Purdue University — Preclinical Data Research (Douglas Brubaker)

Grant investigators: Heather Youngs and Chris Somerville

This page was reviewed but not written by the grant investigators. Purdue University staff also reviewed this page prior to publication.

Open Philanthropy recommended a grant of $1,500,000 over five years to Purdue University to support research led by Dr. Douglas Brubaker on developing a computational model to translate preclinical data in mouse disease models to humans. It is not uncommon that preclinical data from mice fail to translate to similar preclinical results in humans, limiting the applicability of mouse data to human medicine. Dr. Brubaker intends to use this funding to develop a computational model that uses mouse data from an Alzheimer’s disease study conducted by Washington University to attempt to predict the study’s human trial outcomes. Good Ventures, Cari Tuna and Dustin Moskovitz’s foundation, has provided funding for the Washington University study. The foundation, with support from Open Philanthropy, has been investigating how best to fund scientific research that might help reduce the future burden of Alzheimer’s disease. Our scientific research team believes that Dr. Brubaker’s computational model, if successful, could improve drug discovery and reduce reliance on mouse experiments. This falls within our work on scientific research, specifically within our interest in advancing tools and techniques. University of Notre Dame — Nanopore Protein Sequencing (Gregory Timp) (2021) Grant investigators: Heather Youngs and Chris Somerville This page was reviewed but not written by the grant investigators. University of Notre Dame staff also reviewed this page prior to publication. Open Philanthropy recommended a grant of$1,769,056 over two years to the University of Notre Dame to continue support for Dr. Gregory Timp’s work developing an instrument that uses a sub-nanometer-diameter pore (i.e. a sub-nanopore) to read the amino acid sequence of whole protein molecules. If successful, we believe this tool could facilitate a wide range of basic biological research and ultimately allow for rapid detection of pathogens, thereby improving the diagnosis and treatment of disease as well as potentially improving our ability to respond to pandemic threats.

This follows our June 2017 support, which we recommended as part of our “second chance” program for NIH Transformative Research applicants. It falls within our work on scientific research, specifically within our interest in advancing tools and techniques.

University of California, Los Angeles — Social Science Genetic Association Consortium (2020)

Grant investigator: Alexander Berger

This page was reviewed but not written by the grant investigator. SSGAC staff also reviewed this page prior to publication.

Open Philanthropy recommended a grant of $2,250,000 to the University of California, Los Angeles, to support the Social Science Genetic Association Consortium (SSGAC). Our understanding is that SSGAC has received substantially less funding to date than comparable consortia (such as in psychiatric genetics), but still produces high-quality, replicable research and serves as a model of careful public communication, most notably through their discussions of frequently asked questions. Approximately 20% of this grant is intended to support work on bioethics and the public discussion of these topics. This follows our July 2019 support and falls within our interest in scientific research, specifically within our interest in advancing tools and techniques. Scientific American: Lab-Made ‘Miniproteins’ Could Block the Coronavirus from Infecting Cells The Atlantic: The Plan That Could Give Us Our Lives Back STAT: ‘Taste of the future’: New microscopy technique captures stunning images of a fly’s brain Discover Magazine: Meet the Biochemist Engineering Proteins From Scratch Duke University — CRISPR-Based Epigenome Editing Tools (Charles Gersbach) Grant Investigators: Chris Somerville and Heather Youngs This page was reviewed but not written by the grant investigators. Duke University staff also reviewed this page prior to publication. The Open Philanthropy Project recommended a grant of$2,550,171 over three years to Duke University to develop tools to apply epigenome editing to refine genome wide association studies (GWAS). The work will be led by Charles Gersbach, the Rooney Family Associate Professor of Biomedical Engineering. This funding will support research to develop CRISPR-based epigenetic tools to interrogate thousands of regions of DNA, allowing for more nuanced studies of genomic regions identified through GWAS. The grant will also fund testing and verification of the tools by identifying loci implicated in schizophrenia, a poorly understood disorder.

This grant falls within our interest in funding scientific research, and specifically within our interest in developing tools and techniques.

University of Washington — Universal Flu Vaccine and Computational Protein Design (David Baker and Neil King)

Award Date: 11/2017
Grant Amount: $11,367,500 Purpose: To support research by Professor David Baker and collaborators on the development of a universal flu vaccine, and to support improved methods for computational design of proteins to treat disease. Grant Investigators: Chris Somerville and Heather Youngs This page was reviewed but not written by the grant investigators. IPD staff also reviewed this page prior to publication. The Open Philanthropy Project recommended a grant of$11,367,500 over five years to the University of Washington’s Institute for Protein Design (IPD) to support research on the use of computational protein design to develop a universal influenza vaccine. This work will be led by UW Professor David Baker, Ph.D., and UW Assistant Professor Neil King, Ph.D. In addition, part of this funding is intended to improve the Rosetta molecular modeling and design software originally developed in Baker’s lab. UW Assistant Professor Frank DiMaio, Ph.D., and others will work to improve Rosetta to better predict the properties of proteins, which we believe could lead to many helpful applications in both human and animal health, such as facilitating faster creation of antiviral therapies in the event of a pandemic outbreak.

The cause

Developing a “universal” influenza vaccine has been a long-standing goal of the infectious disease community. Influenza causes an estimated 290,000 – 650,000 deaths each year,1 in addition to carrying pandemic risks, such as the 1918 flu pandemic, which may have killed more than 50 million people. There can be up to 36 million cases of influenza annually in the United States alone, costing the U.S. economy an estimated \$87 billion in medical expenses and lost productivity.2

A universal vaccine would protect against all of the many genetic variants of influenza, thereby substantially reducing or eliminating annual deaths associated with the virus, as well as mitigating or even potentially eliminating the risk of influenza pandemics. By administering a universal vaccine early in life, immunity could reach a majority of the world population and potentially eliminate the need for the “seasonal” flu vaccine, thereby reducing the costs and uncertainty associated with current annual influenza vaccination practices.

We are most interested in supporting this work due to its potential to reduce illness and mortality from influenza, as well as the potential to prevent future harm from influenza pandemics. The grant therefore falls within both our scientific research funding category, and our biosecurity and pandemic preparedness focus area.

The researchers

The project will be led by Dr. David Baker,3 director of the University of Washington’s Institute for Protein Design, founded in 2012. We consider Dr. Baker and his team exceptionally well-qualified to accomplish the universal influenza vaccine design.

Dr. Baker and colleagues will also collaborate with Dr. Barney Graham, deputy director of the National Institute of Allergy and Infectious Diseases’ (NIAID) Vaccine Research Center and chief of the Viral Pathogenesis Laboratory at NIAID. Dr. Graham and his colleagues will be responsible for overseeing evaluation of the safety, immunogenicity, and protective capacity of the universal flu vaccine. NIAID is one of the institutes within the National Institutes of Health, which is funding Dr. Graham’s work.

Proposed activities

There are two goals associated with this grant: producing a universal influenza vaccine and improving the Rosetta molecular design and computational chemistry software to better predict properties of proteins.

• Goal 1: Develop a universal flu vaccineDr. Baker and his collaborators will test the hypothesis that immunizing with computationally designed, self-assembling protein nanoparticles displaying highly conserved “epitopes” (fragments of proteins from the flu virus) from all known types of influenza viruses will induce expression of broadly neutralizing antibodies that limit the severity of disease symptoms. Although very rare, such antibodies have been preserved for research after being identified in the serum of people who have previously been infected with influenza virus. When the corresponding genes were expressed in transgenic mice, the antibodies protected the mice against all flu viruses tested.4 We consider this evidence that the approach may work, but we expect the challenge to be developing methods to routinely induce such antibodies with a vaccine in humans. Drs. Baker and King previously used a somewhat similar approach to produce broadly neutralizing antibodies against the respiratory syncytial virus (RSV), which we consider a partial proof of principle. However, because RSV is less variable than influenza, there were fewer challenges to producing that vaccine candidate. Our assessment is that there is an acceptable probability that the proposed experiments will produce a useful flu vaccine that is better than anything currently available.
• Goal 2: Improve the Rosetta molecular design and computational chemistry software to better predict properties of proteinsDr. Baker’s approach to Goal 1 has recently become possible because, during the past several decades, his team and other leading protein chemistry groups have systematically developed sophisticated algorithms that use information about the chemical and physical properties of molecules to facilitate the design and production of proteins with desired three-dimensional structures. This “ab initio” (or “from the beginning”) design approach has made progress but sometimes fails to predict the correct protein structure because some aspects of protein chemistry are not yet completely understood. It is also difficult to make such proteins in a way that accurately resembles the natural three-dimensional structure in the virus, something crucial to a protein’s normal function (for example, generating a robust immune response). Thus, additional research is needed to fully realize the long-term goal of routinely being able to design novel proteins for a wide variety of uses in medicine and industrial applications.Some of this grant funding will therefore support experiments that may facilitate improvements in the ability of the Rosetta software to predict the properties of proteins from their amino acid sequences. Of particular interest, we envision that in the future it may be possible to rapidly design new vaccines or antiviral drugs from the nucleic acid sequences of a new pathogen and to design vaccines that induce immunity against all strains of a pathogen in a relatively short period of time. Drs. Baker and DiMaio have proposed a series of experiments that are designed to improve the predictive power of Rosetta. In brief, they will expand their work in computationally designing self-folding protein scaffolds with shapes customized for applications including binding small molecules and other proteins. They will then systematically synthesize, test, and redesign until the desired properties are achieved. Dr. Baker believes (and we concur) that this approach has a high probability of leading to improvements in our ability to design proteins. We see this approach as timely because it will potentially generate enough information to take advantage of the power of deep learning algorithms to understand protein structure and function.This work is related to Goal 1 above because one of Dr. Baker’s goals is to be able to design therapeutic candidates within weeks of determination of the viral sequence in the event of a viral pandemic outbreak. Therefore, the results are expected to be of general utility. We consider Dr. Baker’s previous work constructing small geometric protein nanoparticles to be particularly suited to mimicking viral structure and antigen presentation.

Sources

DOCUMENT SOURCE
IPD, David Baker Bio, January 2018 [archive only] Source
Nature Biotechnology, Broad protection against influenza infection by vectored immunoprophylaxis in mice, 2013 Source (archive)
Time, Our Complacency About the Flu is Killing Us, 2018 Source (archive)
World Health Organization Fact Sheet, 2018 Source (archive)