals stated above include lack of ability to selectively deliver agents to desired cell types, measure and control the epigenetic state of cells, and understand and control differentiation and functioning of stem cells (plausibly closely related to the previous item). Therefore, progress on these more general themes may assist with extending healthy lifespan. Other types of relatively general research may also be helpful or necessary for substantial extension of healthy lifespan, such as general progress in neuroscience, improved biomarkers for various aspects of aging, and/or improved model organisms for aging. We think substantial progress on many of the themes mentioned above is likely to require decades of work, so our intuition is that long-term, basic research (with an emphasis on tool development) in areas like neuroscience, selective delivery of agents to cells and/or organelles, and epigenetics is likely to be the most important work for making the greatest possible progress relevant to age-related disease and impairment in the long run (though we have a limited sense of which tools and research directions are likely to be most promising and/or neglected). Our reasoning for thinking this work will be more important in the long run can be made clearer by reference to a thought experiment: imagine that 30 years ago, a funder were working toward understanding and mitigating the fundamental causes of aging. Our intuition is that they would want a large share of their effort to go toward supporting very basic work on gene sequencing, microscopy, the areas of cell biology that have led to the field of epigenetics, and topics in cell differentiation that led to the discovery of stem cells – rather than work that might fall under the auspices of “aging research” per se. We suspect something similar is still true today. One observation we can offer in support of this is that many of the important questions relevant to extending lifespan could not even have been asked 30 years ago (e.g. some questions about stem cells and epigenetics). Some of the themes listed above do not seem to have as many basic obstacles as others. For example, it seems plausible to us that some of the above objectives related to senescent cell removal and heterochronic parabiosis could be achieved in the next couple of decades. In these cases, we don’t have a strong opinion about whether supporting research primarily relevant to these objectives or long-term objectives is likely to have greater expected benefits per unit cost. ## 5. Indefinite vs. moderate healthy life extension We think the best case for this cause involves the prospect of healthy life extension within the range that some humans currently live. In contrast, some people who are interested in the mechanisms of aging have promoted the idea of “curing” aging entirely. Some thoughts on this: • Our default view is that death and impairment from “normal aging” are undesirable. However, we would have some concerns about indefinite life extension, mainly related to entrenchment of power and culture. We don’t have internal consensus on whether, and to what extent, such indefinite life extension would be desirable, and don’t consider it highly relevant to this write-up. • We don’t see promising life science research that would result in indefinite life extension in the next few decades, barring a historically exceptional increase in the rate of scientific progress. • When we consider possible transformative technologies that could result in indefinite healthy lifespan, some staff members think some kind of identity-preserving digital emulation is more likely than radical scientific advancements related to physiological aging, but others are more skeptical about the relevance/feasibility of that idea.15 Our program officer Nick Beckstead offers the following forecast to make the above more precise/accountable: By January 1, 2067, there will be no collection of medical interventions for adults that are healthy apart from normal aging, which, according to conventional wisdom in the medical community, have been shown to increase the average lifespan of such adults by at least 25 years (compared with not taking the interventions). (Subjective probability: ≥93%) The prediction is called off if some other innovations cause a historically exceptional increase in the rate of scientific progress during this period (such as the development of transformative AI capabilities). The prediction excludes diet, exercise, and lifestyle, as well as existing medical interventions for healthy people (such as currently available vaccines). ## 6. Who else is working on it? The NIH reports spending$2.7 billion per year on aging research in 2015.16 In the 2015 budget request, $510 million per year is tagged as “neuroscience” and$177 million per year is tagged as “aging biology.”17 We have heard in various conversations that this research is mainly relevant to addressing particular symptoms associated with widely-recognized diseases (e.g., Alzheimer’s disease), rather than on understanding the basic mechanisms that cause aging. This is plausible to us, but we haven’t seen any convincing evidence for it and we do not take it for granted. We sometimes hear the sentiment that research on aging is neglected because of an attitude that “curing” it isn’t desirable, but we haven’t seen any evidence that the NIH takes that attitude.

A brief Google search revealed the following non-profit organizations working in the space, with all funding totals reflecting amounts dedicated to aging-related research: the Buck Institute ($35 million total annual budget in 2014);18 the Glenn Foundation ($11 million total in grants in 2014);19 the SENS Foundation ($1.5 million in grants and$5 million in total expenses in 2014);20 the American Federation for Aging Research ($7.7 million in grants and$10 million in total expenses in 2015);21 the Larry L. Hillblom Foundation ($6 million in grants and$6.8 million in total expenses in 2015).22 The Ellison Foundation is leaving the field.23

## 1. What is the problem?

Sexually transmitted diseases (STDs) are widespread. Hundreds of millions of people are infected with at least one STD,1 and the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated that STDs other than HIV and HPV caused approximately 142,000 deaths in 2013, while HIV caused approximately 1,341,000 deaths in 2013.2

We may conduct a separate investigation into HIV/AIDS at a later date, but did not include it in this investigation.

We believe it is widely accepted that mother-to-child STD transmission can result in stillbirths, infant mortality, and chronic health conditions. Stigma, fear, and avoidance of sexual intimacy associated with STDs may lower quality of life. Common STDs, including genital herpes, HPV, and syphilis, are associated with an increased risk of HIV transmission, but it appears that high-quality evidence of a causal relationship is scarce. (See below for our take on this.)

Vaccines are available to prevent HPV (although note that currently-available HPV vaccines do not protect against all strains of HPV3) and hepatitis B.4 Other STDs, including syphilis, chlamydia, and trichomoniasis, are treatable and generally curable with antibiotics,5 although some STDs, especially gonorrhea, are developing resistance to antibiotics.6

We formulated an initial list of STDs from several other lists of STDs that we found.7 We declined to include infections such as Pelvic Inflammatory Disease (PID) that result from infection with other STDs. Of these, we initially decided to assess the impact of and funding for diseases that are predominantly sexually-transmitted other than HIV, and that are currently difficult or impossible to treat or cure because we thought it was more likely that additional scientific research would be beneficial for cases where reliable cures or treatments have not been found. We later decided to investigate predominantly sexually-transmitted diseases that had a reported impact of greater than five million disability-adjusted life years (DALYs) per year as well, regardless of whether treatments or cures for those are available.8 Based on these processes, we decided to examine herpes simplex virus (HSV), syphilis, and human papillomavirus (HPV) in more detail.

#### 1.1.1 Overall burden

To get a sense of the impact of different STDs on public health, we looked at the most recent estimates of the global annual burden of major STDs (excluding HIV and HPV) in DALYs from the Global Burden of Disease Study (GBD) and the World Health Organization’s (WHO) Global Health Observatory (GHO). The results are below:

DISEASE GLOBAL BURDEN OF DISEASE (2013) WORLD HEALTH ORGANIZATION (2012)
Syphilis 11,324,500 7,038,630
Chlamydial infections/Chlamydia 692,400 1,429,973
Gonococcal infections/Gonorrhea 313,900 545,145
Genital herpes 311,600 NA
Trichomoniasis 113,900 172,850
Other STDs 101,000 734,0759
Total burden of STDs (excluding HIV) in DALYs 12,857,200 9,920,672

However, it’s our impression that these numbers are very uncertain (indeed, they are not in close agreement with one another). The estimates did not include the impacts of neonatal forms of some STDs, and may have missed other impacts as well.10

Additionally, we note that there are major negative impacts of STDs that we do not quantitatively assess in this report, such as the psychological and sociological effects of the presence of STDs in a community (e.g. fear of transmission and stigmatization). In addition, there may be impacts we do not know of and that our brief investigation did not uncover.

#### 1.1.2 STDs and HIV Transmission

There is evidence of a correlation between HIV and infection with other STDs, including HSV, HPV, and gonorrhea.11 Some researchers also believe there are plausible mechanisms by which the presence of other STDs could increase the likelihood of HIV transmission, namely by 1) increasing the incidence of lesioned regions of flesh around the genitals, and 2) recruiting cells carrying CD4 receptors (which HIV uses to gain entry into host T-cells) to the area.12 However, we believe the ability to definitively determine a causal relationship is complicated by confounding variables (for example, behavioral and health-status factors that contribute to the risk of contracting one STD may increase the risk of contracting another), and limitations on the types of experiments that can be performed without harming participants. We are not confident that attempts to fully control for confounding variables are able to do so.

We know of two small RCTs which concluded that HSV antivirals reduced HIV levels, either in the seminal fluids or in plasma and around the cervix.13 However, according to @Mayer and Venkatesh [email protected], in a meta-analysis of randomized controlled trials (RCTs) on interventions to distribute antivirals for HSV and antibiotics for bacterial STDs, six out of seven RCTs they examined did not find a statistically-significant reduction in HIV transmission, nor have studies in subsequent reviews (note that there is overlap between the studies included in the different reviews).14 Given that the majority of studies we encountered did not find an effect of STD treatment and prevention on HIV transmission, we chose not to include a quantitative estimate of the potential impact of STDs on HIV. However, we note that if STDs are in fact responsible for a substantial proportion of HIV transmission, that might make their overall impact substantially larger than our estimates below.15

Some studies have detected an association between HIV and HPV.16 Additionally, mechanisms by which HPV infection could increase HIV transmission have been proposed.17 However, it is our impression that as of 2015, no RCTs have been conducted on the impact of HPV vaccination on HIV transmission.18

We do not know if vaccines or improved treatments for STDs would reduce HIV transmission, or whether increased access to currently-available STD treatments would help prevent HIV.

#### 1.1.3 Genital herpes

The herpes simplex virus (HSV) occurs in two forms, HSV-1 and HSV-2.19 Hundreds of millions of people are infected with one or both types of HSV, although many show no symptoms.20 Both types can be transmitted by sex.21 There is no commercially-available HSV vaccine and HSV infections cannot be cured, but antiviral agents can reduce outbreaks.22

Major sources of disease burden from HSV include:

Genital ulcers: The Global Burden of Disease reports that genital HSV resulted in 311,600 years lived with disability (YLD) in 2013 due to genital ulcer disease.23 We have not vetted this estimate, but did attempt to independently derive it by assigning what we felt was a plausible disability weight to genital ulcers and multiplying by its prevalence, and found that it was within the range of what we expected.

Neonatal deaths from HSV: We found it difficult to come to an understanding the impact of neonatal HSV. This is because:

• We have major uncertainty about current global neonatal herpes incidence, although the data we found suggest that the overall incidence was likely more than 1/100,000 and less than 1/100 in the late 1990s and early 2000s.24
• We are highly uncertain about the neonatal herpes mortality rate, and the sources we’ve found have not given us a strong sense of the likely true number because the estimates vary somewhat. We haven’t investigated their methodology, and we are unsure of how the mortality rate varies by country.25 We don’t know if the difference in estimates of the mortality rates stem primarily from differences in incidence at the different study sites and times, differences in proportion of cases treated, differences in the quality of the treatment, other factors, or some combination of these. We think it require substantial additional work to understand neonatal HSV mortality rates somewhat better, but that even if we put in more time, we might not gain clarity on this.
• We did not look into the number of infants that sustain lifelong sources of disability from neonatal HSV.

Given the number of births/year,26 it seems likely to us that thousands or tens of thousands of infants are infected with HSV every year, and it seems possible to us that more than 10% of those infants die. If that were true, the impact of neonatal HSV might represent a substantial fraction or the majority of the total burden of HSV.27

Severe vision impairment from HSV: One source suggests that 40,000 people per year may become profoundly visually impaired in one or both eyes due to HSV keratitis (an inflammation of the cornea).28 We did not vet this estimate, and are not confident that these numbers reflect the true burden of severe vision impairment from HSV. We don’t know how many DALYs HSV keratitis is likely responsible for. It’s our impression that most cases of HSV keratitis occur late in life but may be more severe in children. 29

In many cases, HSV vision impairment may be the result of HSV-1 that was not directly sexually transmitted. Many researchers believe that HSV-1 can be and often is transmitted by non-sexual kissing (for example by family members) or by sharing items that touch the mouth such as eating utensils and toothbrushes.

Other impacts: We did not investigate several other impacts of HSV, including:

• Sequelae in non-fatal cases of neonatal HSV
• Cases of mildly-moderately impaired vision from HSV
• Oral HSV ulcers
• A proposed connection between HSV-1 infection and the development of Alzheimer’s Disease30
• Encephalitis and meningitis from herpes31

Overall burden: The GBD estimated that genital herpes resulted in approximately 300k DALYs in 2013. Based on our research into conditions caused by HSV but not included in the GBD estimate (namely, the unquantified but possibly-substantial impact of HSV keratitis and neonatal HSV, the possible and (if real) plausibly substantial impact of HSV on HIV/AIDs transmission and Alzheimer’s Disease, and the likely small impact of the other conditions above) we would guess that the true impact of HSV is substantially larger, although we don’t know how much larger.

#### 1.1.4 Human papillomavirus

HPV is a common infection; the WHO estimates that approximately 12% of women with normal cytological findings (which we believe to mean no cellular signs indicating cervical cancer or precancerous changes in the cervix, indicating that this number is likely an underestimate of the proportion of women with HPV) and 21% of men worldwide are infected at a given time.33 There are many strains of HPV, most of which are asymptomatic but some of which increase cancer risk around the infected area (especially the cervix) or cause genital warts.34

There is no treatment we know of for HPV, but there are vaccines that confer protection against some strains of the virus.35 All the vaccines protect against strains 16 and 18,36 which, according to the National Cancer Institute, are together responsible for 70% of cervical cancers.37

There are also procedures that allow healthcare workers to identify and, if necessary, remove precancerous lesions on the cervix.38 According to the WHO, HPV infections of healthy individuals often spontaneously resolve themselves within two years39 and it usually takes approximately ten years for HPV infection to progress to an invasive cancer.40

Major sources of disease burden from HPV include:

Cervical cancer: In 2012 it was reported that there were 528,000 cases of cervical cancer and 266,000 deaths from cervical cancer,41 all the result of some strain of HPV.42 The DALY burden of cervical cancer was estimated at 6.9M in 2013 by the GBD,43 and 9.2M by the WHO in 2012.44

Cancers of the vulva, vagina, penis, anus, mouth, and oropharynx attributable to HPV:

There is evidence linking HPV to cancers of the vulva, vagina, penis, anus, mouth, and oropharynx.45

One source indicated that in 2006, 87.8% of cancers from HPV were cervical cancers.46 so we believe that the estimate of the burden of cervical cancer captures the majority of the known direct harm from HPV.

Other impacts: There are other impacts of HPV which are not included in our calculation of the burden of HPV. These include:

• Respiratory papillomatosis47
• A possible association between lung cancer and HPV. It’s our impression that a causal link has not been established, and we are uncertain about the quality of the evidence for the connection.48
• Genital warts
• Common skin warts and rare skin conditions in immunocompromised individuals.49 However, it is our understanding that these result from strains of HPV that are not predominantly sexually transmitted.

Some research suggests that HPV vaccination may increase the risk of becoming infected with the strains that the vaccine does not protect against.50 We have not fully investigated this claim, and do not know how much it detracts from the public health benefit of HPV vaccines, if at all.

Overall burden: In summary-

• The GBD estimates the burden of cervical cancer at 6.9M DALYs
• The WHO estimates the burden of cervical cancer at 9.2M DALYs
• HPV can cause other cancers as well, but these cancers probably contribute a small proportion of the total burden.
• There is evidence of an associated between HPV infection and HIV transmission, but we are unsure about the strength and cause of this association.
• We have not included other health consequences of HPV, which we believe to be small in comparison.

#### 1.1.5 Syphilis

Syphilis is a bacterial infection caused by the bacterium Treponema pallidum.51 When left untreated, it can lead to sores, rashes, eye problems, neurological and heart problems, and death.52 It can be treated and the infection cured with antibiotics.53

Overall burden: In 2013 the GBD estimated that there were 136,848 deaths due to syphilis, of which 120,537 were in children five years of age or under,54 while the WHO GHO estimated that there were 78,910 deaths from syphilis in 2012, of which 67,489 were in children five years of age or under.55 The DALY burden from syphilis (including neonatal syphilis) was estimated by the GBD at 11.3M DALYs and the WHO GHO at 7.0M DALYs.56 Potential effects of syphilis on HIV transmission were not included in these assessments,57 but we do not know of other direct impacts of syphilis that may have been excluded (despite a brief search).

## 2. Who else is working on this?

We do not have a comprehensive understanding of which organizations fund research on STDs, as opposed to raising awareness, offering services, or advocating on behalf of individuals that suffer from STDs.58 However, it’s our understanding that philanthropic and nonprofit involvement in STD research is minimal. We are not aware of non-profit organizations specifically supporting HSV or syphilis research.

#### 2.1 How much funding is in this area?

Total

The total NIH funding for sexually transmitted diseases/herpes (not including funding for HIV/AIDS, any hepatitis virus, or HPV/cervical cancer vaccines) was approximately $250M in 2015.59 It was our impression of NIH STD funding that there is substantial funding for HPV vaccine trials, testing the effects of the HPV vaccine, and cervical cancer diagnostics. Even though HIV/AIDS had its own section, there seemed to be some funding allocated for HIV/AIDS research listed in the “sexually transmitted diseases/herpes” section, some funding for social science programs on sexual health and safety, and research on HSV and HSV vaccine candidates. We saw several funded projects on potential chlamydia and gonorrhea vaccine candidates.60 In addition, we identified approximately$1.4M in funding for STDs from private foundations in 2012.61

We searched Grantome.com, a database of scientific research grants, for information about grants that included the words “sexually transmitted,” and found that in 2013 there was $188M in funding reported that met these search criteria.62 We looked into the assets and funding from other sources, including smaller sources and those predominantly dedicated to STD advocacy, awareness-building, and service provision rather than research and development, but these numbers did not significantly affect our view of the crowdedness of this space.63 The funding for research and development for each of our STDs of interest is below. HSV • Grantome, 2013, approximate:$104.3M64
• NIH Project Reporter, 2015, approximate: $5.8-137.9M65 HPV • Grantome, 2013, approximate:$147.6M66
• NIH, Estimates for Funding of Varion Research, Condition, and Disease Categories, 2015: $31M67 • NIH Project Reporter, 2015, approximate:$35.2-204.3M68

Syphilis

• Grantome, 2013, approximate: $17.3M69 • NIH Project Reporter, 2015, approximate: :$2.2-22.9M70

## 3. Our process

We initially decided to investigate this area because we thought STD research might be impactful and neglected due to associated stigma. We focused on quickly determining this, without investigating potential interventions in this space. The specific steps we took to investigate importance and neglectedness are as follows.

For investigating importance, we:

• Looked at global DALY burden from each STD in the GBD 2013 and WHO GHO 2012 data.
• Attempted to independently derive DALY estimates, where possible, from lives lost.
• Briefly researched the diseases we focused on, their sequelae, and treatments. We did this by reading fact sheets and Wikipedia articles about the diseases in question, scanning for highly-cited recent articles in Google Scholar about them, and investigating further points that seemed important.
• Looked for relevant Cochrane Library articles on HPV, HSV, syphilis, and STDs in general.

For investigating neglectedness, we:

## 4. Questions for further investigation

Our investigation so far has focused almost exclusively on the burden of these diseases and how much attention they receive from funders of scientific research. If we were to do further research here, our primary focus would be on the tractability of potential research directions. Some questions we might aim to address include:

• What are the greatest barriers to STD diagnosis? Would improved diagnostics for STD infections lead to higher rates of treatment and cure?
• What are the greatest barriers to the development of new vaccines for STDs, including syphilis?
• Would it be practical to deliver a syphilis vaccine to the required population?
• How do HPV vaccines affect the prevalence and transmission of HPV strains against which they do not confer immunity? How is this likely to impact the future burden of HPV?
• To what extent do STDs increase HIV transmission? To what extent do STD treatments and vaccines reduce HIV transmission, if at all?
• What other research and development projects could potentially decrease the burden of STDs?

## 5. Sources

DOCUMENT SOURCE
990 Finder American Sexually Transmitted Diseases Association Form 990 2014 Source
990 Finder National Coalition of STD Directors Form 990 2013 Source
990 Finder The Foundation for Research into Sexually Transmitted Diseases Form 990 2013 Source
990 Finder: HPV and Anal Cancer Foundation Form 990 2013 Source
Baeten et al. 2008 Source
CDC Office of Financial Resources 2015 Annual Report Source
CDC: HPV Vaccine Information for Clinicians Source
CIA World Factbook Source
Clinuvel: Herpes Simplex Virus Source
Cochrane Library Source
Corey and Wald 2009 Source
Farazmand Woolley and Kinghorn 2011 Source
Farooq and Shukla 2012 Source
FDA News Release: Gardasil 9 Source
Foundation giving based on Foundation Center data Source
GBD 2013 DALYs from all causes Source
GBD 2013 deaths from syphilis Source
GBD 2013 International Classification of Diseases codes mapped to the Global Burden of Disease cause list Source
Genital Herpes – CDC Fact Sheet (Detailed) Source
GiveWell: DALY Source
Global Burden of Disease 2013: Mortality and Causes of Death Source
Global Burden of Disease Study 2013 (GBD 2013) Data Downloads – Full Results Source
Globocan Cervical Cancer Fact Sheet Source
Grantome.com Source
Grantome.com “herpes simplex” Source
Grantome.com “hpv” Source
Grantome.com “sexually transmitted” Source
Grantome.com “syphilis” Source
Guo et al. 2015 Source
Houlihan et al. 2012 Source
Human papillomavirus vaccines: WHO position paper, October 2014 Source
ICD 10 Data: Anogenital herpes Source
Johnston, Gottlieb, and Wald 2016 Source
Looker et al. 2015 Source
Looker Garnett and Schmid 2008 Source
Mayer and Venkatesh 2011 Source
Morris et al. 2008 Source
Mutua, M’Imunya, and Wiysonge 2012 Source
National Cancer Institute: HPV Vaccine Fact Sheet Source
Ng et al. 2011 Source
NIH 2015 STD/Herpes project listing Source
NIH Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC) Source
NIH Project Reporter Source
NIH Reporter- Herpes simplex funding, project titles only Source
NIH Reporter- Herpes simplex funding, project titles, terms, and abstracts Source
NIH Reporter- HPV funding, project titles only Source
NIH Reporter- HPV funding, project titles, terms, and abstracts Source
NIH Reporter- Syphilis funding, project titles only Source
NIH Reporter- Syphilis funding, project titles, terms, and abstracts Source
Parkin 2006 Source
Patel et al. 2013 Source
Prabhu Jayalekshmi and Pillai 2012 Source
Rositch et al. 2014 Source
Shrestha and Englund 2010 Source
STD.gov List of All STDs and Their Symptoms Source
Syphilis – CDC Fact Sheet (Detailed) Source
The HPV and Anal Cancer Foundation: Role and Impact Source
The STD Project’s List of All STDs Source
Wald and Corey 2007 Source
Wang and Ritterband: Herpes Simplex Keratitis Epidemiology Source
Ward and Rönn 2010 Source
WHO GHO DALYs by Cause Source
WHO GHO Data Source
WHO GHO Deaths by Cause Source
WHO: Global Burden of Disease Source
WHO STIs Fact Sheet Source
Wikipedia: Causes of sexually transmitted infections Source
Wikipedia: Herpes simplex Source
Wikipedia: Herpes simplex virus Source
Wikipedia: Human papillomavirus Source
Zuckerman et al. 2009 Source

## Cannabis Policy

This is a writeup of a shallow investigation, a brief look at an area that we use to decide how to prioritize further research.

## In a nutshell

#### What is the problem?

Our impression is that despite the spread of efforts to legalize recreational cannabis use, there is currently relatively little discussion of which legislation models are best for public health. We believe ineffective regulation may carry substantial public health costs.

#### What are possible interventions?

A philanthropist could fund research into different legalization models and their effects, or could support increased discussion between advocates of cannabis legalization and public health experts with experience in policy related to intoxicants.

#### Who else is working on it?

A number of foundations do some work on cannabis policy, often within the broader area of drug policy. We are not aware of any major funders who are focusing on designing cannabis policy with a view to protecting public health.

## 1. What is the problem?

Since 2012, four U.S. states have legalized recreational use and commercial production of cannabis.1 Broadly speaking, we consider it likely that the number of states where recreational cannabis consumption is legal will continue to increase. This view is based on conversations with drug policy experts,2 increased support for legalization in national polls,3 and our general impressions of the current political climate in the U.S.

As discussed below, we believe that different ways of legalizing cannabis use are likely to have widely varying public health implications. In this investigation, we focused on these potential public health effects; we did not thoroughly consider other potential effects of legalization, including (for example) effects on arrests or incarceration. We chose to focus on this aspect because we see the question of how to legalize in a public-health-friendly way as receiving significantly less attention than the question of whether or not to legalize. We see the former question as potentially very important if legalization efforts continue to succeed (which we find likely).

#### 1.1 Public health effects of commercial cannabis production

Our understanding is that the public health impacts of cannabis legalization are likely to depend on the specifics of how legalization is carried out. However, our impression is that relatively little is known about how different kinds of regulatory regimes are likely to affect public health.

We believe that it could be especially important for early-moving states to implement well-designed policy, as we consider it likely that later legalization models will be based on earlier ones (i.e. we expect the form that legalization takes overall to be relatively path dependent). Another consideration in favor of careful policy design early on is that it may be difficult to change existing policies once states have legalized cannabis, especially if, for example, a commercial marijuana industry were to emerge and become established.4

An example of how policy design might affect public health is the extent to which cannabis is allowed to be produced commercially. Legalization models that enable cannabis production to be fully commercialized may cause cannabis prices to drop considerably; we have heard estimates that prices under commercialization might be one tenth or less of current prices.5 Such a price change seems likely to lead to increased consumption of cannabis.

In general terms, we expect increased consumption of intoxicants (like cannabis) to have humanitarian costs both for individuals and for society. In addition, our impression is that cannabis specifically can cause harm in a number of known ways. In this investigation, we focused on cannabis dependence as the main relevant harm. Cannabis dependence is associated with a variety of negative effects, including low energy and motivation; relationship and family problems; financial difficulties; and sleep and memory problems.6

#### 1.2 Size of the problem

As part of our investigation, we estimated how much harm could potentially be averted by well-designed legislation. See footnote for more details of the calculation.7 In summary:

• We assumed that the main harms of sub-optimal legalization would be due to increased cannabis dependence, then used our best guesses of how harmful dependence is, and how much it might increase under full commercialization, to estimate what the difference between well- and badly-designed legislation might be.
• About 18 million people in the U.S. use cannabis at least once per month.
• About 7% of these, or 1.25 million people, meet criteria for what we would consider morally-relevant cannabis dependence (although other sources report 12% have “met criteria for cannabis dependence in the past year”).
• We use an estimated disability weight for cannabis dependence of 0.05 (note that this is lower than the Global Burden of Disease study’s disability weight for cannabis dependence, which is 0.329).
• The estimates we’ve seen suggest that if legalization were accompanied by full commercialization (and therefore much lower prices), cannabis consumption would roughly double.
• We assumed that a doubling in consumption would correspond to a doubling in dependent users.

Combining these figures with a cost of $50,000 per disability adjusted life year (DALY), the cost of full commercialization comes out at roughly$3 billion, although we have very limited confidence in this estimate. This is relatively low compared to our rough estimates of the importance of other cause areas within U.S. policy.

## 2. What are possible interventions?

We have focused our attention on ways to help cannabis legalization go as well as possible in jurisdictions where it does take place (rather than focusing on affecting the likelihood of legalization itself, which we see as drawing more attention from funders).

Different legalization models could vary along many dimensions, including the following:8

• What type of organizations are allowed to provide cannabis?
• What regulations apply to these organizations?
• What types of products can be sold?
• How much will the products cost?

A funder in this space might consider supporting:

• Research into different legalization models and their effects, e.g. analyzing previous instances of legalization, forecasting the effects of new proposals, or developing new legislative approaches.
• Increased communication between cannabis legalization advocates and public health experts, e.g. holding meetings to discuss different approaches to legalization.

Work of this kind could affect cannabis policy in the short term (e.g. by affecting the language of a specific ballot initiative) or the longer term (e.g. by promoting effective models of regulation which can be adopted more widely in the future, or more generally shifting the discourse around cannabis policy).

## 3. Who else is working on this?

We do not have a comprehensive picture of which organizations actively support the careful design of cannabis-related policy, as opposed to supporting drug policy reform or cannabis legalization efforts in general. Our impression is that not many groups focus on this aspect of cannabis reform.

The Open Society Foundations (OSF) funds some work on cannabis policy as part of its broader program of domestic drug policy reform but our understanding is that this is not a focus area for OSF.9 A number of other funders, including the Drug Policy Alliance, the Riverstyx Foundation, and the Libra Foundation, fund advocacy around improving drug policy more broadly, but do not focus on cannabis policy specifically as far as we know.10

## 4. Questions for further investigation

If we were to do further research here, questions we might aim to address include:

• How responsive will legalization advocates be to proposed measures to protect public health?
• What policy designs can best capture the benefits of cannabis legalization while preventing large declines in prices and attendant increases in dependence?
• How does legalizing cannabis affect alcohol consumption patterns and their associated social costs?

## 5. Our process

We have been interested in this area for several years. We have had many conversations with experts on the topics of criminal justice reform and drug policy reform, some of which have also included discussion of cannabis legalization. Public notes are available from several of these conversations:

This area is also a personal interest of Cari Tuna and Dustin Moskovitz, co-founders of the foundation Good Ventures, who have made several personal gifts to support cannabis legalization efforts. Cari and Dustin are members of the Open Philanthropy Project Board of Managers.

The Open Philanthropy Project has made grants to support the following:

We are not currently planning further grants in this area in the near future, but may revisit the issue once we have a clearer sense of whether these grants have been successful.

## 6. Sources

DOCUMENT SOURCE
Budney et al. 2007 Source
Burns et al. 2013 Source
Caulkins 2013 Source
Caulkins 2014a Source
Caulkins 2014b Source
Caulkins et al. 2012 Source
Caulkins et al. 2015 Source
GiveWell’s non-verbatim summary of a conversation with Open Society Foundations, November 19, 2012 Source
Global Burden of Disease Study 2010 Source
Mackin, Martin and McGavin 2007 Source
NIDA – Cocaine, Scope of Use Source
NIDA – DrugFacts, Treatment Statistics Source
NIDA – Marijuana, Is Marijuana Addictive Source
Office of National Drug Control Policy, State Laws Related to Marijuana Source
Our non-verbatim summary of a conversation with Andy Ko, November 20, 2013 Source
Our non-verbatim summary of a conversation with Open Society Foundations, November 19, 2012 Source
Our non-verbatim summary of conversations with Gara LaMarche on May 22, May 31, and June 14, 2013 Source
Our non-verbatim summary of conversations with Mark Schmitt on May 22 and June 14, 2013 Source
Pew Research Center 2015 Source
SAMHSA 2014 Source

## Federal Tax Reform

Note: this is a shallow overview of a topic that we have not previously examined. For shallow overviews, we typically work for a fixed amount of time, rather than continuing until we answer all possible questions to the best of our abilities. Accordingly, this is not researched and vetted to the same level as our standard recommendations. If you have additional information on this cause that you feel we should consider, please feel free to get in touch. We use our shallow overviews to help determine how to prioritize further research.

## In a nutshell

#### What is the problem?

The federal tax system in the U.S. is inefficient, overly complicated, unlikely to be able to cover rising federal expenditures in the long run, and may constrain economic growth.

#### What are possible interventions?

Fundamental income tax reforms, including shifting the tax base to consumption or broadening the income tax base by eliminating many tax expenditures, may increase rates of economic growth and help address long-run fiscal issues. Smaller adjustments to federal tax policy may also have substantial benefits. These reforms face several political obstacles, and we do not have a strong sense of how additional funding would be able to create policy change.

#### Who else is working on it?

Federal tax reform efforts attract significant attention from many think tanks and foundations, including the Tax Policy Center and the Peter G. Peterson Foundation, amongst others.

## 1. What is the problem?

Federal taxes in the U.S. are widely believed to be inefficient and overly complicated.1 Even taxpayers with simple tax situations spend considerable time and money filing income tax returns.2 Other individuals and businesses navigate a complex system of around 200 potentially applicable tax expenditures (e.g. deductions, exemptions, and credits).3 The system of tax expenditures makes federal taxes less progressive, narrows the overall base of taxable income, and reduces federal revenue, which may not be sustainable in the long run.4 Many specific tax expenditures reduce federal revenue without achieving any policy goals.5 More fundamentally, many scholars have argued that taxing income (rather than consumption) discourages savings and investment, which may negatively impact economic growth.6

## 2. What policy changes could be helpful?

We consider shifting the tax base from income to consumption or broadening the base of taxable income by eliminating many tax expenditures to be fundamental reforms of the federal tax system.7 We have seen arguments for the benefits of fundamental federal tax reforms:

• Consumption taxes, including value-added taxes (VATs), the “X tax,” and the personal expenditure tax (PET), are simpler and create greater incentives for savings and investment than income taxes, though there seems to be disagreement about the magnitude of the gains from switching from an income to a consumption tax base.8
• VATs require businesses to pay taxes on the difference between their sales and their purchases of inputs (i.e. the business is taxed on the value it adds to products or services). Each business that adds value to a product or service is taxed, which leads to increased retail prices for consumers.9 VATs are well-studied since they have been implemented in 160 countries, and have been discussed as a supplement to or partial replacement of U.S. income taxes.10 Since low-income households spend a greater proportion of their income than wealthy households, VATs are regressive unless they are offset by another program.11
• The X tax is a VAT modified to be more progressive. Businesses pay taxes on value added, but are able to exempt wages from their tax liability. Workers are also taxed at a progressive rate on their wages.12 The X tax is usually discussed as a replacement, rather than just a supplement, for the federal income tax system.13
• The PET is another alternative intended to replace the income tax system. Households are progressively taxed on their total annual expenses, but businesses are not directly taxed.14
• Base-broadening, rate-reducing tax reform would eliminate many tax expenditures while still using income as the tax base. Eliminating tax expenditures increases the overall proportion of income taxed, allowing for (some combination of) lower tax rates and higher federal revenues.15 Lower income tax rates may also incentivize savings and investment.16

Fundamental tax reform that caused greater rates of savings and investment could in turn lead to greater rates of economic growth.17 A dynamic simulation model by Altig et al. 2001 finds that replacing the federal income tax with a progressive consumption tax could increase rates of economic growth and add hundreds of billions of additional dollars each year to the national income while maintaining current progressivity.18 Other fundamental reforms modeled by Altig et al. 2001 would also increase growth rates, but would be quite regressive.19 However, we interpret these growth rate estimates with caution since the models that yield these results rely on relatively strong assumptions about the effects of tax incentives on saving and investment behavior, which may not turn out to be realistic.20 More generally, economists seem to disagree considerably about the magnitude of economic gains that tax reforms might yield.21

We have also seen arguments for the benefits of non-fundamental federal tax reforms:

• Simplifying tax filing: For most taxpayers, the IRS already has all the information it needs for tax filing.22 A “Simple Return” program, for which the IRS pre-files taxes for individuals with uncomplicated tax situations, could save individuals significant amounts of time and money. Goolsbee 2006 estimates that IRS pre-filing could collectively save up to 225 million hours of time and $2 billion a year paid in tax preparation fees.23 • Eliminating specific tax expenditures: Instead of focusing on the tax expenditure system as a whole (which also includes many social programs), reform efforts could target particularly inefficient or ineffective tax expenditures.24 The mortgage interest tax deduction, for example, may not actually promote home ownership as intended.25 • Limits on the use of tax expenditures: Reforms might also raise federal revenues by regulating the use of tax expenditures in upper tax brackets, or by placing a cap on the total permissible value of tax expenditures as relative to income.26 Carbon taxes and land value taxes are also mentioned in discussions of optimal tax policy, but we have not investigated them thoroughly for this overview.27 ## 3. Prospects for reform Federal tax reform faces several political obstacles: • Our impression is that politicians are reluctant to support fundamental tax reform. Although some tax reforms could create widely-distributed long-term benefits, groups that would suffer losses would likely oppose the reforms,28 and the potential for widely-distributed benefits may be illusory.29 • Any fundamental reforms are likely to alienate powerful stakeholders on either the left or the right. The addition of VATs to the income tax system is often opposed both by those who want to limit government spending and those who are worried about the tax’s regressiveness.30 Similarly, an X tax may have difficulty gaining political support both because it would appear that wealthy citizens who primarily make their income from investments rather than wages would only be lightly taxed and because it would actually impose large one-time losses on those existing wealth-holders.31 A PET may also have difficulty gaining public support because no taxes are levied on businesses, and because individuals would be taxed on borrowed money.32 • Anti-tax groups have expressed opposition to reforms simplifying tax filing.33 On the other hand, projected increases in federal spending are expected to eventually require some type of revenue-increasing tax reform.34 In the near future, reforms that place a cap or limit on the use of tax expenditures seem more politically feasible than eliminating tax expenditures.35 All things considered, we’re pessimistic about the prospects of any fundamental federal tax reforms in the near future.36 Some of the smaller reforms discussed above may be considerably more tractable.37 ## 4. Who already works on this? Federal tax reform efforts attract significant attention from a wide variety of players, and we have not attempted to develop a full sense of the landscape. Much of our assessment above has been informed by work from the Tax Policy Center, a joint venture of the Urban Institute and the Brookings Institution, which is a leading voice in tax policy discussions.38 Several major foundations, including the Bill and Melinda Gates Foundation, the John D. and Catherine T. MacArthur Foundation, the Ford Foundation, and the Rockefeller Foundation, support the Tax Policy Center.39 Our understanding is that many foundations tend to support tax reforms relevant to social programs, but not fundamental tax reform.40 A potential exception would be the Peter G. Peterson Foundation, which disbursed around$8.6 million in grants in the fiscal year 2013-2014, and is devoted to addressing long-term challenges to the federal budget.41 Amongst other things, it has promoted reducing the number of tax expenditures and simplifying the federal tax system as a response to projected long-term budget deficits.42

Many other advocacy and interest groups participate in tax policy discussions.

## 5. What could a new funder support?

Funders interested in this area could support a variety of research and advocacy activities aimed at promoting reforms.43

We briefly explored the possibility that technical capacity to translate high-level reforms into detailed technical proposals or legislative text was a gap in the field, but the experts we talked to did not think this was the case.44 We have not otherwise investigated the expected impact of additional funding for different avenues of support.

## 6. Questions for further investigation

Our research in this area has been relatively limited, and many important questions remain unanswered by our investigation.

Further research on this cause might address:

• How likely would further funding for fundamental tax reform research and advocacy be to accelerate reforms?
• How likely is it for advocacy efforts in favor of simplifying tax filing or other non-fundamental reforms to overcome political opposition? Are there fairly tractable short-term opportunities to advance such reforms?
• To what degree do the efficiency-improving justifications for fundamental tax reform apply to more modest reform efforts (e.g. reforming the mortgage interest deduction)?
• What are the distributional consequences of various tax reform proposals?

## 7. Our process

We decided to investigate this area due to our strong impression that the complexity of the U.S. tax code creates significant compliance costs, and due to our weak impression that alternative tax systems could positively impact economic growth.

Our investigation consisted of conversations with tax policy experts and some limited desk research. Public notes are available from our conversations with:

• Alan D. Viard,45 Resident Scholar, American Enterprise Institute
• Bill Gale,46 Senior Fellow, Economic Studies Program, Brookings Institution; Co-Director, Urban-Brookings Tax Policy Center
• Daniel Shaviro,47 Wayne Perry Professor of Taxation, New York University School of Law
• David Kamin,48 Assistant Professor of Law, New York University
• Richard England,49 Visiting Fellow, Lincoln Institute of Land Policy; Professor of Economics and Natural Resources, University of New Hampshire

## 8. Sources

DOCUMENT SOURCE
Altig et al. 2001 Source
Barro 2015 Source
Brown and Gale 2012 Source
Burman 2011 Source
Burman 2014 Source
Goolsbee 2006 Source
Matthews 2012 Source
Nguyen et al. 2012 Source
Our non-verbatim summary of a conversation with Alan D. Viard on March 25, 2014 Source
Our non-verbatim summary of a conversation with Bill Gale on March 28, 2014 Source
Our non-verbatim summary of a conversation with Daniel Shaviro on July 17, 2014 Source
Our non-verbatim summary of a conversation with David Kamin on August 1, 2014 Source
Our non-verbatim summary of a conversation with Richard England on March 27, 2014 Source
Peterson Foundation 990 2013-2014 Source
Peterson Foundation Revenues and Taxes 2010 Source
Tax Policy Center Funders 2015 Source
World Bank GNI 2015 Source

## Alcohol Taxation

This is a writeup of a shallow investigation, a brief look at an area that we use to decide how to prioritize further research.

## In a nutshell

#### What is the problem?

The Centers for Disease Control and Prevention reports that excessive drinking causes tens of thousands of deaths and costs society hundreds of billions of dollars every year in the United States.

#### What are possible interventions?

We focus on alcohol excise taxes in this investigation. The evidence suggests that alcohol consumption is sensitive to price changes, and so alcohol excise taxes are likely to decrease consumption and related social costs. In general, the value of taxes on alcohol has eroded in the past few decades. However, some state-wide campaigns to raise alcohol taxes have been successful in recent years. A funder could support a variety of research or advocacy efforts at the state or federal level to encourage alcohol tax increases.

#### Who else is working on it?

A number of organizations support work related to alcohol abuse prevention and treatment, but our understanding is that few focus on alcohol tax policy, and we are not aware of any major active funders in the area. Some research is being conducted by the US government and other institutions.

## 1. What is the problem?

Excessive drinking has been linked to significant costs to society, including increased liver disease, reckless driving, lost productivity, unsafe sex and STIs, and violent crime.1 Although the exact social cost is uncertain, the Centers for Disease Control and Prevention (CDC) reports that alcohol causes around 88,000 deaths (10% of all deaths among working-age adults) and costs the economy around $224 billion per year in the US.2 Binge drinking (defined as having four or more drinks in one session for women, and five or more for men) is by far the most common and socially harmful form of excessive alcohol consumption in the US.3 However, only a small fraction of binge-drinkers would be classified as “alcohol dependent.”4 Interventions that target binge-drinkers, not just people who suffer from alcohol dependence, may help substantially reduce social harms from excessive drinking. ## 2. What are possible interventions? We began investigating alcohol tax policy after hearing from Mark Kleiman and Phil Cook that they found the research on the impact of alcohol taxes promising.5 In particular, Kleiman claimed that increasing alcohol taxes is likely one of the most effective ways to reduce crime.6 We have focused primarily on alcohol tax policy, which we see as having several advantages as an approach to reducing excessive drinking: • We start with an assumption that raising prices will reduce consumption. • The taxes would be relatively easy to implement and enforce, and governments are incentivized to enforce the law in order to collect revenue. 7 • There has been extensive research on the effects of alcohol excise taxes on harms from alcohol, which we discuss below. We are aware of other potential interventions, but have not investigated them. These include: • Supporting the implementation of social host ordinances. These ordinances render adults criminally and/or financially liable for underage drinking on their property.8 • Further restricting when and where individuals are able to purchase alcohol.9 • Imposing marketing restrictions on alcohol companies, especially for marketing aimed at young people.10 • Increasing the price of alcohol by restricting “happy hours” and other discounts.11 • “Swift and certain” sanctions (mild but almost immediate punishment for alcohol abuse) for people on probation for alcohol-related crimes.12 • Stricter enforcement of current laws and regulations, such as the minimum drinking age and driving under the influence laws.13 • Supporting litigation campaigns against alcohol companies.14 #### 2.1 Alcohol Taxation The tax rate of alcohol in inflation-adjusted terms has decayed significantly in recent years.15 Federal alcohol taxes have not been raised since 1991, and many states have kept alcohol taxes level for decades.16 The experts we spoke with suggested that increasing alcohol taxes can reduce consumption and bring alcohol’s private costs more in line with its social costs.17 Heavy drinkers would bear most of the cost of the tax, and contribute most to raising revenue.18 The Open Philanthropy Project commissioned David Roodman to conduct a replication review of the existing literature to assess the evidence about the likely humanitarian impacts of raising alcohol taxes. He summarizes the large existing literature and estimates that a 10% increase in the price of alcohol would lead to roughly a 5% reduction in the amount of alcohol consumed.19 The best evidence also seems to indicate that higher alcohol prices cause a substantial decrease in alcohol-caused death (particularly due to cirrhosis).20 We have less information about possible tax-induced reductions in violence and traffic deaths.21 Overall, Roodman’s review estimates that a 10% tax-induced price hike in the US would reduce the number of alcohol-caused deaths by 9-25%, which would amount to 2,000-6,000 fewer deaths per year.22 Using the more expansive CDC definition of alcohol-caused deaths and assuming that alcohol tax increases would have the same proportional effect on them, a 10% price increase would lead to 8,000-22,000 fewer deaths per year in the U.S.23 However, our impression is that a 10% increase in prices is significantly larger than recent state alcohol tax increases, which have raised prices by more like 3%.24 #### 2.2 What has the track record of past advocacy efforts been? David Jernigan reports that reform advocates attempt to increase alcohol taxes in 20-30 states per year, of which the vast majority fail.25 At least two states (Illinois and Maryland) have recently raised alcohol taxes, and the Maryland increase included a public health (not just a revenue-raising) rationale; it combined a public health message with a coalition of 1,200 groups and won a sales tax increase of three percent, or roughly five cents per drink, which amounted to a$75 million annual increase in state revenues.26 We do not know how feasible it would be to replicate the Maryland tax increase in other states.

A consideration in favor of state (rather than federal) campaigns is the possibility that the success of several campaigns could create enough momentum to prompt changes in other states or at the federal level. A similar process occurred after several states first altered their tobacco tax policies in response to an increased understanding of the dangers of smoking.27

## 3. Who else is working on this?

Our understanding is that alcohol policy research and advocacy has experienced a decline in private funding and there is little support for alcohol policy reform from large foundations today.28

A number of organizations, such as Mothers Against Drunk Driving, work on alcohol policy.29 These organizations represent a strong alcohol abuse prevention and treatment community. However, our impression is that most concentrate their efforts on scientific research, alcohol addiction, abuse treatment, and decreasing drunk driving, rather than optimal alcohol tax policy.30

We are aware of only a couple small exceptions:

• The Center on Alcohol Marketing and Youth (CAMY) offers research and advocacy training relating to alcohol tax policy increases.31
• The CDC funds a few million dollars’ worth of research and advocacy on alcohol policy each year, including supporting CAMY’s work on alcohol tax policy.32

## 4. Questions for further investigation

Our investigation in this area has been limited, and many important questions remain unanswered by our investigation.

Amongst other topics, our further research on this cause area might address:

• How would additional funding translate into additional advocacy efforts and to what extent is funding the bottleneck to advocacy success on alcohol tax issues?
• How should we think about the “momentum” dynamics at the state and federal level?33
• What are the possible negative social and economic consequences of alcohol tax increases?
• What other interventions might cost-effectively reduce the harms from alcohol?
• Do people displace alcohol consumption with the consumption of other drugs when alcohol taxes rise?

## 5. Our process

We initially decided to investigate this issue because Mark Kleiman, one of our criminal justice reform grantees, told us that excessive alcohol consumption was the most important public policy issue he knew of with no major advocate.34 While Kleiman was primarily focused on the impact of alcohol on crime, the bulk of our research has been on the public health aspects of alcohol consumption.

We’ve spoken to roughly half a dozen individuals in our exploration of this issue to date. Public notes are available from our conversations with:

We also commissioned David Roodman to conduct a replication review for the Open Philanthropy Project on the impacts of alcohol taxes on consumption and health outcomes.

## 6. Sources

DOCUMENT SOURCE
Roodman 2015 Source
Our non-verbatim summary of a conversation with David Jernigan, August 6, 2014 Source
Our non-verbatim summary of a conversation with James Mosher, August 12, 2014 Source
Our non-verbatim summary of a conversation with Mark Kleiman, July 2, 2013 Source
Our non-verbatim summary of a conversation with Phil Cook, July 29, 2014 Source
Our non-verbatim summary of a conversation with the CDC’s Alcohol Program, September 5, 2014 Source
Stahre et al. 2014 Source

## Animal Product Alternatives

This is a writeup of a medium investigation, a brief look at an area that we use to decide how to prioritize further research.

## In a nutshell

• What is the problem? More than eight billion land animals are raised for human consumption each year in factory farms in the U.S. alone. These animals are typically raised under conditions that are painful, stressful, and unsanitary. Chickens account for a large share of the animals affected. Currently, there are no alternatives to meat, dairy, or eggs that have succeeded in displacing a large fraction of the market for animal-based foods.
• What are possible interventions? Successfully developing animal-free foods that are taste- and cost-competitive with animal-based foods might prevent much of this suffering. A for-profit investor could invest in companies developing plant-based alternatives to animal-based foods (such as Hampton Creek and Beyond Meat); cultured egg and dairy products (such as Clara Foods and Muufri); plant-based foods that use bioengineering to mimic the taste and texture of meat (such as Impossible Foods); or cultured meat products (such as Modern Meadow, though Modern Meadow is developing a novel, ‘meat-based’ product that is not a direct substitute for traditional meat). A philanthropic funder could support academic work aimed at developing cultured ground meat or meat with a more complex structure (such as steak or chicken breasts) in hopes of bringing the products closer to development and making them more attractive to profit-motivated investors. Our impression is that developing cultured egg whites will be substantially easier than developing ground meat, which (in turn) will be substantially easier than developing meat with complex structure (such as steak or chicken breasts). Based on cost analyses, comparisons with tissue engineering and biofuels, and discussion with scientists who have experience with cell cultures and tissue engineering, we currently see developing cost-competitive cultured muscle tissue products as extremely challenging, and we have been unable to find any concrete paths forward that seem likely to achieve that goal. We have not closely investigated the challenges associated with creating plant-based alternatives to animal products.
• Who else is working on this? There are well-funded companies developing plant-based alternatives to animal-based foods. The largest potential gaps in this field seem to be for cultured meat and cultured eggs. There are no companies developing cultured meat as a replacement for animal-based foods (though Modern Meadow makes cultured leather and “steak chips”); this problem receives little attention from governments and philanthropy (we estimate < $6M in funding in the last 15 years), and much of the work is unlikely to be done by people in neighboring fields (such as tissue engineering). Because we do not see a concrete path that could lead to commercially viable cultured meat in the short term, we would guess that cultured meat is also a poor fit for profit-motivated investors. We are aware of only one company developing cultured egg whites (Clara Foods), and it has received approximately$1.7 million in funding.

## 1. What is the problem?

See our overview of factory farming for more detail.

## 2. What are possible interventions?

#### 2.1 Overview and general issues

It seems to us that if there were plant-based or cultured alternatives to meat and eggs that were cost- and taste-competitive with animal-based foods, it could greatly reduce the amount of meat and eggs produced, and thereby greatly reduce pain and suffering of animals produced for food.

There are a variety of possible routes to developing high-quality alternatives to animal-based foods, including:

• Plant-based alternatives that simulate the taste and function of animal-based ingredients. For example, Hampton Creek and Beyond Meat are companies working in this space (see below).
• Fermentation (yeast-based production) of ingredients originally from animals using synthetic biology. For example, Clara Foods puts the genes coding for egg white proteins in chickens into yeast so that the yeast can produce the same proteins in fermentation processes.1 Muufri is taking a similar approach for milk.2
• Various types of engineered muscle tissue (aka “cultured meat”). This approach involves growing muscle cells from animals in cell cultures, and forming the cells into tissues that can be eaten. Different versions of this approach include:
• Millimeter-scale muscle strands grown in the lab, (hereafter “ground meat”) which are similar to muscle from an animal and might be used to replace ground meat. For example, Professor Mark Post is working on developing cheap animal-free cell culture media3 (i.e., liquids that provide the chemical environment and nutrients for animal cells to grow in the lab), incorporating separately-grown fat tissue into the ground meat product to improve the product’s taste,4 and working on overall manufacturing scale-up.5
• Large whole pieces of cultured muscle tissue (hereafter “slab meat” in contrast with ground meat). For example, Amit Gefen, funded by Modern Agricultural Foundation, is exploring the feasibility of making a whole piece of chicken meat, such as a chicken breast.6 We have not investigated what technical strategies they are considering.
• Novel meat-based products that would not directly substitute for conventional meat, such as Modern Meadow’s “steak chips.”7

Our investigation focused on cultured meat and yeast-based production of egg whites, rather than other possibilities listed above, because:

• There are a number of well-funded companies pursuing plant-based alternatives (see ‘Private companies’ under ‘Who else is working on this’?).
• There are many more chickens producing eggs than there are cows producing milk,8 so we guessed that the “fermentation” work focusing on eggs would be more promising than the “fermentation” work focusing on milk.

Within our investigation of cultured meat, we focused primarily on ground beef (rather than slab meat or ground chicken or pork) because:

• Work on cultured ground beef seems to be more developed than work on cultured ground chicken or pork.9
• The market for ground beef is much larger than the market for ground pork or chicken (more on this below).
• Our understanding is that progress toward cultured ground beef would be relatively transferable to cultured meat from other animals. Mark Post suggested that work on ground meat is highly transferable between species, noting that he was able to transfer from mice to pork and from pork to beef in his lab in roughly six months in each case.10 Other researchers also reported that the same (or a similar) protocol for culturing muscle cells has worked for multiple species, including mice, rats, and chickens.11
• Apart from an ongoing feasibility study by Amit Gefen (see above), we are not aware of anyone trying to make cultured slab meat. Moreover, we would guess that progress on ground meat would also help with developing slab meat because some of the challenges are shared (e.g., finding a low-cost, animal-free media to feed the cell culture).

We found limited evidence on the question of whether the public would buy cultured animal products and did not pursue the issue further.

#### 2.2.1 Potential impact of taste- and cost-competitive cultured meat

In 2014, ground beef accounted for 43.3% of total beef sales,12 but for other animals, ground meat accounted for a much smaller portion of the total meat market. For example:

• Chicken breasts made up 56% of the market for chicken in the U.S. in 2014, and ground chicken only claimed 1% of the market.13
• Ground lamb was only 6.2% of the market for lamb in 2014.14
• Ground pork was only 1.9% of the market for pork in 2014.15

We would therefore guess that the market for a cultured ground beef product would be much larger than the market for a cultured ground chicken/pork product.

It is possible that displacing a large fraction of the markets for these other types of meat (such as chicken) would require developing cultured slab meat. If so, that would make the value of successfully developing cultured slab meat much greater than the value of successfully developing cultured ground meat because a very large fraction of all land-based farm animals are chickens.16

#### 2.2.2 What is the state of the art for making cultured meat?

Our understanding is that Mark Post’s cultured beef hamburger represents the state of the art for cultured meat.17 The main steps in his process are as follows:18

1. Extraction of satellite cells, which are skeletal muscle stem cells, from a muscle sample of an animal taken using a needle biopsy.19
2. Proliferation phase to grow large numbers of cells from an initial batch by encouraging the cells to divide, producing copies of themselves.20
3. Differentiation of the muscle precursor cells into mature muscle cells. Growing or “conditioning” the cells in the right mechanical environments (attached to scaffold) that allow them to “get exercise” by contracting against structures that offer resistance. The muscle cell contraction boosts protein production in the cells and increases their size.21
4. Harvesting the muscle strands and combining them with color, flavor and texture enhancers, such as separately grown fat tissue.22

As discussed above, our understanding is that the process for making cultured ground meat from other species is/would be similar.

The process for making the “steak chips” that Modern Meadow is pursuing similarly begins with harvesting and growing muscle cells, however the final steps to process the product are different. The first step is a biopsy to harvest muscle cells from a cow and then create large quantities from that sample by growing them in the lab and allowing them to divide and produce more cells like themselves. After growing the cells, the next step is to harvest them by separating the cells from the liquid they are grown in (cell culture media). The final step is to combine the cells with pectin and flavorings (e.g., teriyaki or BBQ) and use a food dehydrator to make them into chips.23 We would guess that the technical challenges involved with making the steak chips are probably simpler than the challenges involved with making ground meat because making ground meat still involves making small chunks of tissue, whereas steak chips could conceivably be made without establishing much (if any) tissue structure. However the manufacturing scale-up challenges associated with cost-effectively producing a large number of cells still remain.24

Methods for making slab meat are currently unknown.25 Here it would seem important not only to have a process for growing and flavoring cells, but also to have a way of generating the (potentially complex) three-dimensional structure associated with non-ground meat.

In 2013 it was reported to have cost Mark Post $325,000 to make a single hamburger with cultured ground beef in a university research lab.26 We do not have a detailed understanding of the costs for Mark Post’s prototype. However, major sources of cost for large-scale manufacturing in tissue engineering include the cost of cell culture media, facilities, maintaining sterile conditions in the facilities, and skilled labor.27 Obstacles to decreasing costs include lack of knowledge of how to make cheap animal-free media (researchers don’t know what ingredients would work), how to cheaply and efficiently grow muscle cells on scaffolding, and how to harvest and process this cultured tissue at massive scales. Researchers also don’t know how to grow cells quickly in culture – academic scientists have estimated one month to grow one batch of meat in a bioreactor.28 Longer production times increase the cost of production and increase the risk that any given batch is contaminated.29 In order to decrease the cost, a funder could support lab work aimed at: • Cheap animal-free media that supports muscle cell growth. Cell culture medium is the liquid that provides the chemical environment and nutrients needed for animal cells to grow in the lab – it is the liquid surrounding the cells in the Petri dish. Standard cell culture media for muscle cells contains fetal bovine serum (extracted from the blood of cow fetuses), which is not suitable for cultured meat production focused on reducing animal agriculture because it is likely that one or more cow fetuses would be required to make 1 kg of meat.30 Currently there are commercial animal-free media formulations that do not contain fetal bovine serum, but we’ve been told these are expensive and may not encourage high growth rates of muscle cells because current animal-free media formulations have not been optimized for cultured meat production. Hence, finding a cheap animal-free liquid medium to grow the cells in is essential to making cultured meat commercially viable.31 Developing a cheap animal-free medium would likely involve guided trial and error of many combinations of potential ingredients that could support good muscle cell differentiation and growth.32 • Established cell lines. When doing research experiments to improve cultured meat development, a researcher must have animal cells to work with. If each researcher uses cells harvested from a different animal, it may be difficult to get reproducible and comparable results across multiple labs, slowing progress in the field because it is harder for separate researchers to build on each other’s work. An “established cell line” is a standard lineage of cells that are capable of proliferating indefinitely (whereas normal mammalian cells can only divide a limited number of times).33 While established stem cell lines exist for humans and mice, they do not exist for agricultural animals such as cows and chickens. Nicholas Genovese is currently working on this. Established cell lines may also be used to form the starting material for manufacturing-level production, reducing the need to continually harvest from animals.34 • Efficient scaffolding designs for ground meat. To develop tissue structure and protein production similar to that of muscles in an animal, muscle cells grown in the lab need to grow on structures (aka “scaffolds”) that mimic the mechanical environment they would experience in an animal. Currently there are at least two main approaches for scaffolding for ground meat or processed meat products: growing tissue in thin sheets (e.g., Modern Meadow) or growing cells and tissues on scaffolds (e.g., velcro) in lab-scale dishes and bioreactors (e.g., Mark Post).35 We do not have a detailed understanding of the imperfections of current approaches to scaffolding, but a number of people we spoke with suggested that improved scaffolding could reduce the costs of producing cultured meat,36 and some people working in the stem cell industry have reported that optimizing scaffolding design made their process substantially more efficient (although we have not closely examined this claim).37 Developing improved scaffolding might involve varying the shapes and sizes of scaffolds and/or the scaffolding materials used, and testing which most improve cell culture growth rates (without introducing other issues). • Developing efficient methods of harvesting and assembling a large number of muscle cells from the scaffold/bioreactor into the final meat product; e.g., perhaps design scaffolding that dissolves or is edible and can be incorporated into part of the product. We are not aware of any existing process for this and have a limited understanding of what challenges might be involved. • Methods to maintain sterility at lower cost. Preventing or minimizing microbial contamination is important because other organisms like bacteria grow faster than mammalian cells and could quickly consume a bioreactor, ruining an expensive batch of muscle cells. Maintaining sterile manufacturing conditions is expensive because expensive fans and filters are needed to keep contaminants out.38 The current tissue engineering industry is already able to create sterile conditions, however maintaining sterility contributes significantly to the high cost of production.39 We have a limited understanding of potential methods for reducing these costs. • Optimization of bioreactor operating conditions. Cells are grown in vessels called “bioreactors,” which control temperature, replenishment, and circulation of the cell culture media, oxygenation, and other conditions that promote cell growth. According to Mark Post, cultured meat has only been grown in small bioreactors (~5L) so far, but will need to be grown in much larger bioreactors if production will be scaled up (~25,000L). Bioreactors will need to be optimized for this larger scale of production.40 Industrial scale-up is a non-trivial engineering challenge requiring significant resources, because the systems are expensive to build and test. However, the biotech and tissue engineering industry are currently working on bioreactor designs and scale-up that may be relatively transferrable to cultured meat production. Our understanding is that scaling-up is one of the most common modes of failure in industries such as synthetic biology which also involve large scale bioreactors.41 Our understanding is that this work would involve designing new bioreactors and testing them for improvements in metrics like cell growth rates and contamination rates.42 #### 2.2.4 Issues associated with taste and consumer acceptance People who tasted Mark Post’s burger said it tasted “close to meat,” but that it was “not that juicy,” had a somewhat unusual texture, and that the lack of fat was noticeable.43 In addition, cultured meat is currently missing some cell types and chemicals found in conventional meat, including blood and connective tissue.44 We would guess that it may be necessary to find the appropriate ratios and arrangements of these ingredients in order to replicate the texture and flavor of natural meat. Potential paths to improving the taste and texture of cultured meat include: • Trying different scaffold designs and media formulations, and testing the taste and texture of the results. • Culturing fat cells and experimenting with incorporating them into the meat. Mark Post is currently working to improve the quality of the cultured meat by adding fat into the burger.45 • Adding flavor enhancers, an approach which is likely already widespread in both ground and whole slab conventional meat production as evidenced by the USDA regulations on labeling of flavor enhancers in meat and poultry.46 Other approaches (which we have considered less and may be more speculative and challenging) include:47 • Experimenting with different ratios and arrangements of connective tissue (e.g., fat, collagen), muscle cells, and blood. #### 2.2.5 Possible approaches that are not, to our knowledge, being pursued within cultured meat research We are not aware of anyone pursuing the following approaches to cultured meat: • Hybrid plant-based and animal-cell-based approaches: These approaches would involve mixing plant-based and animal-cell-based food, and could potentially offer both better flavor/texture than pure plant-based approaches and lower cost than pure animal-based approaches. Plant-based approaches (e.g., Hampton Creek for egg products) are typically significantly cheaper than animal-based food products; however, the challenge has been in producing a plant-based product that tastes like it came from an animal.48 Developers could explore the minimum amount of animal-based product needed to provide a realistic meat-like flavor and texture, when combined with plant-based ingredients. • GMO approaches for cultured meat. Mark Post and Modern Meadow are not pursuing genetically modified approaches to cultured meat.49 According to Mark Post, his decision on this is driven by concerns about lower market adoption.50 However, we would guess that allowing genetic modifications of the muscle cells could help make manufacturing scale-up of cell culture more efficient, as it has in synthetic biological fermentation. For example, we would guess that GMO muscle cells might be made to reproduce faster, significantly reducing manufacturing times (and thus costs). #### 2.2.6 Will it be possible to make cultured meat cost-competitive with conventional meat? Some estimates of the possible future costs of cultured meat are below: ESTIMATE BY: COST OF CULTURED MEAT (USD) ASSUMED MANUFACTURING VOLUME YEAR Vandenburgh$5M / kg51 Small-scale production in laboratories52 200453
Exmoor €3300 – 3500 / tonne

(€3.3 – 3.5 / kg)

Scaled-up to large volume 2008
Van der Weele and Tramper €391 / kg assuming typical media cost of €50,000 / m³. One estimate of the lowest possible cost of media is €1,000 per m³, but we do not know what this estimate is based on. Plugging this assumption into Van der Weele’s model would imply that €8 of media is needed for 1 kg of meat.54 Scaled-up to large volume55 2014

The Exmoor estimate seems very optimistic to us. For example it assumed $0 cost for growth factors in media,56 but it could be one of the more expensive components.57 Note that the cost of production of beef at the time was ~€3600/tonne. 58 The study notes that cell culture media cost €7000-8000/tonne, and needed to reach < €350/ tonne for commercial viability.59 Isha Datar, now the Executive Director of New Harvest, said this estimate was preliminary and “could be largely inaccurate.”60 We are highly uncertain about the eventual cost per kg of cultured meat, and have not closely examined the above cost estimates. However, none of these estimates suggest a cost competitive with that of conventional meat. The Van der Weele and Tramper estimate is based on back of the envelope calculations by academic researchers. They argue that even if we reduce the price of animal-free medium to what they believe is its lowest possible cost—€1 per liter—it will be insufficient to make cultured meat cost-competitive with conventional meat.61 Van de Weele and Tramper do not explain why €1/L is the lowest possible cost of animal-free medium, but their claim that a cost of less than €1/L is required seems correct to us because meat costs a few dollars per pound, and we would guess that a minimum of a few liters of serum-free media would be required to produce 1 kg of meat. For reasons explained below, it seems to us that it will be extremely challenging to get the cost of animal-free media this low. Currently, a major cost of animal-free media is the cytokines (cell-signaling molecules) that encourage cell proliferation.62 Two approaches to reducing the cost of cytokines include: • Trying to find small molecule replacements for cytokines. While inexpensive small molecule replacements for some cytokines have been discovered, we were told that it has proven challenging to find replacements for others, and we would need to replace all the expensive cytokines used in order to get costs below €1/L. We are not aware of how many cytokines would need to be replaced, but would guess that manufacturers of animal-free media could answer this question. • Trying to culture genetically engineered yeast cells (or other host organisms) to produce cytokines through fermentation. We have a limited understanding of this approach. Steve Oh, a scientist who has worked on decreasing the cost of animal-free media, told us that it would be extremely challenging to get the cost of animal-free media below ~€1/L through either of these approaches.63 Even if the cytokines could be produced at zero cost, we would guess that that would not suffice to bring the cost of animal-free media below €1/L because, as of 2006, “basal medium,” a sort of medium without cytokines, still cost$1-4/L.64 We have not closely investigated the feasibility of decreasing the cost of the basal medium, but it may be challenging because many of its ingredients sound like commodities (based on a first-glance review of the list of major ingredients).65

#### 2.2.7 How long will it be before it is possible to make cultured meat cost- and taste-competitive with conventional meat?

We have seen only a couple of informed estimates of how long it might take to make cultured meat cost- and taste-competitive with conventional meat. Mark Post estimated 7-10 years,66 and a scientist in the tissue engineering field said that cost-competitive cultured meat would be very unlikely to be available in the next 10-15 years, absent a major technological breakthrough.67 We have a very limited understanding of what these estimates are based on.

We are highly uncertain on this topic because we believe there is essentially no industrial data around cost of scaling up cell production to these levels. Many non-trivial unknowns may exist associated with a new endeavor like this, making it very challenging to accurately predict the costs. For example, synthetic biology company Amyris (described more below) took longer to scale up biofuel production than anticipated.68

One way to consider likely future cost reductions is to compare cultured meat with progress in the closest industry analogues we’ve been able to identify in tissue engineering and synthetic biology:

• Organogenesis (a tissue engineering company) was founded in 1985 and had its first skin graft product, Apligraf, approved in 1998.69 Their product, Apligraf, is a wound care patch (75 mm diameter circular disc that is 0.75 mm thick), is functionally similar to skin, and is used to cover wounds and speed up the healing process in patients with certain leg and foot ulcers.70 Manufacturing Apligraf is similar to manufacturing cultured meat because it involves culturing multiple cell types and combining them with collagen and other chemicals into a tissue substitute.71 Unlike cultured meat, there is much lower cost pressure on medical products, and Apligraf had to pass FDA regulatory approval. We have a limited understanding of the state of their program in 1985, but it was early-stage academic research, and the early years of the company were heavily research-based.72 The product volume required for that product is much lower than for meat (making for a less challenging scale-up problem) and the cost pressure is much lower (they can charge a premium for high-value medical product, rather than competing with a commodity like conventional meat). Since then, they have further reduced the real cost of their skin grafts by roughly a factor of three.73 Based on rough back of the envelope calculations, we would guess that the manufacturing cost of Apligraf is on the order $90,000/kg.74 • The synthetic biofuel company Amyris was founded in 200375 and started fuel production in Dec 2012.76 We would guess that at founding, Amyris was mainly based on early stage academic work and had done little work in manufacturing scale-up.77 Moreover, we would guess that biofuel may be a simpler product than cultured meat because the final product, a liquid biofuel, does not require cells or three-dimensional tissues.78 Despite$700M investment in the company, Amyris has not been able to compete on cost with conventional fuels.79

Judging on the basis of the above two examples, the challenges involved in dramatically reducing the cost of animal-free media, and our holistic assessment of the challenges involved in reducing the cost of cultured meat, discussion with scientists who have experience with cell cultures and tissue engineering, we currently see developing cost-competitive cultured meat products as extremely challenging, and we have been unable to find any concrete paths forward that seem likely to achieve that goal.

#### 2.3 Cultured slab meat

We investigated cultured slab meat less closely because it seems more challenging and we are not aware of anyone who is working on it now, except for a group doing a feasibility study on chicken (see below).

Slab meat poses additional challenges because it would likely require cell cultures with multiple types of tissues that grow in appropriate complex formations.80 In addition to the interventions listed above—which would largely help with the development of cultured slab meat as well—a philanthropist interested in accelerating the development of cultured slab meat could support:

• The development of scaffold/bioreactor designs able to feed and support thick three-dimensional structures of cells. Thicker multi-layer tissue structures may require vascular systems to deliver nutrients deep within the tissue.81
• Feasibility analysis of slab meat, e.g., as Amit Gefen is doing for chicken.
• There may also be approaches involving self-assembly and 3D-printing, however we have not closely considered these possibilities and would guess that they would be difficult to implement in the near future.82

We would guess that developing cost-competitive cultured slab meat is a challenge in the same rough ballpark of difficulty as developing transplant organs in vitro because both would likely require growing large, complex, multi-layered 3D structures and vascular systems. We would guess that cultured slab meat would be technically easier to achieve without cost constraints (since it would not be necessary to fully replicate as many natural functions), but also that price pressure on in vitro organs would be much lower.

#### 2.4.1 Potential impact of taste- and cost-competitive cultured egg whites

In 1996, approximately 12% of the total eggs produced in the U.S. went towards making processed egg whites,83 out of the 65 billion eggs produced in the U.S. overall.84 In 2014, the number of eggs produced in the U.S. had risen to 100 billion.85 We would guess that the development of cultured egg whites that were cost- and taste-competitive with traditional egg whites would significantly reduce the amount of eggs produced.

#### 2.4.2 What methodology is currently used to make cultured egg whites?

We are only aware of one company developing cultured egg whites: Clara Foods. Clara Foods is a biotechnology company founded in 2015 working on developing cultured egg whites. It is still in development stages. Its process involves:

• Putting genes for chicken egg white proteins into yeast cells using genetic engineering techniques.
• Growing the yeast cells that produce the egg white proteins in a fermentation process.
• Letting the yeast produce the egg white proteins.
• Separating the egg white proteins from the yeast through a purification process.86

Clara Foods is working on protein purification methods to efficiently extract the egg white proteins from the “soup” of yeast fermentation.87 Their founders have created a prototype to demonstrate that only a subset of egg white proteins are needed to functionally substitute for egg whites. To make the prototype, they extracted a subset of proteins from real egg whites and showed that it was possible to make meringues using this subset of proteins. All of these steps are aimed at making the cultured egg whites cost competitive with conventional egg whites.88

#### 2.4.3 Will it be possible to make cultured egg whites cost-competitive with conventional egg whites?

Our understanding is that the main hurdle for cultured egg whites is in achieving scaled-up manufacturing that is cost-competitive with conventionally farmed eggs. We would guess that it will be significantly easier to meet this challenge with cultured egg whites than with cultured meat because:

• Cultured egg white protein production is more similar to already demonstrated industrial biotech processes (e.g., synthetic patchouli).89
• Rather than producing tissues (which are arrangements of entire cells), producing egg whites likely only requires manufacturing a small number of proteins (which is much simpler).90

#### 2.5 Plant based alternatives

We did not closely investigate this topic because our impression is that work in this area is well-funded. See below.

## 3. Who else is working on this?

#### Key Companies Developing Alternatives to Animal-Based Foods

COMPANY PRODUCTS IN DEVELOPMENT CELLS / GENES FROM ANIMALS? MAINLY PLANT BASED DIRECT SUBSTITUTE FOR CONVENTIONAL ANIMAL PRODUCTS FUNDING
Modern Meadow Leather, possibly steak chips91 Yes (cells)92 No No $10.4M93 Breakout Labs,94 ARTIS Ventures, Francoise Marga, Healthy Ventures, Horizons Ventures, Interplay Ventures (Partner: Mark Peter Davis), Karoly Jakab, Iconiq Capital, Sequoia Capital95 Clara Foods Egg white produced by yeast via synthetic biology96 Yes (genes)97 No98 Yes99$1.7M100
David Friedberg, Gary Hirshberg, Ali and Hadi Partovi, Scott Banister, SOSventures101
Impossible Foods Plant-based meat and cheese alternatives using bioengineering techniques to combine select plant proteins and molecules to replicate the experience of animal-based foods.102 No Yes103 Yes104 $183M Bill Gates, Horizons Ventures, Jung-Ju (Jay) Kim, Khosla Ventures, UBS, Viking Global Investors105 Beyond Meat Extruded plant-based chicken substitute106 No107 Yes108 Yes109 Undisclosed amount, completed Series D in 2014. Bill Gates, DNS Capital, Kleiner Perkins Caulfield & Byers, Obvious Ventures, S2G Ventures110 Muufri Milk produced by yeast via synthetic biology111 Yes (genes)112 Some plant-based fats113 Yes114$2M + $30k SOS Ventures, Horizon Ventures115 Hampton Creek Plant-based versions of products containing eggs, such as mayonnaise, cookie dough, scrambled egg mixture (in development)116 No117 Yes118 Yes119$120M
Ali and Hadi Partovi, Ash Patel, Brian Meehan, OS Fund, Collaborative Fund, Demis Hassabis, Eduardo Saverin, Far East Organization, Founders Fund, Horizon Ventures, Jean Piggozzi, Jerry Yang, AME Cloud Ventures, Jessica Powell, Kat Taylor, Khosla Ventures, Marc Benioff, Mustafa Suleyman, Scott Bannister, Tao Capital Parters, Tom Steyers’ Eagle Cliff, Uni-President Enterprises Corporation, Velos Partners, WP Global Partners120, Bill Gates 121

#### 3.2 Academic researchers and non-profit organizations

Key Academic Groups Developing Alternatives to Animal-based Foods

RESEARCHER WORK APPROACH DEVELOPING MEAT/EGG ALTERNATIVE?
Mark Post Cheaper animal-free cell culture media, adding fat to cultured meat to improve taste122 Cultured animal tissue123 Yes124
Nicholas Genovese Establishing new lab in stem cell biology for meat production125 Developing stem cell lineages for cultured meat126 Yes127
Amit Gefen Feasibility study on making whole cultured chicken meat Cultured animal tissue128 Feasibility study129

#### 3.3 Potential gaps in the field

Plant-based alternatives appear relatively well-funded (see ‘Key Companies Developing Alternatives to Animal-Based Foods’).

We see cultured meat and cultured eggs as the largest potential gaps in the field. To our knowledge, Clara Foods is the only organization working on a cultured egg product (egg whites specifically), and it has received about $1.7M in funding since they were founded in 2015 (see Key Companies Developing Alternatives to Animal-Based Foods’). Cultured meat also receives a limited amount of funding (we estimate <$6M over the last 15 years),130 though it has a longer history and a larger number of people involved. We discuss it in more detail in the following section.

#### 3.4.1 Current activity

We are aware of only one company working on cultured meat today: Modern Meadow. As noted in the table ‘Key Companies Developing Alternatives to Animal-Based Foods’, they are currently focused on leather and possibly steak chips, which would not translate immediately into alternatives to meat. However, we would guess that there could be substantial overlap in research and development pathways (such as developing less expensive animal-free media, finding low-cost methods of maintaining sterility, and optimizing bioreactor operating conditions) but perhaps less overlap related to scaffolding.

There are a few academic groups worldwide working on cultured meat,131 but our understanding is that very limited grant funding is available for cultured meat132 and others we spoke with suggested that the work is considered fringe by the academic community.133 Mark Post has talked about how his family was disappointed when he switched his research to cultured meat.134 Among the limited amount of work on cultured meat, beef is receiving more attention than chicken or pork as seen in the tables ‘Key Companies Developing Alternatives to Animal-Based Foods’ and ‘Key Academic Groups Developing Alternatives to Animal-based Foods’.

New Harvest is a small non-profit that makes seed grants to entrepreneurs and academics working on cultured animal products.135 In 2013, their annual expenditures were about $60,000.136 Mark Post plans to start a company focused on commercial production of cultured meat, in hopes of replacing conventional ground beef.137 #### 3.4.2 Past activity There has been work on cultured meat at least since Willem van Eelen began promoting research efforts in the late 90s.138. Other past projects include: • In 2002, NASA funded Prof. Morris Benjaminson of Touro College to culture goldfish muscle tissue.139 This was very preliminary work – he took samples from animals and showed that their size increased after growing in a dish, in order to investigate the potential of culturing meat for human consumption in space.140 • As an art project in 2003, Oron Catts cultured frog muscle cells into a small “steak” which was eaten in public (four of eight tasters spat it out).141 • Vladimir Mironov performed research on cultured meat (although his U.S. lab closed) and collaborated with Nicholas Genovese who is continuing work on cultured meat.142 • Mark Post began work on cultured meat in 2008. His work stems academically from early cultured meat proponent Willem van Eelen.143 • In 2010, a startup company called Mokshagundum Biotechnologies was interested in making genetically modified meat by harnessing tumor-growth-promoting gene, but we found no record of this company since then.144 • In 2013, Singularity University produced a startup team called LifeStock aimed at producing animal-free meat, specifically focused on the scaffolding component.145 However, we have not found recent activity (2014 and onwards) mentioning LifeStock, and the website listed on their Facebook page does not appear to be active.146 There have been at least four symposia/workshops on cultured meat since 2008: • The first cultured meat symposium was held in 2008 in Norway.147 • In 2011, there was a workshop by the European Science Foundation held in Gothenburg, Sweden, with 25 attendees.148 • In 2012, a panel on tissue engineered nutrition was held at the TERMIS (Tissue Engineering and Regenerative Medicine Int’l Society) conference in Vienna.149 • In May 2015, New Harvest and the IndieBio accelerator hosted an event in San Francisco called “Edible Bioeconomy”, convening those involved with the development and promotion of animal product alternatives.150 • There is also a symposium planned for the fall of 2015, the “First International Symposium on Cultured Meat”, focused on discussing tissue engineering for cultured meat, which is organized in association with Maastricht University and New Harvest.151 #### 3.4.3 Related work in tissue engineering Over$4.5B of capital investment went toward tissue engineering efforts worldwide between 1990 and 2002, and over 90% of the investment came from the private sector.152 Tissue engineering efforts focus on many of the same challenges facing cultured meat: developing scaffolds,153 scale-up, and tools to accelerate the research.154 However, we would guess that some of the challenges associated with making cultured meat cost- and taste-competitive with cultured meat are unlikely to be addressed by people working in tissue engineering unless they are done specifically for manufacturing cultured meat. Two such examples include:

• Creating extremely low-cost animal-free media: Tissue engineers in the medical field already have incentives to use animal-free media because it improves reproducibility.155 Our understanding is that cell media is a significant cost for tissue engineering companies,156 but because the prices of tissue engineering products are much higher than the price of meat,157 we would guess that tissue engineering companies may not be incentivized to lower costs of animal-free media to the levels that would be required for cultured meat to be commercially viable.
• Scaling up production of cultured meat to vast quantities: The volume of tissue production required for biomedical applications (such as skin grafts and organ replacements) is significantly lower than the volume required for meat.158 We would therefore guess that they will not need to develop as large-scale production facilities as may be required for mass-produced cultured meat in the near future.

#### 3.4.4 Availability of funding from for-profit investors

Our impression is that venture capitalists generally seek investments that could provide a significant return within several years.159 However, as discussed under above, we would guess that it will take longer than that for cultured meat to become cost- and taste-competitive with natural meat. One potential goal of philanthropic funding would be to allow work to progress without expectations of a near-term return on investment in hopes of de-risking cultured meat to the point where a profit-motivated investor would be willing to finance further development.

## 4. Our process

We initially decided to investigate the cause of alternatives to animal-based foods because:

• We believe that, for someone who cares about the welfare of farm animals, the treatment of animals in industrial agriculture is an extremely important problem. For more detail, see our overview of industrial animal agriculture.
• It seems to us that if there were plant-based or cultured alternatives to meat and eggs that were cost- and taste-competitive with animal-based foods, it could greatly reduce the amount of meat and eggs produced, and thereby greatly reduce pain and suffering of animals in industrial agriculture.
• The area seemed unlikely to get financial support from traditional sources that support research and development in the life sciences.

We spoke with 8 individuals with knowledge of the field, including:

• Isha Datar, Executive Director, New Harvest
• Mark Post, Professor of Vascular Physiology and Chair of Physiology, Maastricht University
• A scientist with 18 years experience in the tissue engineering industry
• Five individuals who spoke with us off-the-record.

In addition to these conversations, we also reviewed documents that were shared with us and had some additional informal conversations.

## 5. Questions for further investigation

We have not deeply explored this field, and many important questions remain unanswered by our investigation.

Among other topics, our further research on this cause might address:

• How quickly and in what directions are commercial and academic tissue engineering advancing? How transferable might this work be to cultured meat?
• If funded, what is the potential impact of additional academic research in cultured meat?
• Is it possible to make a realistic cost model in which cultured meat/egg products are cost-competitive with traditional meat/eggs? What advances would be needed to put such a model into practice?
• How long will it take to develop cost- and taste-competitive cultured meat/eggs?
• How could additional funding advance the development of cultured egg whites?
• What could be done to advance the development of cultured slab meat? How much more challenging would it be to develop cultured slab meat in comparison with cultured ground meat?
• Would the public buy cultured animal products?

## 6. Sources

DOCUMENT SOURCE
2014 Consumer Perishables Databook Source (archive)
Amyris company history Source (archive)
Angel.co company profile, Hampton Creek Source (archive)
Angel.co company profile, Muufri Source (archive)
Apligraf website, How is it Made Source (archive)
Apligraf Medicare Product and Related Procedure Payment, 2015 Source (archive)
Apligraf website, What is Apligraf Source (archive)
Amyris 2013, Amyris and Total Announce Successful Demonstration Flight With Renewable Jet Fuel During Paris Air Show Source (archive)
BBC 2011, Grow your own meat Source (archive)
Benjaminson, Gilchriest, and Lorenz 2002 Source (archive)
Biofuels Digest 2011, Amyris opens first commercial facility Source (archive)
Bloomberg 2013, Modern Meadow Makes Leather and Meat Without Killing Animals Source (archive)
Breakout Labs portfolio company page, Modern Meadow Source (archive)
BusinessWire 2013, Beyond Meat Completes Largest Financing Round to Date Source (archive)
Category share of beef sales in the United States in 2014, by cut type Source (archive)
Category share of chicken sales in the United States in 2014, by cut type Source (archive)
CBInsights company profile, Modern Meadow Source (archive)
CNN 2009, Lab meat Source (archive)
Crunchbase company profile, Hampton Creek Source (archive)
Crunchbase company profile, Impossible Foods Source (archive)
Crunchbase company profile, Impossible Foods Investors Source (archive)
Crunchbase company profile, Modern Meadow Source (archive)
Danoviz and Yablonka-Reuveni 2012, Skeletal Muscle Satellite Cells: Background and Methods for Isolation and Analysis in a Primary Culture System Source (archive)
Datar and Betti 2010, Possibilities for an in vitro meat production system Source (archive)
DFJ Portfolio Source (archive)
Discover Magazine 2012, Steak of the Art: The Fatal Flaws of In Vitro Meat Source (archive)
Economist 2011. Global Livestock Counts Source (archive)
Edelman et al. 2004, In vitro cultured meat production Source (archive)
Exmoor In Vitro Meat Consortium Preliminary Economics Study, March 2008 Source (archive)
Fast Company 2012, THE RISE AND FALL OF THE COMPANY THAT WAS GOING TO HAVE US ALL USING BIOFUELS Source (archive)
Fastcoexist 2013, Lifestock: The Newest Player In The Growing Lab-Made-Meat Industry Source (archive)
First International Symposium on Cultured Meat, 2015 Source (archive)
Food Safety News 2012, Lab-grown meat? Source (archive)
FoodProcessing.Com.Au 2015, Producing Egg Whites Without Chickens Source (archive)
Forbes 2014, Bill Gates-Backed Food Startup Hampton Creek Source
Forbes 2014, Yum! Petri-Dish Beef Is like “Jerky Melting in Your Mouth” Source
Galef 2011 Source (archive)
Genetic Engineering & Biotechnology News 2014, Driving Down the Cost of Stem Cell Manufacturing Source (archive)
Genetic Engineering & Biotechnology News 2015, Biopharma Demand Is Driving the Cell Culture Market Source (archive)
GiveWell’s non-verbatim summary of a conversation with a scientist with 18 years experience in the tissue engineering industry, April 23, 2015 Source
GiveWell’s non-verbatim summary of a conversation with Isha Datar, March 10, 2015 and July 24, 2015 Source
GiveWell’s non-verbatim summary of a conversation with Mark Post, March 24, 2015 Source
GiveWell’s non-verbatim summary of a conversation with Steve Oh, October 7, 2015 Source
Gizomodo 2011, The first lab-grown hamburger will cost $345,000 Source (archive) Guardian 2012, Fake meat Source (archive) Heartblog on growth factors Source (archive) Hochfeld 2006 Source Hunsberger et al. 2015, Manufacturing Road Map for Tissue Engineering and Regenerative Medicine Technologies Source (archive) i24news 2015, Israeli researchers developing first lab-grown chicken Source (archive) IEET 2014, Interview with Nicholas Genovese Source (archive) Impossible Foods website Source (archive) Independent 2013, Lab meat taste test Source (archive) Jacklenec et al 2012, Progress in the Tissue Engineering and Stem Cell Industry Source (archive) Jochems et al., The use of fetal bovine serum: ethical or scientific problem? Source (archive) Lees 2008, The taste of test tube meat Source (archive) Lifestock Facebook Page Source (archive) Maastricht University, Cultured Beef Project Fact Sheet Source (archive) Maastricht University, Mark Post bio Source (archive) MacKay 2006, Bioactive wound healing, bioaesthetics and biosurgery Source (archive) MIT Technology Review 2014 on Modern Meadow Source Modern Agriculture Foundation Press Release, Jan 2015 Source (archive) Modern Meadow FAQ Source (archive) National Chicken Council, Per Capita Consumption of Poultry and Livestock Source (archive) National Geographic 2014, Meat grown in a lab Source (archive) Nature Bioentrepreneur 2005, Commercializing synthetic biology Source (archive) Nature News 2010, Food: A taste of things to come? Source (archive) Nature News 2011, Meat-growing researcher suspended Source (archive) NBC News 2013 on Brin and Post Source (archive) NBC News 2013, It’s (not) alive! Franken-meat lurches from the lab to the frying pan Source New Harvest 2014, World’s First In Vitro Meat Symposium Source (archive) New Harvest 2015, Edible Bioeconomy Event–Recap Source (archive) New Harvest 2015, Willem Van Eelen obituary Source (archive) New Harvest Expenditures Source (archive) New Harvest Profile of Marianne Ellis Source (archive) New York Times 2013, Building a$325,000 Burger Source (archive)
New Yorker 2011, Test-tube burgers Source (archive)
Oklahoma Food Safety Division, How Much Meat? Source (archive)
Organogenesis company profile Source (archive)
Pavillon 35, In vitro meat as art Source (archive)
Post 2012, Cultured meat from stem cells Source (archive)
Post 2014, An alternative animal protein source: cultured beef Source (archive)
Post and Courier 2011 on lab meat Source (archive)
Q+A with Modern Meadow CEO, Andras Forgacs Source (archive)
SBIR 2012 grant, Engineered Comestible Meat Source (archive)
Schwartz 2015, NT Cattlemen’s Association to hear that ‘cultured meat’ could end their industry within decades Source (archive)
Science Daily 2011, Growing meat in the lab Source (archive)
Science Insider 2014, PETA Abandons $1 Million Prize for Artificial Chicken Source (archive) Scientific American 2013, Test-Tube Burger Source (archive) Techcrunch 2015, Clara Foods Cooks Up$1.7M in Funding Source (archive)
Technologist 2014, From stem cells to Big Macs Source (archive)
Technology Review 2012, Why Amyris is Focusing on Moisturizers, Not Fuel, for Now Source
The Guardian 2014, Would you eat lab grown meat to save the environment? Source (archive)
Time 2014, The Surprising Reason ‘Pink Slime’ Meat is Back Source (archive)
U.S. Poultry & Egg Association 2015, economic data Source (archive)
USDA Grant for Engineered Comestible Meat Source (archive)
USDA, Egg Products Processing and Distribution Module Source (archive)
USDA, Natural flavorings on meat and poultry labels Source (archive)
USG 2007, Advancing Tissue Science and Engineering Source (archive)
Van der Weele and Tramper 2014, Cultured Meat: every village its own factory? Source (archive)
VentureBeat 2014, Hampton Creek’s data scientists team up with chefs to find the holy grail of plant proteins Source (archive)
Verge 2013, Lab meat Source (archive)
Wall Street Journal 2013 on Steve Jurvetson Source (archive)
Wall Street Journal 2014, The Secret of These New Veggie Burgers: Plant Blood Source (archive)
Walpole et al. 2012, The weight of nations: an estimation of adult human biomass Source (archive)
Washington Post 2014, Can this company do better than the egg? Source
Washington Post 2014, Man-made cow’s milk Source
Wikipedia Growth Medium page 2015 Source (archive)
Wired 2013, Alton Brown on the End of Meat as We Know It Source (archive)
Wired 2014, Forget GMOs. The Future of Food Is Data—Mountains of It Source (archive)

The CrunchBase pages we archived are covered under the Creative Commons license.