A Man of Many Hats
David Topham chases pathogens, talks computerese and has a quest of his own.
By Michael Wentzel
Ask biologist and influenza researcher David J. Topham, Ph.D., what he does at the University of Rochester Medical Center and you could get a long answer.
Topham is a University vice provost and executive director of the Health Sciences Center for Computational Innovation.
He is director of the National Institute of Allergy and Infectious Diseases (NIAID) Respiratory Pathogens Research Center, which is based at the Medical Center.
He is co-director of the New York Influenza Center of Excellence (NYICE), also at the Medical Center.
A professor of microbiology and immunology in the David H. Smith Center for Vaccine Biology and Immunology, Topham also oversees his research lab and mentors scientists.
“I do wear a lot of hats,” he said.
Topham has so many jobs that he has to use two business cards because he can’t fit all his titles on one card.
“David Topham is a productive and insightful scientist. His leadership and his versatility are essential for our research utilizing high-performance computers,” said Mark B. Taubman, M.D., dean of the School of Medicine and Dentistry. We’re aiming high and we have confidence the potential will become results.”
A biologist by inclination and by training, Topham has concentrated his research on immune responses to virus infections, with an emphasis on respiratory infections and influenza.
His early career work produced a series of significant and influential papers establishing the relative importance of CD4 and CD8 T cells, B cells and cytolytic pathways in controlling influenza in the respiratory tract. After joining the Medical Center faculty, he shifted his research to secondary immunity and mechanisms of cross-reactive immune responses to influenza.
He and his team discovered that the collagen IV-binding alpha-1 integrin is essential for establishing and maintaining memory CD4 and CD8 T cells in the respiratory tract.
In the absence of these tissue-memory T cells, protection from secondary infection is severely diminished in spite of substantial memory in the lymphoid organs. These studies demonstrate the critical role of tissue-localized memory for immune protection in non-lymphoid peripheral tissues.
Topham has moved into clinical and translational studies of human immune responses to natural infection and experimental vaccines, with a major emphasis continuing to be cross-reactive T and B cells. Working with computational biologists, he has developed highly sophisticated mathematical models that simulate the adaptive immune response to influenza.
His newest hat is as director of the Respiratory Pathogens Research Center (RPRC) that NIAID views as a resource to do research on respiratory infections, targeting most other fungal, bacterial and viral pathogens, but excluding mycobacterium tuberculosis.
“It surpasses anything we’ve ever done in ambition and complexity,” Topham said. “I’m called the director but I’m only a ringleader. This is the work of many people. We had to have a very substantial infrastructure to do the studies they want us to do. I can’t take credit for winning the award. We’re relying on expertise in Rochester, which is substantial.”
Ann R. Falsey, M.D. (R ’86, FLW ’91), professor of medicine at the Medical Center and an infectious disease specialist at Rochester General Hospital, helps direct the RPRC. She is an internationally known expert on respiratory syncytial virus (RSV) and leads the team’s efforts to understand the virus and any future trials of vaccines and treatments.
More than a dozen researchers are involved in the RPRC.
Edward E. Walsh, M.D. (R ’77, FLW ’82), a professor of medicine at the Medical Center and also an infectious disease specialist at Rochester General, for example, is investigating severe RSV disease in children younger than one year of age. Gloria S. Pryhuber, M.D., a neonatologist and the George Washington Goler Professor of Pediatrics at the Medical Center, is building on her well-established work in inflammatory lung disease in children.
The RPRC establishes a new model for the way research will be conducted in the future, Topham said. The New York Influenza Center of Excellence, for example, follows a traditional model in which individual investigators conduct individual projects in their own research domain.
“It’s all focused on influenza, but it is not necessarily a coordinated effort where all the resources of the center focus on a small number of problems,” he said. “The RPRC is different. We research questions that could come from NIAID or from clinical faculty. We build an infrastructure to address the questions that involves many different technologies.
For one investigator to do all these together is a lot. By having investigators each take a piece, we can address some big questions and do it in a coordinated fashion. The idea is to integrate data sets once they have been generated by the different investigators. We’re pulling in new investigators and new resources from across the University. This is how research is going to be done down the road.”
Topham envisions a project on lung infection that not only involves a study of gene expression, but also investigations of microbes present in the gut and the respiratory tract during infections and how that conditions the immune system. This data would be combined with disease information and medical histories from subjects themselves to better determine how the disease works and how vaccination works.
“It’s pretty ambitious,” he said. “It requires multiple investigators. You have to be able to organize them, keep them focused and keep them happy.”
Blue Gene muscles
These days, Topham also often finds himself knee-deep in the world of high-performance supercomputers with his work in the Health Sciences Center for Computational Innovation (HSCCI).
For the last seven years, he has been involved in a project utilizing mathematical modeling of immune responses to influenza. It has transformed into an informatics approach, studying gene expression, proteomics, cellular parameters
and clinical parameters to try to develop a multi-level model to identify the key control points of the immune responses to flu vaccination. This project in the Center for Biodefense Immune Modeling at the Medical Center, directed by Martin Zand, M.D., Ph.D., and Hulin Wu, Ph.D., demonstrates the possibilities of biomedical informatics, Topham said.
This summer, as part of a partnership between the University and IBM, the University received IBM’s Blue Gene/Q, one of the most powerful and efficient computer systems in the world. The Blue Gene/Q will provide additional muscle for the HSCCI that Topham leads.
In 2008, the University created the HSCCI in partnership with IBM. In the same year, IBM gave an earlier generation Blue Gene supercomputer system – the Blue Gene/P – to the University. Since that time, more than 500 scientists at the University have used high-performance computing in their research and the center has helped attract at least $107l; million in new funding.
“I’m not an IT whiz and some of this goes way beyond my personal comfort zone,” Topham said. “But one of the things I am realizing is that I am good at is getting people to work together. I’m good at setting up collaborations, good at identifying scientific direction for different projects. It’s not my skills in computing or modeling or even immunology that were reasons they wanted me to lead the center, but because I could communicate with computational biologists and our researchers. I know enough about both domains to at least get the conversation started. I can identify who should be talking to one another and facilitate those collaborations.”
Falsey agreed with Topham’s self-assessment, saying he is “quite adept at identifying good people and bringing them together for productive collaborative research.”
“He has a unique ability to understand the science of respiratory research on a very deep level yet also has the vision to imagine what a center should be and how to grow a program,” she said.
The HSCCI should move to expand more deeply into computational biology, Topham said.
“I am encouraging everyone to move in that direction. I am looking at investigators across the University who have informatics or computational needs but don’t know how to access the technology,” Topham said. “I view one of my roles as opening up these tools to those investigators. There are opportunities all over the place for others to benefit.”
At meetings with high-performance computer scientists, Topham admits, he finds it difficult to “talk the talk.”
“But that isn’t what they need,” he said. “What we need are translators. When you have computational biologists, mathematicians, statisticians and basic immunologists, biologists and clinicians come together, they talk different languages. They can work together, but they find it very hard to communicate. We have a data problem. We need to build the translators who work at the interface of molecular biologists, the cellular biologists and clinicians and people who use computational and mathematical approaches to deal with the data that is generated. We now can generate far more data than we can ever analyze or interpret, so we have to create tools and methods and hardware and software to really make the most of the studies we are doing and data we generate.”
Topham and others at the University are discussing a training path for “translators” that could develop into an undergraduate and graduate program.
Part of a grand plan
Kristin M. Scheible, M.D. (M ’04, R ’07, FLW ’10), assistant professor of pediatrics at the Medical Center, found herself in Topham’s lab as a neonatology fellow. She had little laboratory training, but was interested in a research career.
“I soon learned that Dave’s willingness to take on the training of novices is not a common trait in competitive academic research,” Scheible said. “It is a characteristic, however, that defines him as a scientist. Dave is consistently able to identify potential in his trainees as future scientists moving the field forward, potential in his colleagues as future collaborators, potential in new technology to advance discovery, and potential in ideas to enrich scientific understanding. He approaches other perspectives, whether clinically or laboratory-oriented, with a positive attitude, providing a fertile environment for novel ideas and connections. No idea or individual is ever dismissed.”
Although Topham’s lab focuses on influenza research, he provided guidance and resources to Scheible so she could pursue her own research interest in neonatal T cells. For some time, Scheible said she could not envision how her work would benefit the lab’s mission. After several years, Scheible said she saw the grand plan.
“One of the priority projects for the Respiratory Research Pathogens Center addresses infant immune development, specifically how an infant’s T cell responses are shaped by the viruses and bacteria to which they are exposed,” Scheible said. “Partly through his investment in my tangential project, he was able to build collaborations and experience that resulted in a fundable translational study. This was one more example of Dave’s ability to focus beyond the present and his commitment to a bigger vision that moves science forward.”
Topham’s T cell quest
Since he was a post-doctoral fellow more than a dozen years ago, Topham has maintained a personal quest as a scientist.
“I always have wanted to understand how cytotoxic T cells function in the airways,” he said. “Influenza is an infection that only takes place in the epithelial cells that line the respiratory tract. Immune cells have to get from the lymph nodes through the blood to the tissue and then exit to the epithelial layer where they seek out infected cells and kill them. That means they have to move a lot. We don’t know how this is regulated. We have some ideas of what molecules and receptors might be important, but no one has been able to directly test at the site of the infection in tissue to see how these cells work.”
The technology now exists to make site visits possible. Using a multiphoton microscope, scientists can image the cells in real time in live animals.
“We can watch the cells migrate. We can interfere with them. We can see the target cells,” Topham said. “We’re trying to study the environment of the tissue, the proteins that form the structure of the tissue, because the T cells have to interact with those structures. I want to see this project develop because it is important. This is where we will find new ways to combat infection. Having virus-specific T cells in the airways at the time you encounter a new infection means you can resist an infection more effectively. If we can immunize in a way to place those cells in those locations, we would have better vaccines. First, we have to understand how they get there, how they stay there, and how they move around before we can figure out how to immunize in a way that promotes those cells.”
His work with the New York Influenza Center of Excellence (NYICE), which is directed by John J. Treanor, M.D. (M ’79, FLW ’85), has echoes of his personal research target.
“Our main question is: How does an influenza infection or vaccination affect the immune system?” Topham said. “How did the virus or vaccine modify someone’s immune status? Were more antibodies elicited or different kinds of antiÂbodies that could neutralize the virus or cross-react with other viruses? Would the virus or the vaccine modify T cells, what their specific functions are?”
A better understanding of the immune response to influenza could result in the ability to design a way to immunize so the immune system would cross-react to many influenzas.
“Some people call it a universal vaccine. I hesitate to say that. It is almost a clichÃ©,” Topham said. “We know cross-protection exists, but we don’t know enough about how it works. So, we have a lot of projects focused on it. The jury is still out on this but we (the NYICE investigators) found that, with CD4 T cells, the immune system predominantly responds against pieces of the influenza virus that it has seen in the past.
“With the CD8 response, we actually found the near opposite. When the immune system sees a new virus, not only does it respond with T cells that have seen the influenza before, it also mounts new responses to the virus to things that are unique to the new infection. That is a pretty fundamental, new piece of information. We now know the immune system, at least in healthy young-to-middle-age adults, remains plastic and mounts new responses. That is important if you want to design a vaccine. If you can’t respond to new things, you want the vaccine to contain a lot of the old things that are conserved among many viruses. If they can see new things you can immunize and tailor it to what is circulating today.”
Topham’s enthusiastic commitment to his work is infectious too, Treanor said.
“I think David has a remarkable ability to remain optimistic in the face of daunting challenges, and to see the opportunities in situations that may not be obvious to others,” Treanor said. “Both of the two large projects that I am involved in with David, NYICE and the RPRC, were really intense competitions with other groups, most of which were considerably larger and probably more accomplished than we were.Â But David has this vision of ways that we can contribute something that others can’t and this real knack for figuring out the pathway for bringing a lot of people together in unique collaborations.
“Obviously, it’s driven by a very broad understanding of scientific topics from multiple points of view, but it’s also a product of a very engaging personality and this sort ofcan-do” perspective towards problem solving. David is extremely passionate about his work, and I think that rubs off on others also.”
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