The House that Bruce Built

A look inside The Ragon Institute at their efforts to tackle the most vexing challenges hindering HIV vaccine research

By Kristen Jill Kresge and Regina McEnery

You could say the “B” in Boston stands for Braniac. After all, the cities of Boston and Cambridge, its

 Phillip "Terry" Ragon, left, and Bruce Walker at a WhizzKids United event in Durban, South Africa, in 2007
Photo by Jonas Steengaard, courtesy of The Ragon Institute

neighbor across the Charles River in Massachusetts, encompass the heaviest concentration of engineers, scientists, and researchers in the country, according to Wired magazine. And Harvard and the Massachusetts Institute of Technology (MIT), two of the premier universities in the US, are continuously pumping more young scientists into the metropolitan area. If you’ve seen The Social Network, you get the idea—it’s the kind of place where today’s computer geek can become tomorrow’s social media giant.

Still, were you to take a stroll around this science and technology hub you might have a hard time finding one of Greater Boston’s newest centers, The Ragon Institute of Massachusetts General Hospital (MGH), MIT, and Harvard. Launched in 2009 with a US$100 million donation from technology magnate Phillip “Terry” Ragon, and his wife, Susan, who reside in Cambridge, The Ragon Institute represents a collaboration modeled after its neighbor, the Broad Institute of MIT and Harvard, which engages scientists across different disciplines to solve biological problems in a systematic way.

But The Ragon Institute has a more specific mission: melding physicians, basic scientists, and engineers from MGH, Harvard Medical School, and MIT to study HIV’s interaction with the immune system to try to solve some of the most vexing challenges that have hindered the development of an effective AIDS vaccine.

In the labs: Sylvie Le Gall
Role: Assistant Professor of Medicine

Focus of lab:Studying the mechanisms of viral protein degradation, epitope processing, and presentation to immune cells.

Sylvie Le Gall, an assistant professor of medicine at Harvard Medical School, is interested in how HIV antigens get processed into epitopes and presented to immune cells. “If we better understand how that process occurs, we think that’s going to helps us design [vaccine] immunogens,” says Le Gall, whose lab at The Ragon Institute is focused on just that.

Using multiple approaches, Le Gall and colleagues are studying the in vitro degradation of HIV proteins in different cells that are infectable by the virus. Then, using high performance liquid chromatography and mass spectrometry, they can determine how fast the protein is degraded by peptidases and what epitopes it’s being chopped into. How fast the proteins are degraded affects how antigens get presented and shapes the overall immune response to HIV. The earlier the presentation occurs, the better it is for the immune system as it tries to mount a defense against the virus. HIV may avoid production and presentation of some epitopes altogether as a means of immune escape. Other epitopes are decoys, distracting the immune system.

Le Gall has observed that there is a big difference in the timing of HIV antigen presentation and she has identified certain motifs that result in better antigen presentation and improved killing by immune cells. When HIV proteins are modified to contain these motifs, the degradation of the protein can be augmented by 10-fold. Le Gall says this work will help inform immunogen design by allowing researchers to specifically present the epitopes that will give good immune responses. “I don’t think there is agreement about what should go into an immunogen right now,” says Le Gall. “Maybe the immunogen is going to be the parts of the virus that elicit good immune responses.”

Le Gall’s lab is currently collaborating with James Mullins, professor of microbiology at the University of Washington, to study what epitopes are produced from HIV immunogens that are based on the conserved regions of the virus. This work could also be extended to understanding the processing of mosaic antigens, which are computationally designed to achieve optimal coverage of the many versions of HIV in circulation.


At the helm of The Ragon Institute sits Bruce Walker, whose office, for now, is housed in the sprawling MGH center in the Charlestown section of Boston. Walker has been working in the field of AIDS since the pandemic began unfolding 30 years ago, but his research has taken new directions since receiving the gift just two years ago, the largest donation in MGH’s history. “This has been the most exhilarating period of my entire career,” says Walker.

When Walker begins describing the Institute, he quickly directs the conversation to South Africa—the country with the highest HIV prevalence in the world. It becomes clear that the devastation wrought by HIV/AIDS is his motivation. He cares deeply about science and harnessing its power to end the pandemic, but he is just as comfortable describing its nearly unparalleled toll on human life.

Another thing about Walker that strikes you almost immediately is his boyish exuberance, which is not that surprising given the golden opportunity The Ragon Institute is providing: a generous source of flexible funding over 10 years that enables researchers to engage in the kinds of high-risk projects that big grant-making organizations like the US National Institutes of Health (NIH) are less willing to fund. “I think everybody has far greater potential than they think they have,” says Walker. “What we’ve created is an environment where it’s easier for people to realize that potential.”


In the labs: Darrell Irvine
Role: Associate Professor of Materials Science Engineering and Biological Engineering

Focus of lab: Working at the interface of materials science and immunology.

The job of cytotoxic T lymphocytes is clear. But exactly how these killer CD8+ T cells execute their targets is a mystery that Maria Foley, a doctoral candidate in the laboratory of Massachusetts Institute of Technology polymer scientist and immunologist Darrell Irvine, is trying to solve using electron microscopy. Foley says this is the first time this technology has been used to study the killing of HIV-infected cells, and the images the lab has been able to capture have been instructive and surprising. The experiments begin with CD8+ T-cell clones taken from a cohort of elite controllers that was begun by Ragon Institute Director Bruce Walker. This group of HIV-infected individuals is important in the study of killer T cells because their ability to control the virus for years without the benefit of antiretroviral therapy is speculated to be due in large part to their cellular immune responses.

The CD8+ T-cell clones are loaded into a collagen matrix, a simplified model of 3D tissue that allows the cells to engage in a microbiological cat and mouse. Videos show that some of the CD8+ T cells annihilate the HIV-infected T cells quickly, while others successfully interact with their target cells, mechanically engaging receptors. However, the target cell eventually escapes, likely because there isn’t strong enough T-cell receptor binding with the target cell. Other cells engage in an “hour-long fight,” according to Foley, before they successfully kill their target cells. “The CD8 cell really fights hard to catch and hold on and kill that target cell,” she says, speculating that this is something that CD8+ T cells from elite controllers might be better at doing. Interestingly, says Foley, the films show that when CD8+ T cells do manage to inflict a fatal blow to their targets—usually within 20 minutes—they continue to circle their prey for several more hours. “We think that the CD8 cells are collecting more specific signals from dead targets to turn on genes and secrete factors important for inhibition of the virus,” says Foley.

Others in Irvine’s lab are focused on ways to improve vaccine delivery. Peter DeMuth, a doctoral candidate, is testing a vaccine delivery platform that employs microneedle arrays—rows and rows of microneedles occupying a space that measures about a centimeter in circumference—to deliver vaccines subcutaneously in a pain-free fashion. Unlike conventional vaccination, this strategy avoids the blood supply and delivers the vaccine components directly to antigen presenting cells, mostly Langerhans cells, which reside just below the skin’s surface. Irvine’s lab is also developing a nanoparticle vaccine delivery system.


One of Walker’s guiding principles for The Ragon Institute was to interest researchers whose work was not already focused on HIV to apply their expertise in this area. Two years later, Walker says the institute has brought 40 new scientists to work on HIV, and he thinks this has been a major driver of innovation. “We’re already turning away people with good ideas,” he says.

Walker, who looks younger than his 59 years, has the casual yet classic look that can only be described as Ivy League. In the corner of his office on the seventh floor of MGH is a “stressless” Swedish chair that seems a suitable antidote to his busy schedule, which includes regular teleconferences with Ragon Institute staff and their collaborators at The Scripps Research Institute (TSRI) in California, Oxford University, and the Doris Duke Medical Research Institute in South Africa and the University of KwaZulu-Natal. He travels to South Africa every month, a journey he notes takes 24 hours door-to-door. And in addition to these hefty administrative and fundraising duties, Walker oversees five post-doctoral candidates in his laboratory at the Institute, which is focused on mechanisms of immune control in HIV infection. Despite all this, Walker insists he gets plenty of sleep. “We have such good people and everyone is taking on so much responsibility that my job has actually gotten so much easier since Ragon got started,” he says.

Plans are now in the works for a building specifically for The Ragon Institute, and the hope is that by August of next year there will be a permanent home. Not all Ragon investigators will work there—it will be up to individual investigators whether they stay in their current location or have a second location at the Institute.

Meanwhile, Walker is working to raise additional money to continue funding innovative, collaborative research projects. “We are talking now about trying to replicate what Terry and Susan have done,” says Walker. “It would be great if we could find a couple of donors who would do that.” As research money gets tighter, Walker thinks it’s important to teach people how to communicate with donors and how to give them a message that is compelling. The most important thing, he says, is to have a vision. “You can’t be in the position we’re in and in good conscience not ask people for money,” he says. Although, Walker recognizes most researchers are not comfortable asking for money. “It’s not something that any of us are taught to do but I think it’s something we can learn.”

In the labs: J. Christopher Love
Role: Latham Family Career Development Associate Professor of Chemical Engineering

Focus of lab: Developing new processes for analyzing large numbers of individual living cells quantitatively and dynamically.

If you had to guess what the Love Lab at the Massachusetts Institute of Technology (MIT) was working on, you probably wouldn’t come close. Rather than matters of the heart, this research group housed in the department of chemical engineering is focused on characterizing the dynamic biological responses of individual cells subjected to defined perturbations. The irresistible name of the lab comes not from its work, but from its leader, J. Christopher Love, an MIT professor of chemical engineering and an investigator with The Ragon Institute.

When researchers try to extract information from biological samples, they are often hindered by the quantity of cells they are able to analyze. Whether peripheral blood mononuclear cells or B and T cells from mucosal tissues, the number of cells available, as well as the number of assays that can be used to determine what these cells are doing, is rather limited. “As engineers, what we’re very interested in trying to understand is how to enhance the amount of information you can extract from a given clinical sample,” says Love.

To do this, the Love Lab is using nanotechnology to look at populations of cells individually. They’ve developed a microfabricated slide containing 250,000 wells, each of which can hold a single cell, and a stamping technique that allows them to transfer the analytes they are interested in from one slide to another. Because this process of stamping can be done serially, you can significantly increase the number of parameters that can be measured from a single cell. This helps eliminate the decisions many researchers face about which assays to run with their precious samples. It also is much faster than the traditional high-throughput screening methods. “We screen tens of thousands of B cells for interesting characteristics in an afternoon,” says Love, who is collaborating with both the HIV Vaccine Trials Network and IAVI’s Neutralizing Antibody Consortium to develop methods for screening both B and T cells.

Love is even optimistic that this process could eventually be used to develop a “nano-scale neutralization assay,” which would be able to identify neutralizing antibodies on a much smaller scale than the current miniaturized system used by Monogram Biosciences that does micro-neutralization assays with 384 well plates.

When Bruce Walker, director of The Ragon Institute, approached Love, he was not working on HIV, but it became clear that their interests overlapped. “There was a certain synergy that made it obvious that we should get involved,” recalls Love.

The $100 million question

By the mid-1980s, Walker began pondering why the immune systems of so many HIV-infected individuals eventually lost the battle against the virus. This question led him to study a small subset of HIV-infected individuals who managed to defy the odds and live with undetectable viral loads for up to 20 years, without the benefit of antiretroviral therapy. Walker is now following a cohort of about 1,600 HIV controllers, in hopes of discovering what genetic or immunological factors contribute to this impressive control. About one in every 300 HIV-infected individuals is thought to be an elite controller.

In 1998, Walker’s research shifted to South Africa when one of his post docs secured a small grant from the Elizabeth Glaser Pediatric AIDS Foundation. This effort soon led Walker to seek funding from the Doris Duke Foundation in hopes of “building the best biomedical research facility in the middle of the epidemic.”

“We actually did that,” recalls Walker, “but we couldn’t in good conscience let [HIV-infected] people die, so we started a pilot treatment program.” It was this pilot treatment program housed at St. Mary’s Hospital in Durban, South Africa, which ultimately brought Walker and Ragon together. The hospital was using an electronic medical records system known as TrakCare that had been developed by a US company. Walker didn’t know much about the company and was much too busy during his visits to South Africa to meet with the company’s country manager. But then, one day, when Walker was awaiting a flight out of Johannesburg on one of his many trips to South Africa, he finally sat down with the regional manager, who suggested Walker meet with the company’s owner Terry Ragon, who lives in Cambridge.


In the labs: Arup Chakraborty  
Role: Robert T. Haslam Professor of Chemical Engineering, Chemistry, and Biological Engineering

Focus of lab: Using computational immunology to understand the adaptive immune response to pathogens, including HIV.

Although immunologists have made strides in understanding how the adaptive immune system is regulated, there are still many unanswered questions. “We still don’t know the principles that lead to the emergence of an immune response,” says Arup Chakraborty, a professor of chemistry and chemical engineering at Massachusetts Institute of Technology (MIT).

To shed light on these immunological mechanisms, Chakraborty began applying theories of statistical physics to immunology, and since he joined The Ragon Institute, he has been using this approach to study HIV. A newcomer to the HIV field, Chakraborty’s lab in collaboration with Bruce Walker’s group, recently published papers in Nature and the Proceedings of the National Academy of Sciences that focus on HIV. Most recently, they used random matrix theory, a mathematical tool previously applied to high energy physics, economics, and the study of an enzyme family, to identify regions of the HIV proteome that are vulnerable to immunological pressure, what Chakraborty calls the Achilles’ heels of the HIV proteome. For the stock market, random matrix theory identifies groups of companies or sectors for which stock prices fluctuate in a correlated fashion. For example, fluctuations in the stock prices of car manufacturers and car parts companies are typically correlated. While identification of economic sectors is largely intuitive, the interpretation of the HIV proteome is not.

When Chakraborty and colleagues used this model to analyze the available bank of HIV sequences, they identified groups of amino acids or sectors in the HIV proteome that co-evolve to influence viral fitness, with different groups evolving essentially independently. They then identified sectors in which multiple mutations were less likely to occur, presumably because if they did, the fitness cost for the virus would be too great. The most vulnerable sector they identified was in the p24 protein. Researchers have previously shown that six p24 proteins form hexamers and that these hexamers form the honeycomb shape of the viral capsid. Chakraborty’s lab discovered that the amino acids they identified in the vulnerable sectors were at the interfaces between p24 proteins in the honeycomb structure. If too many mutations occur in p24, the hexamers can’t form and align, hindering formation of the viral capsid. Chakraborty and Walker found that the immune systems of HIV controllers disproportionately target these vulnerable sectors.


Now, Chakraborty and colleagues are trying to develop antigens that would direct the immune response to target these vulnerable sectors.

Ragon, a graduate of MIT, founded the software company InterSystems in 1978. Headquartered in Cambridge, the company now has offices in more than 23 countries and assets totaling $335 million. Ragon’s interest in international development stems from his childhood. He recalls riding the bus to his exclusive high school in Bogota, Colombia, and seeing children on the street without a stitch of clothing. As he became more successful in business, Ragon was interested in how he could make a difference to these children and others throughout the world.

To connect with possible charities, Ragon asked his regional managers at InterSystems to keep an eye out for any projects they came across that might be interesting. This is how Ragon eventually connected with Walker.

When the two first met, Ragon recalls Walker saying, “I have absolutely no idea why I’m here.” Ragon suggested he tell him about the things he was doing in South Africa. After that conversation, it was agreed that Ragon would accompany Walker on his next trip there, which happened to be two weeks later, to see some of the work first hand.

Ragon remembers telling Walker, “I go on a lot of trips like this and I rarely give any money.” While in South Africa, Ragon visited patients who were dying of AIDS. “It was quite a shocking event,” he recalls. Ragon also toured the research facilities and saw WhizzKids United in action, a non-profit organization that teaches kids leadership skills through football and also delivers HIV prevention and support services. “I don’t see how anybody can see what I have seen and not want to get involved,” Ragon told Walker. “What do you need?”


In the labs: Douglas Kwon  
Role: Physician/Scientist whose clinical practice in Infectious Diseases is at Brigham and Women’s Hospital

Focus of lab: The application of new technologies to the study of immune responses against HIV at mucosal surfaces.

Because HIV is most often spread through sexual transmission, scientists have long been interested in learning more about what happens at the mucosal surfaces of the genitals or the rectum. In addition to being the primary site of HIV transmission, mucosal surfaces, particularly the gut, also represent the largest reservoir of viral replication. Nonetheless, the study of HIV-specific immune responses has been largely conducted in peripheral blood, which contains just 2-3% of all lymphocytes, because material that can be obtained from mucosal surfaces is limited. “It is challenging to look at immune responses in tissue because it involves an invasive procedure and the amount of material you can obtain is small,” says Kwon.

His lab uses multiple methods of mucosal sampling, including upper and lower endoscopies, biopsies, lavage, and cytobrush. But there are still challenges. “It’s kind of like taking the tools you would use to fix a car and using them to try and fix a wrist watch,” says Kwon, referring to the limitations of conventional assays. His lab hopes to overcome some of these limitations by applying new technologies. “To approach these questions in tissue, you need to develop new tools,” says Kwon. One approach he is applying in collaboration with Chris Love, a chemical engineering professor at the Massachusetts Institute of Technology, uses single-cell assays that allow the analysis of multiple types of immune responses to be done simultaneously on different cell types from a single tissue sample.

Kwon is also looking at ways to “miniaturize” other technologies such as killing assays, where CD8+ T cells from mucosal compartments are analyzed to see how effectively they kill HIV-infected CD4+ T cells. There are many ways to miniaturize assays, such as developing methods to examine cells individually or in smaller groups, or taking a single biopsy and cutting through it to generate dozens of different sections, which can then each be analyzed for the expression of different genes by fluorescent microscopy. Another approach uses microfluidics—a technology that pushes cells suspended in droplets through small channels. B cells in the droplets line up in the channels enabling researchers to choose the cells that exhibit properties they are interested in analyzing further. “Those new tools will expand the types of questions you can ask and the amount of information you can extract,” says Kwon. 


Topping Walker’s wish list was funding for a collaborative research effort that would bring together researchers from different disciplines to solve the long-standing problems that have prevented the development of an AIDS vaccine. Walker had hoped to tap into the $300 million, seven-year virtual consortium known as the Center for HIV/AIDS Vaccine Immunology that was awarded in 1995 by the US National Institute of Allergy and Infectious Diseases (NIAID), but his application was rejected.

Ragon agreed that the idea of an institute sounded interesting, but at that time the idea wasn’t fully formed and so Ragon agreed to fund one of Walker’s vaccine trials.

Three years later, Walker was having lunch with Dennis Burton, professor of immunology and microbial science at TSRI, and Wayne Koff, IAVI’s chief science officer, at the 15th Conference on Retroviruses and Opportunistic Infections in Boston when the talk, once again, turned to the idea of doing something bold and innovative.

Walker phoned Ragon and he, Burton, and Koff ended up having a conversation with Ragon that day about the lack of innovation in the HIV vaccine field. “The thing most people don’t realize is that scientists don’t have flexible funding,” says Walker, adding that the constant chase for grants prevents creativity and discourages innovation. “Failure is a no-no.”

When Walker returned from the conference, he had an appointment on his calendar with Ragon. Once again they discussed this idea and at the end of that conversation, Ragon said that it sounded like Walker would need $10 million for 10 years to be able to get this idea off the ground. “My wife and I would like to do that,” Walker recalls him saying, likening his initial response to an out-of-body experience. This flexible, unrestricted funding allowed the establishment of the institute, which Walker wanted named after Terry and Susan Ragon.


The Leaders  

Bruce Walker, M.D. 
The Ragon Institute 
Program: Adaptive T Cell Immunity

Marcus Altfeld, M.D., Ph.D. 
The Ragon Institute 
Program: Innate Immunity

Dan Barouch, M.D., Ph.D. 
Beth Israel Deaconess Medical Center 
Program: Vaccine/Vector Design

Dennis Burton, Ph.D. 
The Scripps Research Institute 
Program: Adaptive B Cell Immunity

Arup K. Chakraborty, Ph.D. 
Massachusetts Institute of Technology 
Program: Computational Biology

Mary Carrington, Ph.D. 
National Cancer Institute, SAIC-Frederick 
Program: Genetics

Laurie Glimcher, M.D. 
Harvard Medical School 
Program: Basic Immunology

Darrell J. Irvine, Ph.D
Massachusetts Institute of Technology 
Program: Technology Development



Nurturing creativity

Researchers affiliated with The Ragon Institute still apply for NIH grants, and Walker says he spends more time than he’d like on fundraising, but the gift from Ragon, in addition to $14 million donated by Mark and Lisa Schwartz, have created a nurturing research environment for Ragon investigators.

Galit Alter, an assistant professor of medicine at The Ragon Institute, whose laboratory team focuses on innate immunity, primarily natural killer cells, likens The Ragon Institute to a family. “There is just no place like Ragon,” she says. “There is a clear path toward developing your own research. The atmosphere is nurturing and supportive, and you have access to cohorts and technology. If you can’t succeed here, you can’t succeed anywhere.”

This nurturing environment is particularly inviting for researchers who’ve come to Ragon from outside the HIV field, or are early on in their careers. Douglas Kwon, a 39-year-old physician at Ragon whose six-person laboratory is primarily focused on mucosal immunity, is one of those newer scientists. He says flexible funding is especially important when you are starting out. “If you are new and have an idea you believe in, there are mechanisms in place to get support, even if it is just in the initial stages,” says Kwon. “That is something that is unique and great here.”

The Ragon Institute has tried to support young investigators by offering innovation awards of up to $100,000. “When you give young, talented, creative people that flexibility, those sorts of things are transforming,” says Walker. “It’s incredible.”

But others suggest Walker also deserves credit. “There’s no question that money helps,” says Ragon. “But money alone certainly doesn’t do it. It’s Bruce’s ability to get people working together that makes a difference.”

Thumbi Ndung’u, scientific director of the HIV Pathogenesis Programme at the Doris Duke Medical Institute in Durban, South Africa, which Walker helped launch, says The Ragon Institute has helped solidify longstanding academic and research relationships in South Africa. It has also expanded opportunities for young investigators to train at laboratories in Boston and then return to South Africa, or vice versa.

“The model that Ragon has used to do their work in South Africa has very much adhered to the idea that the research should be done locally, usually by South African scientists, even students,” says Ndung’u, noting that this model is unusual, even in a middle-income country like South Africa. “A lot of other groups working in the developing world do their research elsewhere and when they publish papers, they are the lead authors.” Ndung’u, who met Walker when he was studying at Harvard, says The Ragon Institute director has an “infectious optimism.”

Arup Chakraborty, a professor of chemistry, chemical engineering, and biological engineering at MIT, was one of the researchers recruited to Ragon from outside the field of HIV. Chakraborty’s work involves applying statistical physics to understanding basic immunology. Prior to joining Ragon, this meant working mostly with cell lines and mouse models, but Chakraborty is now spending more and more time focusing his skills on HIV. “I’m really enjoying what I’m doing with HIV,” says Chakraborty. “I don’t think I’ve enjoyed science so much. And it’s funded by something that allows me a lot of leeway to think about new ideas,” he says.

When Walker came to talk to Chakraborty about joining The Ragon Institute, he wasn’t interested initially because he was happy with what he was doing, and he felt too many other researchers were studying HIV.

“It seems to me you need to be super bright to contribute something, and I’m not super bright,” Chakraborty told Walker. “Why would I do this?”

So Walker asked Chakraborty to travel to South Africa with him. When he returned from his three-day trip, Chakraborty had a different take. “I felt that even if I contribute in some small way it was worth doing.”

Two years of progress

Walker believes the 14 laboratories that comprise The Ragon Institute have a chance to do transformational science that will contribute to the development of an AIDS vaccine. “I’m absolutely convinced that this is a viable recipe to speed scientific discovery,” he says.

However, not everyone agrees with some of the research approaches The Ragon Institute has taken. Mark Connors, chief of the HIV-specific immunity section at NIAID, disagrees with some of the conclusions the researchers have drawn using computational immunology. “We need to understand why people don’t control the virus and a lot of this basic immunology,” says Connors. “But is taking a space shuttle view of the problem and coming up with an attractive answer moving the field forward? I’m not so sure.”

Connors cited a few examples. The first was findings published this year in Science that suggested the mechanism by which protective human leukocyte antigen (HLA) alleles function is through specific amino acids in the binding groove. But Connors says that these amino acids are the signature for the B57 protective alleles and so are simply a proxy for B57. In another example, control of the virus was associated with having CD8+ T cells with certain specificities.

He went on to cite, among other examples, findings published last year in Nature from a computational model developed by Chakraborty. The findings suggest less rigorous thymic selection may explain why people with human leukocyte antigen B57 gene are able to better control HIV, and that people with B57 can better control viral load in part because their CD8+ T cells are more likely to recognize a diverse array of HIV peptides presented by major histocompatability class I molecules on the surface of HIV-infected cells (see Research Briefs, IAVI Report, May-June 2010).

Connors says the model runs counter to a considerable body of work and should have been validated to see if the findings held up. “Computational models are an interesting exploratory tool, but the answers that come out of them need testing in additional cohorts and experiments that rigorously test the hypotheses to determine if they are correct,” says Connors.

But others say the work being done by The Ragon Institute enriches the field. David Baltimore, a Nobel Laureate who helped found the Whitehead Institute, thinks Chakraborty’s work is the best example of this. “I think it will be quite significant because it enables people to think about making a vaccine in new and sophisticated ways,” says Baltimore. “In the spirit of trying every possible avenue to this difficult problem, collaborations between physics, chemistry, and biology are very important.”

“This is one of the rare occasions when what’s occurred has actually exceeded my expectations,” says Ragon. Earlier this year when the second scientific advisory board meeting for the Institute took place, Ragon says the board members were “taken aback by the work that had been done.”

Certainly, the determination of Walker and the Ragon investigators is unwavering. “I believe that this is a solvable problem,” says Walker. “It’s going to take a lot of people working together. We’re going to do everything we can to contribute to a community effort to solve this problem. Our goal is not that we be the ones to make a vaccine; our goal is that we contribute to making a vaccine.”