The chasm between promising lab breakthroughs and actual products or treatments has long been called the “valley of death,” a place where 90% of ideas die. It’s not because the science is flawed. It’s not because the ideas aren’t useful. And it’s not for lack of need. This problem has been recognized everywhere: At universities, at nonprofits, in the private sector, and here at the foundation.
I have seen it myself.
Before coming to the foundation, I worked for 10 years as a medical doctor treating people with kidney disease. I also had earned a Ph.D. in immunology and was conducting research that complemented my clinical practice, focusing on how the innate immune system sees pathogens. It was fascinating work.
But over time, I began to feel that I knew more and more about less and less. The path that could take lab research into the broader world was both daunting and unclear.
So when I joined the foundation in 2013, I wanted to find ways to clarify that path, to help turn it from a bumpy road filled with dead ends to a smoother one that flowed more directly from research to reality.
That’s the mission of the foundation’s Discovery and Translational Sciences team, where I serve as deputy director. We’ve spent the past several years working on better ways to bring some of the most promising global health research into real-world applications. Collaboration has been a key ingredient.
This isn’t a new idea, of course: Scientists have been collaborating for generations, and science is always a process of building from one idea to the next. The TB Drug Accelerator is structured around a model of R&D collaboration. So is the Collaboration for AIDS Vaccine Discovery (CAVD). Some labs consider collaboration a point of pride. But for the most part, cooperation tends to be more ad hoc than baked into the system.
Our team has been working to build collaboration into the architecture of even more of what we do. Since early 2020, we’ve been focused on connecting scientists with the cutting-edge tools and technologies they need to help elevate the best ideas faster and more equitably. We’re calling it the Global Health Discovery Collaboratory. I often describe it as a kind of matchmaking service for global health.
As it turns out, COVID-19 has been a proving ground for the power of the Collaboratory. It has already helped usher two vaccine candidates from the lab to clinical trials.
I’d like to share more about this evolution and explain just how powerful we think it can be.
Matchmaking for global health
There are a lot of reasons why promising lab research doesn’t make it into the real world and instead languishes in the valley of death. For one thing, if someone is an expert in, say, computational biology, they’re unlikely to also have the expertise to optimize the machinery that produces vaccines. And yet small decisions in the lab can play a huge role in manufacturing. It could even mean the difference between 100,000 and 1 million doses.
It’s also more than that. A researcher working on one aspect of a new vaccine may not know that halfway around the world another scientist is working on something that could help her. It’s not just vaccines, of course: You’ll find the same issues in just about every field of research. One factor is the general lack of incentive for collaboration that underpins everything from tenure decisions to funding mechanisms in academia.
Looking at the foundation’s portfolio of grantees and partners a few years ago, we saw a broad spectrum of talent and innumerable great ideas, some of which had been seeded by Grand Challenges and Grand Challenges Exploration grants. But we realized that these often weren’t connected in a deliberate way. A lab here doing protein research. A lab over there studying the immune system. And so on.
We had all the pieces of this rich discovery engine in place. All we had to do was connect these promising researchers with others who could help move their discoveries closer to real-world applications. If we could make those connections, our grantees could make faster progress on their projects.
Starting in 2014, the team identified three key Discovery Hubs, each of them working in different areas: the Stanford Center for Systems Immunology, the University of Washington’s Institute for Protein Design (IPD), and Calibr at the Scripps Research Institute. Each had visionary leaders—Mark M. Davis at Stanford, David Baker at IPD, and Peter Schultz at Calibr. They also had an established inclination for partnership and a record of ongoing innovation. And rather than concentrating on a particular disease, each had developed unique platform technologies. The beauty of these platforms is that they could be used to find answers about any number of diseases, including those impacting the poorest people. They continued their lines of research, and, with the added support of the foundation, they also began looking at questions of global health.
The next step was connecting them in a way that would help move their great ideas forward. At the foundation, we have several models of collaborative effort, but they’re generally focused on specific diseases, such as CAVD for AIDS or the Collaboration for TB Vaccine Discovery. The Collaboratory is disease agnostic. The idea is to make cutting-edge technologies and approaches available to those working on the problems the foundation wants to help solve.
In 2019, the Hubs began working together under a collaborative umbrella on a problem around adjuvants. These are molecules that help make a vaccine more potent, and there aren’t enough on the market right now. By developing new adjuvants, the hope is that they can be more widely used in vaccines for communicable diseases such as malaria or influenza that are a substantial burden in low- and middle-income countries.
Then came COVID-19.
As the foundation focused on funding diagnostics, therapeutics, and vaccines that would be affordable in low- and middle-income countries, the Hubs were eager to contribute. Soon, IPD was sharing reagents. Calibr was providing access to its drug discovery library. Stanford was examining how COVID-19 differed across geographies. And they were all sharing with the broader research community.
Nanoproteins and an immune system in a dish
The connection between IPD and Stanford—and, as I’ll explain later, an additional connection to a manufacturing partner in South Korea—is one example of how collaboration benefits everyone.
At IPD, Associate Professor Neil King had been using computers to design novel proteins that he hopes will prove useful for any number of vaccines, including for flu or HIV. By designing them from scratch, you can build something to precisely address a particular problem. Down the hall in the lab, his colleagues turn these computer models into actual nanoparticles for further study as potential vaccines.
Shortly after the SARS-CoV-2 genome sequence was published last year, Dr. King and his colleague David Veesler wanted to design a COVID-19 vaccine using their computational approach. The idea was to mimic the genetic sequence of the virus’ spike protein.
Over at Stanford, Dr. Davis had been working on another kind of platform technology. His lab had developed a way to essentially grow a piece of the human immune system in a dish. He uses cells from tonsils, which are lymph nodes. The great thing about these petri dish tonsils is that the lab can quickly run hundreds of tests on them to assess vaccine candidates.
For the past few years, the lab had been testing the tonsil cells’ immune response using commercial flu vaccines. Now connected through the Collaboratory, they’re testing King’s computer-designed vaccines. They’re also testing adjuvants designed by Schultz’s team at Calibr, looking for one that might help supercharge vaccines.
Davis’ technology is still new, and his team is working to hone and prove it. But it’s already clear that testing on tonsil cells is easier—and cheaper—than animal tests. He hopes little dishes of organoids like this will eventually speed the process for other vaccines, quickly eliminating poor candidates. And because these are human cells, he also hopes the test will be more accurate than animal testing.
Another Stanford lab, led by Bali Pulendran, is testing King’s nanoproteins in nonhuman primates. A third lab is testing them in humanized mice. Others are doing immunology and adjuvant formulation studies. All of this has been going on in parallel and at lightning speed.
Manufacturing vaccines
Meanwhile, our team was thinking further down the road. We reached out to manufacturers that produce affordable vaccines for low- and middle-income countries, to make them aware of the work of IPD and other grantees and to gauge interest in possibly working with them to develop vaccines.
The matchmaking was a success. IPD was connected with SK Biopharmaceuticals, a vaccine manufacturer in South Korea that otherwise might not have known of IPD’s work. This has shaved years off the normal process. Phase 1 clinical trials have started, and if everything goes well these partnerships could deliver something on the order of 2 billion doses.
It’s way too soon to know whether any of these ideas will work in the real world. But one thing is already clear: They’re not languishing in the R&D valley of death.
Sharing data and resources
There’s another kind of matchmaking under the umbrella of the Collaboratory, through the Global Health Vaccine Accelerator Platforms (GH-VAP). Using the online GH-VAP portal, grantees can access industry-caliber tools, which are often underapplied to global health research. It’s a way to democratize access so people with good ideas, no matter where they live, can find collaborators who have the technologies to help them succeed. Karen Makar, who has led the effort for six years, calls it “team science at a global level.”
There are 14 GH-VAP platform partners, each with distinct expertise: Specialists in adjuvants, humanized immunoglobulin mouse models, innovative biomarker assay technologies, and more. They’ve all agreed to work with any foundation grantee to augment their research. So far, 125 organizations around the world have signed on to participate, including a number of researchers in Africa and South Asia. IPD, for example, has sent their proteins to over 100 research groups worldwide, thanks to the GH-VAP connection.
Data sharing is also central to Calibr’s work. They have a library of compounds that have already been approved for medical use. Could any of them be repurposed for COVID-19? Or to boost vaccine efficacy for other diseases? Our team has done some matchmaking that has led them to share that library with dozens of labs.
To access GH-VAP or the Calibr library, researchers must agree to share what they learn from those resources. These agreements make access more equitable.
New challenges beyond the pandemic
Throughout the pandemic, there has been a remarkable level of cooperation, even among private-sector entities that normally compete with one another. The foundation hopes to keep that cooperation going among its grantees and partners long after everyone has received their vaccine.
The world can’t afford to go back to business as usual.
Moving forward, the Collaboratory will help create new connections, bringing even more people to the table, especially in low- and middle-income countries. We’ll also announce new challenges for researchers to work on together. One will aim to build an antibody discovery network across the African continent. Another will develop programmable antivirals for pandemic response. A third will optimize human organoids to facilitate drug discovery. What they all have in common is that they’re big technical challenges that can’t be solved by a single researcher or institution.
The solutions will come through global collaboration.
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