Esther Ndungo

Esther Ndungo

Credit: Kartik Chandran

The road to Ebola

A structural biologist, a molecular virologist, and a microbiologist walk into a bar. It could be the start of a bad joke—or a meeting of diverse researchers who have converged on the study of the Ebola virus. Ebola research, which until recently was chugging along more or less unnoticed, is populated by a diverse group of scientists. Some are focused on developing vaccines and therapeutics; others work out in the field. A third group primarily studies basic biological questions about how the virus works—although, even before the recent outbreak, their work was starting to shift toward the translational. The outbreak raging in West Africa finds them in an unexpected spotlight and highlights the chance events that can be seminal in a research career. 

Serendipity stories

Structural biologist Erica Ollmann Saphire, a professor at the Scripps Research Institute in San Diego, California, started to think seriously about Ebola as her postdoc was drawing to a close. A two-body problem was keeping her at the institution where she studied HIV for her postdoc (and her graduate training), and she didn’t want to compete with her former advisers. She happened to be reading Virus Hunter: Thirty Years of Battling Hot Viruses Around the World, in which virologist C. J. Peters describes his work combating Ebola in Africa, Nipah virus in Malaysia, and Bolivian hemorrhagic fever, among other viral scourges. “I was fascinated by the tales of that generation of scientist and what they did going into the field,” Saphire recalls. It “drew me into the primary literature [about Ebola], and I saw there were all these questions that really needed an x-ray crystallographer to solve.”

When I started, therapeutics were not on my mind, but I think it’s a natural evolution.

—Kartik Chandran

Erica Ollmann Saphire

Erica Ollmann Saphire

Courtesy of The Scripps Institute

She was particularly intrigued by evidence that the viral protein crucial for infecting cells is only produced when the cell's machinery misreads the viral DNA; otherwise, the gene produces a “decoy” protein that is secreted. The proteins have similar sequences but potentially different structures, which is contrary to conventional wisdom. Digging into this question appealed to her on two levels. On the one hand, she says, “there’s the purely nerdy intellectual question of, 'Can this be true and where else might it exist?' ” On the other hand, there was the potential to help inform the development of vaccines and treatments down the road, because the decoy protein could interfere with treatments targeting the critical protein. “This virus is one of the worst we know, and we need something to fight it,” she says.

Now, 11 years after deciding to tackle the virus, she directs the Viral Hemorrhagic Fever Consortium, a collaborative global effort to develop and test antibodies for viral disease vaccines and treatment. The consortium’s work was crucial for the development of ZMapp, the experimental antibody cocktail used to treat a very small number of Ebola patients, including two American aid workers infected while in Africa.

Kartik Chandran, an associate professor at the Albert Einstein College of Medicine in New York City, ended up studying Ebola due to similar coincidences of timing and circumstance. Chandran started working on Ebola in 2003 during his postdoc with virologist James Cunningham at Harvard Medical School. He wanted to study the mechanism of viral entry into cells, and Ebola provided an interesting case. “Something with Ebola didn’t quite add up,” he says. It seemed to be “violating the dogma” established with HIV and flu that the viral surface protein needs to be cleaved for the virus to enter the cell. The virus he had studied previously suggested an explanation for this puzzle, so he felt he was “sort of primed” to investigate the mechanism in Ebola. “I was just the right person to ask that question at that particular time.”

One thing that inhibits research into Ebola is the safety precautions needed; the virus can only be studied in biosafety level 4 (BSL-4) labs, which are rare and in high demand, and working with the virus in these labs requires extensive safety training. But the stars aligned again for Chandran. A system developed a few years earlier meant that researchers could use a common laboratory model virus to study individual Ebola virus components, allowing Ebola research to extend beyond BSL-4 labs. This development was all Chandran needed. “I jumped onto that [system] because we didn’t really understand much about Ebola, and there were some interesting questions that were raised by previous work,” he says. As his research progressed and he and others began unraveling the sophisticated mechanism by which the Ebola virus enters cells, he was “bitten by the Ebola bug” and made studying the virus a key focus of his lab, which he started up in 2007.

Basically translational

Kartik Chandran

Kartik Chandran

Courtesy of the Albert Einstein College of Medicine

At first, Chandran's focus was still mainly on fundamental biological questions, but over time, he has become increasingly interested in applications, while maintaining the basic research side. “When I started, therapeutics were not on my mind, but I think it’s a natural evolution,” he says. Right now, for example, his lab is part of a consortium that is working to understand how ZMapp works. This basic question about viral behavior has significant translational implications. The results could help scientists develop a new formulation that is more effective, or easier to manufacture, by suggesting, for instance, that certain elements of the cocktail should be removed or replaced. Over time, and especially in light of the current crisis, “I’ve definitely been taken with this idea that we could try to do something to help with the human disease in terms of leveraging the work that we’ve done.”

Christopher Basler, a microbiology professor at Icahn School of Medicine at Mount Sinai in New York City who began investigating Ebola after spending much of his training studying influenza, also straddles basic and translational research. He has developed a variety of high-throughput screening assays, initially with the intention of dissecting the mechanism by which viruses, including Ebola, inhibit cells’ innate immune response. Understanding this basic question is still a large component of his work, but time and the recent outbreak have shifted his perspective. Over the years since starting his lab, in 2002, he has adapted these screens to identify novel treatments for the virus, and he plans to continue pushing in this direction. “It’s a natural progression,” he says. “The scope of the epidemic and the fact that cases were imported into the United States and Europe reinforces the importance of these viruses as pathogens and public health threats, and drives home for us the idea that we need to be looking really seriously at ways we can translate our basic science into potential therapeutics. Moving forward, I’m much more likely to take our basic observations to screening assays” to identify novel drugs and drug targets.

While the current outbreak increases the scientists’ focus on vaccines and therapeutics, they emphasize the generalizability of their work. “I always try to paint it broadly, that my work is not just about Ebola but also about understanding the basic mechanisms of viruses,” Chandran says. “If you can uncover principles of engagement between virus and host, you learn lessons that are often broadly applicable.”

Saphire, who among other topics investigates the unusual behavior of Ebola proteins, sees her work as an opportunity to explore the boundaries of what biology can do. Because viruses can evolve so quickly, she says, they may provide examples of biological behaviors that haven’t developed in more slowly evolving organisms. “Looking at what a virus can do, you learn a lot about what a protein can do, and you learn a lot about the immune system,” she says.

The future

While many of the Ebola researchers active prior to the outbreak took winding roads to the virus, the emergence of Ebola as a global threat is attracting new scientists to the field. “We’re definitely having a lot more people calling to collaborate, people who have never wanted to work on Ebola before,” Saphire says. Basler says he has been “inundated” with requests for reagents from researchers who have not previously worked with Ebola.

“It’s opening up synergies for us,” Chandran says. While his work has always included collaborations with experts in other disciplines, including genetics and biochemistry, he sees the current environment as an opportunity to participate in interdisciplinary research that had not previously been possible. He hopes to pursue projects such as developing therapeutics with chemists, working with biophysicists to study protein conformational changes relevant to viral entry into the cell, and investigating cellular trafficking pathways relevant to the viral life cycle in collaboration with cell biologists. He suspects that if he had approached these scientists a year ago, they would not have worked with him because the motivation and money weren’t there. Now, though, with the outbreak raging and new urgency to develop therapeutics and vaccines, “that calculus has changed” and they’re knocking on his door.

Basler, too, views the new interest in the field as advantageous. Having more researchers “approaching the field with a different perspective is probably beneficial,” he says. He hopes that those who enter do so because they “want to provide some unique insight into the field and think they have something unique to offer.”

Esther Ndungo

Esther Ndungo

Credit: Kartik Chandran

For trainees with interest in Ebola, including Esther Ndungo, a fifth-year graduate student in Chandran’s lab, more researchers in the field could mean more opportunities to study different aspects of the virus. She is not sure whether she will continue studying Ebola during her postdoc, she says, but she is excited to have more choices than she might have had just a few years ago. “I hope I have more opportunities to choose from and that I can really think about what part of the problem I want to work with,” she says. 

Those working with the virus don’t seem to be worried about increased competition per se, but Saphire hopes the field’s culture doesn’t change too much. “A nice thing about the filovirus field is that it was populated by very straightforward, salt-of-the-earth people,” she says. “It was founded by people who were willing to get on horses and go to some remote place and find some deadly virus. … Personal glory doesn’t matter. Authorship doesn’t matter; you just want to save lives.” Saphire cites the Viral Hemorrhagic Fever Consortium, which required collaboration between many researchers in the field who shared their best antibodies with each other, as an embodiment of that spirit. “I don’t know if in any other field you could have gotten everyone to cooperate like that,” she says. “If there’s a flood of entirely different people, will the flavor and collaborative nature of the field change? I don’t know. Probably.”

Regardless of the eventual outcome, the Ebola epidemic and its resulting effects on basic and translational research, whatever they may be, illustrate how difficult it is to predict the future of a research area and the great extent to which the unexpected influences careers.

Advice for those considering a career working with Ebola

  • Read the literature. Learn how Ebola is different from other viruses. Figure out what specific questions need attention. 
  • Think about how your training and expertise could provide a unique perspective that would be valuable to the community.
  • Don’t enter the field if your interest might be short-lived. The research effort will be damaged if investigators flood in and then leave before they can make an impact.
  • Be patient. Even scientists already working with Ebola are unlikely to play a direct role in resolving the current outbreak. The impact is more likely to be seen in the long run, so don’t get frustrated if your work doesn’t have an immediate impact.
  • If you’re not interested in doing BSL-4 research, cultivate good relationships with people who can do that work. You will need their cooperation to validate any results you obtain from the model systems used to study the individual viral components. It is crucial to confirm your discoveries early in the live virus so you don’t waste time chasing artifacts.
  • If you're an established scientist, collaborate with people already working in the field. If you're a trainee, find a mentor or senior collaborator. The knowledge and relationships you gain will help lubricate your entry into the new field and allow you to leverage their knowledge to do the most impactful work possible.

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