How did you get interested in virology? My father was a physician in ‘general practice’ who made rounds at the hospital on Sundays after church. I went with him frequently and stayed in laboratories and not on the patient wards. I loved seeing all the equipment in a lab, fascinating since I wanted to know what all those things did. My father and grandfather, also a physician, were both students of medicine and medical history so I was aware of Pasteur, Fleming, Osler and Semmelweiss long before any of my classmates. I still have many of my father’s books in my library at home. After graduating from Holy Cross College in Worcester, MA, I worked for several years as a lab assistant for Dr. Sue Hanlon in the Department of Biophysics and Biochemistry on DNA structure, a brand new science then in the late 60s. The Microbiology Department was down the hall and one of their faculty had been at UC Berkeley with Sue. He would stop in the lab and chat about working on viruses that caused cancer, a new finding then, the mouse mammary tumor virus. I got interested in that since I usually did experiments in biophysics using analytical ultracentrifugation and moving boundary electrophoresis, the forerunners of optical based laser sensors today. I never saw anything I worked with since base stacking interactions of nucleotides were only visualized as images and then interpreted by mathematical calculations. I would make a few analytical runs over one week and then calculate data using a number 2 pencil and yellow pads for maybe 3 weeks. So when I saw that experimental animals developed large tumors in a few months that were caused by an infectious agent like a virus, I gravitated to that work, remembering some early reading of those medical history books. When did I come to NIH and what brought me here? What brought me here were owl monkeys who had intracranial injections of this new human polyomavirus, JC virus and then developed gliomas not progressive multifocal leukoencephalopathy (PML). I worked with BK virus as a postdoctoral fellow and helped establish the Tumor Virus Genetics Group at the University of Illinois Medical Center where I got my doctoral degree studying the Oncogene hypothesis. Dr. John Sever was the Chief of the Infectious Diseases Branch (IDB) at NINDS. His group investigated more conventional agents of infection in humans so took on the challenge of trying to make a non-human primate model of PML, but was getting only gliomas. John knew that I was in Chicago, now at Loyola University Medical School faculty but that I was the first to describe the oncogenic potential of BK virus in 1974 that was published in PNAS. So he invited me to do a sabbatical for one year in 1981 at the IDB and put together a working group for JC virus. After the year ended, I was given the opportunity to stay at NINDS. That was a difficult decision both professionally and personally since I was tenured in Chicago. The position in Chicago and Bethesda could not have more different. But if I wanted to make a difference in medical science, NIH was the place to do that. So I like to say that I have had a more than a 3 decade sabbatical here. How has science evolved over the years at NIH and in the academic community? There are several differences in the way we do our work today compared with even 10 years ago. First, the accessibility of research materials is much greater from common lab reagents to more sophisticated gene clones, molecular techniques, and contract companies to do the tedious work. Many components come in kits these days, it’s the ‘lego world’ so we only need to piece things together. Second is the increasing number of opportunities to publish with so many journals available to send in manuscripts. Certainly not all journals are equal in quality but with such rapid publication and Pub Med reaching so many scientists globally, the emphasis seems more on getting something out, incrementally, and not on substantial results. Third is the sense of competition among labs and scientists. There should be more collaboration and less competition. But at times of resource restrictions, it is inevitable that competition takes the lead. But that creates an environment of mistrust; and a healthy science community relies heavily on the opposite, a trust based, honor system. The NINDS and NIH have evolved as the times have changed, mostly driven by technology. In the time here, I have seen HIV/AIDS, the Human Genome project (and the incessant need to call a project area an ‘ome’), more clinical trials, biomaterials and biodefense stratagies, new technologies at the nano level. The NINDS has moved and adapted well to the recognition of the nervous system, mostly the brain, as the ‘new frontier’ to study. In that arena however there is a division between fundamental neuroscience and neurological disease as to which should be the starting point for investigations of that ‘frontier’. With technology advancing at rapid paces, there has been an introduction of stronger administrative influence over programs and their support. Of course the NINDS and NIH have grown to twice their budget since the late 80s so oversight was necessary but it should match the NIH mission and not drive that mission. As a government agency however, the NIH increasingly tries to navigate its way through environments of regulations and guidelines that are neither relevant nor applicable to an organization whose main goals are discovery. I like to say that we at the NIH are in ‘the discovery’ business unlike most other federal government agencies. So we rub against trying to be a part of a larger structure like the federal government while working in medical science in our own unique way. So it’s not surprising that this results in ‘inflammation, acute and chronic’, that is treated mostly symptomatically without a direction for a cure. All that said, there is no better place to accomplish great things than at the NIH. What are your major accomplishments? I’ll keep to the work on PML to answer that. As a lab chief here and before, I have always taken the approach of identifying the problem first and then looking for answers to solve the problem. I have often told the NINDS that working in human virology requires research to be disease oriented. That has always been of greatest interest to me anyway. PML was considered such a rare disease that I would include it only at the end of my medical school lectures as what I called the ‘back of the text book’ diseases, spending maybe 5 minutes on it out of 28 lectures. So when asked in 1981 to tackle PML as a viral induced demyelinating disease caused by JC virus, I knew we had to create new tools to get answers and then focus on the disease pathways. Since it was clear that primary infection with JC virus was not in the brain, we started looking at other peripheral organs. And to do that we had to build new tools, new techniques to get answers. To summarize a list of ‘big results’, I’d say 1. making the SVG cell lines from human fetal brain to allow more available relevant host cells, that later led to 2. isolating human neural stem cells from the developing brain using 3. our unique anti-nestin antibody that the NIH now has licensed to 13 commercial companies for sale contributing to stem cell biology; 4. Developing in situ DNA hybridization methods for JC virus DNA detection that led to 5. Identification of immune system cells as a primary site of infection and the link between cells of the immune system and the brain at the transcriptional, molecular level’ that led to 6. Involvement of hematopoietic stem cells and similarities to neural stem cells; and 7, the development of quantitative specific measurement of viral DNA in clinical samples, qPCR, that were validated and certified as a diagnostic for PML. The LMMN has become the global focal point for studies on JC virus and PML from the fundamental molecular biology of the virus of its narrow host range to cell models of infection to pathogenesis in patients; a problem solving approach not so much a technical focus although we built a lot of new technology to do the problem solving. I think there are a few more ‘big results’ left to come. This would and should be in areas of therapies for PML patients. What is the next major challenge in PML research? The current emphasis is on determining which patients with underlying immune deficiencies are at greatest risk for developing PML. The use of biological therapies, mostly monoclonal antibodies, that modulate the immune system like the α 4 integrin inhibitors such as natalizumab for MS patients has focused attention on PML as much as HIV infection. Actually the highest incidence of PML as a percentage of patients treated occurs in MS patients treated with natalizumab. That has always impressed me since I am not sure that two neurological diseases occur in the brain of a single patient much less two demyelinating diseases. The emphasis is now on what is called ‘risk stratification’, driven a great deal by the FDA that requires biotech and pharma companies to include metrics for assessment of PML as well as education programs for treating physicians and their patients. In order to do risk assessment however, we need to know what is most important to measure about JCV and PML. There is a great deal of work (and competition) to determine whether that measurement should be antibody to the virus, presence of virus in circulation, new clinical neurological symptoms or new brain lesions or what I prefer is a combination of all of these events. Of course as I mentioned, some way to treat PML patients or patients on therapies or have underlying diseases that place them at greatest risk for PML. So an investigation that combines knowledge of risk factors with a treatment strategy for prophylactic and therapeutic use should be the highest on the list. What has been your experience on the interactions of academia with industry? I cannot stress enough the importance of collaborations with all aspects of the scientific and medical enterprise particularly in these times of resource distribution for research that is increasingly diminishing in government like the NIH. My lab here at NINDS has had agreements of all types with both academic and industry for years. There are over 12 companies that we have worked with from the start of Enzo Biochem for the development of the in situ DNA hybridization test, the JCV probe they sell still use our first paper for their QC sheet, to the recent patent on the multiplex qPCR assay. No one group has all the expertise to compete these days on important projects worth doing. Reaching out to stakeholders, offering your knowledge, ideas, and methods to join forces is the most productive course to take. Is it difficult at times to convince others to join in or worth the complex paper work to forge agreements, the answer is absolutely. The best way to overcome obstacles is to create opportunities to work with others regardless of their institutions, find common ground in which all parties are equal contributors, everyone brings something to the task at hand. The one caveat in this however is to select partners in this enterprise carefully, choose people first then institutions. The advice that resounded from the book by Tom Peters ‘In Search of Excellence’ on organizational structure was ‘only work with people who are nice’. Sometimes you’ll have to compromise on that but it is a goal to keep in mind. When I was Acting Deputy of NINDS, Bob Waterman was on the NINDS Council. Bob was co-author on that book so we spent some time talking about large and small companies and their organizational plans, how they did business. Running a research lab or clinical practice is not that much different than running a small company. What advice do you have for young investigators? Be committed to what you want to do, move your career in a direction that is aligned to what you are passionate about, be strategic in planning, and just plain work at it. It’s always good to remember there is lots of competition for resources and that competition is working at goals 7 days a week, in the lab, the clinic, and on line. And don’t be afraid to move into new areas or take on new challenges if that is consistent with your goals. I would never have made the switch from viral oncology to neuroviology unless I saw that I could take all the tools I had, the interest in infectious agents, and background in DNA structure and apply those to working in the brain. I’ve never formally studied neuroscience or neurology but have had ‘on the job training’ for more than 3 decades now. It’s been fascinating and challenging and very rewarding. And if a new field in science seems interesting, see how you might incorporate that into your work. That’s how we got into the stem cell field, found neural progenitor cells and then used viral infections to investigate stem cell differentiation. It all fits from various approaches to a single focus. I would also suggest reading two books that are not in the medical lexicon of bibliography. One is Thomas Freidman’s ‘The Lexus and the Olive Tree’ that describes the influence of history and culture that has deep roots in behavior symbolized by the olive tree rubbing up against the fast paced and technical precision of modern life represented by the Lexus luxury automobile. The other book is Jim Collins, ‘Good to Great’, describing what factors make for successful organizations, the characteristics of leadership, and what are the best motivators for success. Both books emphasize the importance of self awareness, how you might measure your own success, and what drives your work ethic. I have several copies if anyone wants to borrow them! Collins did a very short but powerful book a few years ago, ‘How the Mighty Fall’, a must read for anyone with a critical thought. Of course Freidman’s book ‘The World is Flat’ is a chronicle of how we live now and in what world we live in. What are your future plans? I had decided to step aside from public service after 33 years at NIH in January of this year, add another 8 years from times in Chicago and you have over 40 years since I was awarded my Ph.D. degree. I am now a Senior Advisor to NINDS so have a different role but still in the discovery business with PML and all its challenges in the lab and in the clinics helping to support patient oriented work. I do have time to continue to work with academics and industry but more as an independent person with insights and ideas that I think need expansion in a different environment. And of course there is always that temptation to write that great story or chronicle the history of NIH in the modern era. I have a colleague whom I have known since we were graduate students in the late 1960s. We have many fascinating experiences in this business and NIH. We sat down years ago and started dictating our view of what goes on in the research world, the people, the intrigue, how progress is made or blunted. We may go back to the tapes we started and move on from there. Not likely a big seller if we ever finished. And I still remember writing a great story about my first trip to Italy, sending it off to The New Yorker, and getting a short reply of rejection. That letter is framed in my library at home, keeps me more realistic, but at least The New Yorker read my story. The nice thing about future plans at this stage in my career is that trying new things is the accomplishment. Whether success comes later is important and needed but that can be managed more easily; success is measured differently now. And of course there are the 5 grandchildren; they are the ones with the future plans. |
