Dan Colley’s Autobiographical Physical and Conceptual Meanderings
Professor and Director of Center for Tropical and Emerging Global Diseases
The University of Georgia
Department of Microbiology
"A child was born, just the other day. He came to the world in the usual way." But wait, that’s neither my song (apologies to Harry Chapin; Cat’s in the Cradle), nor was it "just the other day." While in some ways it does not seem so long ago (to me), I was born in Buffalo, New York in the middle of World War II, which actually is a long time ago. After all, while bacterial transformation in pneumococci was about to be ascribed to DNA, it was not known for another 10 years how DNA held the code of life. Likewise, I was in college when people first began to think that lymphocytes might be the cells that provide "specificity" to the acquired immune system. It was while I was a post-doc that lymphocytes became T cells and B cells. Having now established that there was a lot fewer facts for me to learn while I was in training than those going through it today, it should be remembered that there was a lot of conjecture to be learned, and then unlearned --- "back in those days." In any case, it was not "just the other day." Rather it has been many, many days, and this piece is about how I passed those days getting to where I am now (which is working on my laptop on the porch of a flat in Kisumu, Kenya, drinking my breakfast tea, looking out over Lake Victoria). If this takes a while I will change that tea for a Tusker, and move inside before dark, to get away from the Anopheles ladies who would make me their dinner.
I will dwell a little on my growing up phase, not because it is particularly interesting (to anyone but me), but more because of that. I think the point is that ending up doing what I do does not require any given avenue to get there. I was raised in western New York, moving with my family several times before I graduated from high school. We lived in south Buffalo, East Aurora, Holland, and Niagara Falls, with the two in the middle being the places where I primarily developed into whoever I am. East Aurora was a small town 20 miles from Buffalo, which became, during those years, what we now call suburbia. I lived there between the ages of 6 and 12, and it was an idyllic setting – the 1950s. My childhood there was pretty much what you would envision if all you ever learned about that time was gathered from "Leave it to Beaver" TV reruns. Holland was more rural, a town of about 2000, about 35 miles from Buffalo. Holland was where I grew up, ages 13 – 16. It too was idyllic, with lots of fields and woods to roam in, a great public high school, lots of freedom to go and come as one pleased, and it was the age of the young Elvis Presley, the Everly Brothers, and the birth of "American Bandstand" (which my cousin Dick and I were actually on once, in Philadelphia). My family moved once again when I was going into my Junior year in high school, to Niagara Falls, New York. My father had just been ordained an Episcopal priest (pretty much of a shock for me, as a teenage son of a man in his mid-40s). I guess the lesson that I learned from that is if you want something bad enough, and are willing to work hard enough, and have sufficient focus, you can become anything you want to be, regardless of what you were or how you trained. In Niagara Falls I attended DeVeaux School, a small private Episcopalian all-boys school, where I really learned what it meant to study.
As I approached high school graduation, and started looking for a college or university to attend, I decided that wherever I went, it had to be: 1) small; 2) co-ed; and 3) away from home. That just seemed like the best formula for me. Oh yes, it also needed to be reasonably strong academically, but relative to the other 3 things, that was a side issue. I had no idea what I wanted to do, other than "go to college," so a liberal arts college looked like the best choice. By a process no more sophisticated than looking up schools in the "College Handbook" published by the College Boards people, I decided on, was accepted by, and provided a scholarship by, Centre College of Kentucky, in Danville, Kentucky. Centre met my criteria right down the line. It was small (I mean to say "tiny"), with a total of 525 students at the time. It was co-ed, and it was there that I met and wooed my life-long partner, soul mate and wife, Mary Paxton Colley, nee Durr. It was 500 miles away from home (which, by virtue of my family moving to northwestern Connecticut, was then in Bantam, Connecticut). At Centre I was the quintessential liberal arts student. This is to say, I had no clue on what I wished to focus, or how I wanted to someday apply that which I studied. [I did learn how to write complex sentences that were grammatically correct, but nevertheless not interpretable – but no, I did not go on to Law School.] The environment at Centre was superb. It had a very good faculty, who were there because they wanted to teach and interact with eager students. Outside of class it was also very enjoyable. You could participate in just about any activities offered. Even I played intercollegiate football, concluding early on that I could learn to enjoy getting my head beat into the ground, but that I definitely did not have a future in the NFL. Academically, I ended up majoring in Biology, by virtue of being forced to declare a major (the Dean threatened me that I absolutely had to declare my major, in the middle of my Junior year), but also ended up with minors in Chemistry, English and History. I really did not have any solid idea of what I wanted to do, but I enjoyed the biology courses I had taken. It was also my Junior year that I decide I probably wanted to be a professor in a school like Centre "when I grew up." It was clear that if that really was my goal, I would have to get a Ph.D., in something.
Because I thought I wanted to teach in a college setting like Centre, it occurred to me that essentially all schools, even those of that size, had courses in bacteriology/microbiology. Since I saw faculty members at Centre who really never got to teach courses in the areas in which they had obtained their degrees (because they were too specialized), I decided I would go to graduate school (as if I knew what this meant) in microbiology. I would get my Ph.D., and I would then find a nice small college where I would live my fantasy life as a college professor. Who knows, maybe I would even learn to smoke a pipe and wear cardigan sweaters. So, I applied to graduate schools, and was really surprised when Tulane University’s Department of Microbiology not only accepted me, but also offered me a stipend, as a student on their NIH predoctoral training program. This was in 1964, and I had already, in 1962, signed on with the United States Marine Corps in their officer training program (the Platoon Leader Class program). This was so I could serve my military duty (this was the time of the draft) as an officer, and save money for graduate school. Now I had a fellowship (which I had not known existed) to go straight to graduate school and even straight for the Ph.D., without getting a M.Sc., which was really something new at the time. So I had to do some decision making about what to do in regard to my Marine Corps obligation. I had just spent the 12 weeks between my Junior and Senior years completing Boot Camp, so I was all ready to be commissioned as a 2nd Lieutenant in the Marine Corps, upon graduation (May, 1964). As it worked out, at the time, if you declined your commission, they busted you to Private, E-1 and put you in the U.S. Marine Corps Reserve for the remainder of your obligation. So that is what I did. I declined my commission, accepted the fellowship to Tulane, and trundled off to graduate school. Given the times, although I was not smart enough to foresee it, that decision quite likely saved my life. Had I not done that, the odds were very, very good that I would have been sent to Viet Nam (1965-on was the big build-up), and it would not have been to study malaria. Second Lieutenants did not have a high return rate during the years I would have been there. So, my 4 remaining years in the Marine Corps Reserve coincided with my 4 years in graduate school, and in 1968 I got out of both. I am not, in any way, equating them ….. – except in their tenures.
At Tulane, the Department of Microbiology is located downtown in the Medical School. It actually shared the same floor as the department that housed all those famous parasitology-types, Drs. Paul Beaver, Tom Orihel, Dale Little, et al., but I never met them, nor did I take any of the fine courses they offered. I was a microbiologist-turned-immunologist. I started out working on replication mechanisms of a bacteriophage (fX 174), but when my major professor-to-be (Dr. C.E. Dowell) moved to California, I elected to stay and become an immunologist, under the tutelage of Dr. Charles W. DeWitt. Dr. DeWitt was the transplantation immunologist at Tulane, an integral part of the kidney transplant team, while also a full member of the Department of Microbiology. My dissertation research was focused on developing an in vitro system to culture rat lymph node and spleen cells that would allow allogeneic stimulation and proliferation – the mixed lymphocyte reaction – with rat lymphocytes. Inbred rats were an important model for transplantation, but at the time the in vitro cultivation of rat lymphocytes had not been accomplished. In my dissertation research I managed to get this standardized and asked a few other questions of the system.
Some time during about the middle of my graduate school years I decided that while I might go back to someplace like Centre College and teach biology, microbiology, comparative vertebrate anatomy, embryology, histology, physiology and evolution, I really liked this research stuff, which I had never tried before, and I thought I should do a postdoctoral fellowship. My father actually questioned me fairly extensively on this decision. He wanted to know if it were really a choice that I had made, or something that I just sort of slipped into, because of those around me were doing it. He made me think about it, and to actually decide that this was what I wanted to do. The point here is that you are usually better off making a decision about such life choices, rather than merely slipping into whatever is the next most obvious thing – especially if that was not your original plan. That way, if you later decide you do not like what you are doing, you can always go back to that decision point, realize that you made the decision, and make a new decision to do something different. I think my father had a point, and his advice and insistence that I actively make that decision has since stood me in good stead on many other such life choices.
So, approaching the point at which I would garner a Ph.D. in immunology, I decided to do a postdoc, and try out this research stuff at the next level. Now, where to apply, and what to do it in? One of the members of my dissertation committee was Dr. John Wallace. John was not only a good immunologist and an outstanding person, he had been on the faculty at several schools before coming to Tulane. He knew a lot of people in the world of immunology, and was also quite widely known. He suggested that I consider Dr. Byron Waksman’s laboratory at Yale University School of Medicine. He also contacted Dr. Waksman on my behalf. After visiting Byron at Yale, I was offered a secure fellow’s position, but also asked to try to underwrite it by applying for an NIH individual postdoctoral fellowship. During my 2 years in Bryon’s laboratory I primarily worked on the maturation of lymphocytes in the rat thymus. I got to draw on skills and approaches I had developed in my dissertation research, but I could apply these abilities in completely new areas of immunology. It was a magic time for the new field of cellular immunology, and people at Yale were very much in the thick of it. This made me a part of it. A very small part to be sure, but at least I got to watch, and occasionally participate, in the tremendous excitement of being in Byron’s laboratory and to also interact a lot with Dr. Dick Gershon and a lot of other really outstanding immunologists. The environment was very different than that of Dr. DeWitt’s laboratory at Tulane. Dr. Waksman and Dr. DeWitt are both excellent scientists, but they are very different people, and they also came at their research in very different ways. An essential part of my postdoc experience was realizing that both of these wonderful mentors did first class science, but they did it in different styles and ways. The learning opportunity here was that if they, as differently as they approached science, could both make real scientific contributions to their field, then I could blend things from each of them, mix in what I learned (in terms of both science and management), add that to who I am, and then fashion all of that into what my approach should be to doing good research and running a laboratory.
One day, when I was about three-fourths the way through my postdoc, and beginning to seriously think about "what next," Bryon came to the door of the laboratory and said "Who wants to go to Brazil?". My lab desk was closest to the door, and my hand shot up first. I have no idea what I was thinking. I had never been out of the USA except to spend frequent summers vacation trips to Ontario, Canada with my grandparents, and a weekend in Tijuana and Ensenada, Mexico, while at "summer camp" one year with the Marine Corps Reserve. Those hardly count, compared to going off to Brazil. Dougie Naysmith, from Scotland, another postdoc in Byron’s laboratory at the time, was also wildly waving his hand, but he was on the other side of the lab benches, and could not be seen. Dougie is now a Member of Parliament, representing Bristol. Who knows where either one of us would be today if our lab desks had been reversed? After having gotten Bryon’s attention that I wanted to go to Brazil, I asked what for, and for how long? He replied that it was to teach a course in immunology and help my hosts reorganize their research, and it might be as long as 6 months to a year. I was pretty sure I could teach a course in immunology (although I was also pretty sure I could not do it in Portuguese), and I thought that the time seemed reasonable (what did I know?), but then I thought to ask what the topic of the research would be. His response was "schistosomiasis." My response was "What is that?"
In going back to my Freshman Zoology text from Centre, I found that I actually had heard (or at least read) about schistosomiasis, because it was the example given in our text of a life cycle involving two different hosts. I know I read it, because it had been underlined. I remembered nothing of this, 9 or 10 years after having done that underlining. So, there I was, sitting in Byron’s lab saying I wanted to go to Brazil and work on this thing, whatever it was. Going home and talking to Mary Paxton about it, was the next step, and she (also never having gone anywhere but Canada and Mexico) agreed. Twenty-seven is a wonderful age. If you think you can do something, you probably can. Based on absolutely no evidence, I was convinced that I could teach an immunology course in Recife, Brazil, and that I could help reorganize someone else’s research program on a totally unknown topic. Mary Paxton and I decided to do it. I actually did look into the schistosomiasis aspect a bit more. Byron arranged for me to visit the Drs. H. and S. Hsu at the University of Iowa, and to spend several days with Dr. Ken Warren, a maven of immunoparasitology, and Dr. Dov Boros, at Case Western Reserve University. Dov was essentially the first (and at that time only) person doing cellular immunology on schistosomiasis or just about any other parasitic worm infection. Byron also had me go down to New York University to visit with Drs. Victor and Ruth Nussenzweig, expatriates from Brazil (due to the military dictatorship there at the time) who were also leading lights in immunology and parasitology. Following my brief visit with Ken Warren, he made a critical move on my behalf when he, learning that I was headed off to Brazil (which he had done when he got interested in schistosomiasis), insisted that I visit him at the Rockefeller Foundation schistosomiasis study site on St. Lucia, in the West Indies, called Research & Control. When I finished my post-doc, and it was time for Mary Paxton and I go to Brazil, Byron solicited the NIH to allow me to use what was left of my fellowship to stop on St. Lucia on our way to Brazil.
Oh yes, there was one other critical piece that I needed to get this to happen. I did not want to leave my post-doc and go to Brazil for 6-12 months without a job to which I could come home. During the time I was finishing my post-doc and getting ready to go to Brazil, I was also looking for a job that would hire me, and then let me go away for up to a year. Fortunately for me, the Chief of Medicine at the Veterans Administration Medical Center in Nashville, Tennessee, Dr. Roger M. DesPrez, was recruiting an Assistant Professor level immunologist to join his Infectious Disease Training Program faculty. He was doing this jointly with the Acting Chair of the Department of Microbiology at Vanderbilt University School of Medicine, Dr. John H. Hash. Incredibly, upon hearing of my desire to get hired and then go off to Brazil to study something I had never worked on, they agreed. I will never be sure if Roger thought I said Histo, instead of Schisto, but for whatever reason, he agreed and I had found the perfect job. One that would first hire me, then let me go, then support me in many, many ways upon my return.
Mary Paxton and I left New Haven in June, 1970 to start our great adventure. As I mentioned, it began on St. Lucia, with a two week stint at the Rockefeller Foundation field site, where Ken Warren had a project. Research & Control was the home of a remarkable longitudinal, comparative study of different schistosomiasis control methods and their effectiveness in the field. It is pretty special when you and your spouse get the opportunity to first experience the tropics on St. Lucia. It is equally special, scientifically, when you get to spend two weeks on a small island with some of the world’s greatest experts in the field to which you aspire, but know nothing about. I am sure that those two weeks formulated (long before I knew it) what my career path and scientific goals would be. Certainly my subsequent time in Brazil, followed by the multiple other overseas programs of which I became a part, helped to solidify this path and those goals, but it really all started in St. Lucia, with Joe Cook, Ken Warren, Speed Unrau, Bob Sturrock, Guy Barnish, Pip Jordan, and the rest of the wonderful staff who made up Research and Control. They gave me the "Berlitz Course in Schistosomiasis" during those two weeks, by letting me tag along with them to the clinic and the field and watch, and then come to tea in the mornings and afternoons, and listen.
After that terrific introduction (in English) to both schistosomiasis and the tropics, we made the next leap of faith, off to Recife, Brazil. My host, colleague and mentor during the next 8 ½ months was Ageu Magalhaes Filho, of the Department of Pathology at the Universidade de Pernambuco. The adventure was just what it was supposed to be – full of highs and lows, spectacular experiences and shared joys, discoveries and mishaps. The first and most important thing we discovered was that Brazilians are wonderful people. They opened up their homes and hearts to us. They made the time with them enjoyable and productive. I taught the post-graduation course that I was there for, and we forged ahead on some new approaches to research on schistosomiasis in Recife. We actually did a mouse study on cercarial penetration, which did get published (my first American Journal of Tropical Medicine and Hygiene publication). Some things worked and many did not, as with any active research program, but I learned early on that ingenuity and dealing with circumstances as they come up is a critical part of an investigator’s armamentarium. This is always true, wherever you do your research, but it is especially true when you are pursuing field studies in developing countries with which you have no prior experience. After a fruitful time and a learning experience that could not be surpassed, Mary Paxton and I "returned" to my new job at the VA Medical Center and Vanderbilt University School of Medicine, in Nashville, Tennessee. We went back to the States with very different perspectives on the world and a new appreciation for the many different types of opportunities available to us in work and life.
Arriving in Nashville in March, 1971, I proceeded to set up my research program on the immunology of schistosomiasis in the mouse model. Shamelessly and gratefully, I did this fashioned after what Ken Warren, Dov Boros and Pierre Peters had shown me when I visited Case Western Reserve University. I wanted to ask cellular immunology and immunoregulatory questions of this infinitely complex, immunologically fascinating, chronic infection, schistosomiasis mansoni. I realized that I was not a parasitologist, but an immunologist who had a fervent desire to work on this parasitic disease and bring his immunologic insights to bear on that disease. Nevertheless, being the only person in the entire medical school who could apparently spell and pronounce the name of any parasitic disease, I was co-opted to teach parasitology to the medical students, and quickly (with a couple of years coaching by Dr. Harold Brown, of textbook fame) learned to fake it as a parasitologist – at least to 2nd year medical students. I also realized that while I was working hard to establish a mouse-based, experimental schistosomiasis immunology laboratory, I also wanted to work on the immunology of people with schistosomiasis. I made myself a bargain that once I got the mouse work funded and on the way to stability, I would also pursue the second prong of my research desires, human studies in areas endemic for schistosomiasis. There were very few cellular immunologists working in parasitic disease systems at that time. Because of this paucity of seasoned veterans in this field, in 1974 I was tapped at the ripe old age of 31 to become an Associate Editor of the Journal of Immunology and a member of the NIH Tropical Medicine Parasitology (TMP) Study Section. Taking on such responsibilities and putting forth the effort needed (especially if you are not facile with the topic, i.e., parasitology) can be a sizeable burden for one just starting out. However, not only do I think this type of responsibility should be shouldered, in the name of good scientific citizenry, I am convinced that these two "burdens" were instrumental in a very positive way, in my subsequent career. Early on I was forced to read and think about a wide variety of immunoparasitiology studies, either in grants or manuscripts I reviewed. This broader perspective and the breadth of interest it sparked not only became a driving force for my approach to this field, it made concrete contributions to how I thought about and designed my own research, first on schistosomiasis, then Chagas’ disease, and even my brief interlude into the world of trachoma.
By 1974 I was fortunate to have NIH-funded and VA-funded research going on the mouse experimental model of S. mansoni, in the laboratory, and I had hired my career-sustaining chief technician, George L. Freeman, Jr. It was time (according to my promise to myself) to try to fund and pursue human immunology studies on schistosomiasis. Once again, the Rockefeller Foundation project on St. Lucia, Research and Control, proved to be a marvelous initial stepping stone for me, my family, my laboratory, and my research. The Rockefeller Foundation, in the form of Virgil Scott funded me, Joe Cook, Richard Bartholomew, Pip Jordan, later Rick Goodgame, and the rest of the Research & Control staff welcomed me. My laboratory became the beneficiary of longitudinal studies of schistosomiasis patients who were superbly defined in terms of their parasitology and clinical status. Pursuing immunology studies in patients who are not well defined in this regard is essentially useless. Therefore, I was a most fortunate recipient of a veritable research gold mine, in the form of these well defined, very compliant patients of the Research and Control longitudinal studies. This grant and our 4 years of studies on St. Lucia established the pattern that my family life and my laboratory life were to take for the next 17 years. Mary Paxton, our son Tom (who was 2 ½ years old in 1975), one or two people from the lab, and I spent the summers (2 ½ to 3 months each summer) of 1975, 1976, 1977 and 1978 doing research on the human immunology of schistosomiasis on St. Lucia. It was utterly delightful, often challenging and ultimately productive. This was before the age of FAXes, no less e-mail or instant messaging, and telephone connections were unreliable and prohibitively expensive. Therefore, communication between the Colley Lab in Nashville and the Colley Lab on St. Lucia was by post, which took about two weeks. In short, there was not a lot of communication. However, those in the Lab in Nashville got an exhaustive plan for their summer’s research activities, and they always seemed to handle everything just fine without me – rather sobering, actually. Between 1975 and 1992 there was one summer (1984) that I did not have a human project grant, and the family spent that summer at the MBL in Woods Hole, Massachusetts, where I taught in (and took) the Biology of Parasitism (BoP) course, and had a delightful time with John and Roberta David, the rest of the faculty, and all those in the course. Other than that summer, the Colleys and various trainees were oveseas for 2 ½ - 3 months. So, from 1975 until 1992, my laboratory life was split between mouse work in Nashville and human work in St. Lucia, Brazil, and Egypt.
Actually, this extended time period away from Nashville started in 1974, when I spent 3 months (without Mary Paxton and Tom) in Belo Horizonte, Minas Gerais, Brazil, with Giovanni Gazzinelli – again, teaching a course in immunology and doing some research. This came about from meeting Giovanni at a US/Japan Cooperative Medical Science Program Parasitology meeting at the Asilomar Conference Center near Carmel, California in 1973. He asked if I would come back to Brazil some time, and I said "Of course, anytime." He then went about arranging for me to teach a PAHO-supported course in Belo Horizonte, but neglected to tell me about it. One day I got a call from PAHO asking if I could leave for Brazil the following week, and I decided that "anytime" could mean just that. I ended up leaving a few weeks later, and while the time was both enjoyable and productive, Mary Paxton and I learned that from then on, any trip more than 3 weeks, everyone would go, or no one would go. That was our family decision, and we have actually stuck with it ever since. Therefore, all those summers doing overseas research really involved the whole family, as well as various lab members.
The majority of these summers were spent with Giovanni Gazzinelli and his many fine colleagues at the Centro de Pesquisas, Rene Rachou (CPRR), one of the FIOCRUZ institutes of the Ministry of Health of Brazil, in Belo Horizonte. Giovanni is one of those wonderful people who is not only fun to work with but is also inquisitive, smart, practical and effective. His approach to science is absolutely straight-forward and his approach to life is the same. You simply could not ask for better characteristics in a collaborator. Giovanni had, by the time we began consistently working together in 1980, an established career as a parasite biochemist. He was well published and had made insightful findings regarding cercarial enzymes. He had also already done a top notch job of training many of the next generation of Brazilian parasitologists. He and I got a WHO/TDR grant to set up an immunology lab at CPRR, and he (at the age of 53) started a new career as an immunoparasitologist. When we began it was just Giovanni, a technician, a student and me. Over the next 12-15 years that lab has blossomed into a major contributing laboratory with multiple principal investigators, lots of graduate students and post-docs and a great staff. Rodrigo Correa-Oliveira now overseas this group, with Giovanni still contributing, and the laboratory has many international collaborators and is funded from many different national and international sources. Over the years several Brazilian students from this program came to do the research portions of their Ph.D.s with me in Nashville, and I was also an integral part of many other students’ dissertation research in Brazil, plus many others with whom I had more minor roles. It is very satisfying to have been a cog in the wheel that helped Giovanni to develop so many now successful scientists. It is really fun to look at the current literature and granting lists and see what they are up to now.
For a period of time (about 6 years) I maintained two active overseas programs, the one with Giovanni, et al., in Brazil, and another with Mohammed El Alamy and his longitudinal epidemiologic schistosomiasis program with Barney Cline, in Qualub (in the Nile Delta) in Egypt. These were very productive and interesting times for the Colley lab. In Egypt we actually did both schistosomiasis and trachoma immunology studies (since our patients often had both infections). It was a time that we learned a lot about comparing and contrasting studies from different field sites. However, it eventually proved to be just too much to try to keep all the balls in the air simultaneously in two overseas sites and Nashville. We ended up focusing on Brazil and were fortunate to get an NIH ICIDR Program Project grant to allow us to study schistosomiasis and Chagas’ disease immunology with Giovanni, Zigman Brener, and Rodrigo Correa-Oliveira and their many talented colleagues, trainees and staff.
During 1992 I made a major decision and moved from the VA Medical Center and Vanderbilt to the CDC, in Atlanta. I still do not know why I came to such a decision, or what I really expected to find at the CDC. I went to become Branch Chief of Parasitic Diseases, within the Division of Parasitic Diseases, in the National Center for Infectious Diseases. Since I was already a VA employee this was a lateral transfer within the federal government, so that part was relatively easy. However, the culture shock was pretty great. I was not a public health person, and of course public health is the business of CDC. It is absolutely true that there is a great deal of first class scientific research that goes on at the CDC, but their first call is to public health. Those at CDC know this, and that is why they are there. I "sort of knew this," and I was not sure why I was there. Far too soon after I arrived, my new colleague and boss, Bob Kaiser, retired. Sadly, Bob died soon after that. It was my huge loss that I never got much of a chance to learn all the many things that he had to teach me. Upon Bob’s retirement I became Director of the Division of Parasitic Diseases – having never had a course in parasitology, and knowing next to nothing about public health in the USA or globally. But there I was. It was time to learn from all the many incredibly dedicated, first class people around me. It was to my distinct advantage that it was in the best interest of all those around me that I not remain ignorant. CDC is a fairly hierarchical sort of place, and as Division Director, I ended up having to speak for those in the Division far more often than I wished to do so, but that was the job. Therefore, those in the Division quickly realized that they better teach me what they could, before I misrepresented them and messed up badly. This crash course in parasitology and public health started off very soon after I went to CDC, with the Milwaukee outbreak of cryptosporidiosis – an emerging infectious disease that produced very bad dirrhrea in over 400,000 people in Milwaukee, Wisconsin, all within about a 3 - 4 week period. This serious, life-threatening for the immunocompromised, parasitic disease was now my problem – at least to the extent that CDC needed to respond and do so effectively in conjunction with state and local health departments. These were relationships I did not know about, dealing with threats and challenges that I knew very little about. Fortunately, those around me did, and I just had to get up to speed in a hurry. These sorts of things continued to pop up during my 9 years at CDC, and with the expertise around me, we survived and responded well in some critical national arenas, ranging from waterborne diseases to the blood supply.
I also think that my tenure as Director of DPD lead to some excellent scientist/public health officials in DPD doing front line scientific research that then contributed to our ability to respond to the public health challenges. The sorts of research that I refer to involved everything from immunology and entomology studies affecting under-five mortality due to malaria, to developing genetic tools to understand the epidemiology of cryptosporidiosis, to doing the research that would allow effective implementation of global elimination programs on filariasis. The research came from across the board, from hard-core bench science to slog-it-through field studies. The answers came, as they always do in research, in fits and spurts, but with determination findings were made, and translations to policies were accomplished. It was, for me, a different world in many ways. I learned an incredible amount from extremely talented colleagues, and I also learned some global perspectives on parasitic disease challenges that I could not have learned anywhere else. This has led me into dealings that have involved several different global control, elimination or eradication programs regarding various parasitic diseases, and that has been highly educational and rewarding. In 1992 I had the honor to be the President of the American Society for Tropical Medicine and Hygiene, and even before I had learned much about this perspective, my presidential address (Colley, Amer. J. Trop. Med. Hyg., 50:1-12, 1994) was based on the need for continuity along the spectrum of basic research to implementation of public health measures. All too often this "spectrum" is not really a continuum, but is, in fact, quite polar. I do not think this is a productive way to approach the translation of basic research findings into clinical treatments or public health interventions.
During my 9 years at CDC, I was also kept alive, scientifically, mainly by 3 people that I was allowed to hire when I went there. One was the aforementioned George L. Freeman, Jr. George moved with me to CDC from the VA Medical Center in Nashville. Actually, he preceded me and set things up before I even got there. As chief technician in the lab for 28 years, George is obviously the person who really trained those 16 graduate students who got their Ph.D.s with me, and the 29 post-docs, plus others, who trained in "my" lab. He certainly knew more about what I did that I did. Along with George, I was able to hire Drs. W. Evan Secor and Malcolm (Mack) R. Powell, who scientifically kept me in the loop on what "my" lab was doing in schistosomiasis and Chagas’ disease, respectively. Many of our previous scientific themes continued while at the CDC, and some new things were started. When I went to the CDC I had to turn in my new NIH R37 grant (a MERIT Award) and our ICIDR program project with Brazil, as well as my VA Merit Review Award, and that was pretty hard to do. However, their were new opportunities to develop at the CDC, and in 1995, Evan and I began a wonderful collaboration that continues today with Dr. Diana Karanja of the Kenya Medical Research Institute (KEMRI) in western Kenya (in Kisumu and Kisian). I am writing this (as I mentioned above) sitting on a porch overlooking Lake Victoria, in Kisumu, while I am here on one of my ~ 3 time a year visits to Diana on our NIH-funded research project on correlates to resistance in occupationally exposed car washers in Kisumu. For almost 25 years, CDC has had field stations in Kenya (with KEMRI) and Guatemala (with Universidade del Valle). The former had worked mainly on malaria and the latter on leishmaniasis, malaria and onchocerciasis. Based on being Director of DPD and who I am, I thought they could also work productively on schistosomiasis and Chagas’ disease, respectively. In short, the highly competent staffs and collaborators of these field stations, along with Evan and Mack, and sometimes me, set up good science- and public health-based research projects, most of which are continuing in some form today.
Our studies in Kenya began when I was at CDC, but have continued, now that I am at the University of Georgia (UGA). After 9 years at CDC I decided that it was time to get back into academia, and fortunately for me, Dr. Rick Tarleton at UGA had just convinced the upper UGA administration that UGA’s Center for Tropical and Emerging Global Diseases needed a Director other than himself. Rick had gotten CTEGD started in late 1998 and was its Director, but he yearned to get back full-time into the lab and leave the administrative stuff to someone else. While the directorship of CTEGD can be a fairly administrative post, it is in no way comparable to the administrative load that I dealt with as Director of DPD. Thus, a position to become Director of CTEGD, set up my own lab again, and teach, was just exactly what suited me, coming out of CDC. So, in December, 2001 I went to UGA to do just that. The CTEGD now has 13 on-campus faculty members and 3 off-campus, adjunct faculty members. It is an interdisciplinary, multi-faceted group of principal investigators who, at this time, all work on various aspects of parasitic diseases (http://www.ctegd.uga.edu). We recently were awarded an NIH T32 Institutional Training Grant, and have hired a Georgia Research Alliance Eminent Scholar (Dr. Roberto Docampo). This is a very special group for me. While I very much enjoyed my time at Vanderbilt and the VA Medical Center, it was in some ways a challenge to be the only person working on a parasitic infection in the whole medical center. Fortunately, Clint Carter and Burt Bogitsh were in the General Biology Department working on parasites, and I also had an active adjunct appointment at Meharry Medical College, where George Hill and his colleagues were. However, the parking lot was never overly crowded when you called a meeting of parasitology types. I say this, not to denigrate my colleagues or time in Nashville, both of which were great, but to merely point out the stark contrast between being relatively alone, and being a part of a vibrant situation that has 16 active laboratories with interactive ties. The cross-interest, cross-fertilization opportunities within CTEGD are terrific, and people really take advantage of them.
Walking into a "stone cold" laboratory, alone (no technician, no graduate student, no post-doc) is always an invigorating (and scary) challenge. To do so after having been "kept on scientific life-support" by George, Evan and Mack for 9 years, while I learned how to be a public health official and manage a Division at CDC, was terrifying (and exciting). I have been at UGA for 3 years now, and the laboratory has slowly but steadily grown to several people. The group is now comprised of an undergraduate lab assistant, a technician, two graduate students and a post-doctoral fellow. Being in an undergraduate setting for the first time, I am also learning how research opportunities for undergraduates can be rewarding for both the student and the mentor, and I already have had several great experiences in this regard. I was fortunate to get an NIH R01 grant to support the project focused on immune responses in the above mentioned car washers in western Kenya, and I am still working on getting our experimental mouse schistosomiasis studies extramurally funded.
I think the message of all of the above wanderings and musings is that if you demonstrate your ability to someone, and you want to do something or need to do something badly enough, and you are willing to put in the effort and focus, you can travel many different pathways to get where you want to be. Furthermore, you can make decisions and change directions. The effort to do so may make it more work than it is worth to you, but if it is a sufficient driving force, and if you decide to do it, you can change course. At each step, it is important to work hard and do well, in whatever it is you are doing, because that is the ticket to being able to move on. So much for the homily --- I guess I am my father’s son.
What about the scientific findings? What did I actually do all these years in all these projects? Well, that’s what the papers and chapters are for. You just enter "Colley DG" into PubMed, and wow, they’re all (almost) there. Just to give a flavor of what is buried in a lot of different publications; I will summarize our major areas of emphasis, although, if you are interested, you should read the papers and decide for yourself if you believe what has been done. Nevertheless here are some short introductions to the scientific findings and ramblings of my career, so far.
The aspect of the immunology of schistosomiasis (or Chagas’ disease) that has been my major interest has been the immunoregulation of the immune responses generated during infection. The main point is that this is a chronic infection with an intravascular worm, and it is intriguing to think about how the worm and its host come to a point that allows chronicity, and why, in most of those infected, this chronicity leads to "relatively" lower levels of morbidity. The worms do not multiply, so the host does not have to worry about controlling their replication, but they do make a lot of eggs (24 hours a day, 7 days a week, 52 weeks a year), many of which do not exit the body in excreta, but get retained (with S. mansoni mostly in the liver and gut wall). These eggs produce a lot of highly antigenic material, and stimulate strong immune responses, both humoral and cellular, leading to major lesion formation in the form of anti-egg granulomas, and subsequently periportal fibrosis. In severe cases this leads to portal hypertension, collateral circulation and esophageal varices, resulting in bleeding to death. However, this progression "only" occurs in ~ 5-8% of those infected, if untreated. The good news, of course, is that we have a good drug (praziquantel) with which to treat schistosomiasis, and therefore this should not happen to anyone. It does still happen, but much less frequently now. Still, why do ~ 40% of those infected have essentially no morbidity (they don’t particularly feel better on treatment), 50% of those infected have "moderate" but still important morbidity (and feel substantially better when treated), and only < 10% get sick and die, if untreated? The working hypothesis is that most people (and most mice) regulate their anti-egg responses sufficiently to allow a balance between the parasite and the host, and thus allow chronicity.
Our studies on this system accompany those of many others, but in 1976 we demonstrated that spleen and lymph node cells from chronically infected mice, adoptively transferred to mice early in infection, lead to down regulation of the "hyper" granulomatous responses of early infection (Colley, J. Exp. Med., 143:696-700, 1976). This, and the work of others, has resulted in many follow-on studies of the cells involved, the responses they make and how this might occur. The complete story is not in, or at least the pieces are not yet fully integrated, but it is now known that many anti-egg responses start out (briefly) as primarily Th1-like responses and switch quickly over to Th2-like responses, and that regulatory T cells (notice I did not use the politically incorrect term, T suppressor cells), are heavily involved. It is also known that antibodies or B cell responses may be involved, but they are not as well studied. What is still not known, and what we hope to continue studying in the mouse, is how is the decision made to go down one path (that of immunoregulation and chronicity with less severe disease) vs. another (that of less or ineffective regulation, severe morbidity and mortality). Fortunately, over the co-evolution of schistosomes and their hosts, the "road less traveled" is the one that leads to severe disease, but why a host goes down that road, vs. the other available pathway, is not understood. What is the deciding factor? We are currently interested (as is half the immunologic world) in the role(s) that dendritic cells play in such decision making processes (Colley, et al., Parasite Immuno., In press, 2005). We have a model system in mice that allows us to study severe vs. moderate disease (Henderson, G.S., et al., Amer. J. Pathol., 142:703-714, 1993), and we hope to continue to pursue dendritic cell interactions and T regulatory mechanisms in this model. We have a lot of tantalizing immunologic data that indicate major differences between mice that develop these two morbidity patterns, but they are not yet definitive in regard to potential mechanisms of immunologic decision making.
We do know that what you are exposed to during perinatal life can influence how you will make this decision when you are subsequently infected as an adult (Montesano, M.A., et al., J. Exp. Med., 195:1223-1228, 2002). This is true in mice, where we can manipulate it, and we suspect it occurs in people, where we know that cord blood cells from babies born of S. mansoni-infected mothers are already programmed for certain responses, due to an immunologic influence from their mothers (Eloi-Santos, S.M., et al., J. Clin. Invest. 84:1028-1031, 1989). I think that this, and a lot of other findings that we have published, is all wrapped up in something called idiotypic regulation, which was a big thing in the 1980s, but is not even mentioned in textbooks any more. Idiotypes, anti-idiotypes, etc., and their involvement in the generation of immune responses and immunoregulatory responses was once-upon-a-time a much published upon topic. However, while none of those studies have ever been disproved, it is a very complex area, and has been (except to some extent in the world of B cell lymphomas and experimental autoimmune encephalomyelitis) totally abandon. Still, the data are the data. Until I can come up with another explanation of our findings (which would be fine by me), I am stuck believing that at least part of the immunoregulatory story in schistosomiasis (and probably many other chronic, endemic diseases) involves idiotypic regulation, which can be due to maternal/perinatal influences. You can read the papers and decide for yourself what the explanation of the data might be.
In any event, there is a decision made during most schistosome infections that differentially leads either to strong immunoregulation or strong responsiveness, and the latter is generally associated with severe disease. Therefore, unlocking the mystery of how this happens could be very good for an understanding of schistosomiasis, and could also fit into why some people fail in their immunoregulation and develop autoimmune diseases, or it could tell us how to induce strong immunoregulation in settings involving transplantation immunity, or it could influence how to down regulate regulation in the setting of tumor immunology. Thus, this infection of 200 million people can be studied in its own right, as an important human malady, and/or as a model system for how the immune system works or does not work in many different settings.
Another area of schistosome immunology that I have worked on (off and on) for many years is the role of the eosinophil. At least we think there is a role for the eosinophil. Eosinophils are beautiful granulocytes in the tissues and the blood that are generally associated with atopic allergies and infections by tissue-dwelling helminths. What these two situations have in common are eosinophils and IgE isotype antibodies. Why this is true is only now beginning to be elucidated, and is a fascinating area of current research. Suffice it to say that I have been intrigued and defeated by the eosinophil for many years, and many of my trainees have labored long in the eosinophil arena. We have uncovered some of its secrets, such as its responsiveness to IL-5 and GM-CSF, its ability to wreak some havoc on schistosome eggs in vitro, and its correlations with resistance to re-infection with schistosomes in humans. Nevertheless, these have been hopefully important, but relatively minor victories. Overall, we still do not know much about the secret lives of eosinophils, at least not enough to tell us if they are causative in any of the observations we have made. They are still out there (in there), dancing in and out of the tissues, being pretty on staining, and luring new converts to their enigmatic field of study. Good luck on this one.
Through the years, although I have never actually worked in the vaccine discovery arena, I have continued to be interested in resistance and susceptibility to infection with schistosomes, and the possibility of vaccine development. This area is poles apart from the immunopathology story mentioned above, although it may still turn out to involve immunoregulation. In the resistance, susceptibility and vaccine world, we are talking about immune responses against cercariae, schistosomulae, or juvenile worms, almost certainly before they mature and start making eggs (which are then the focus of the immunopathology story). I have studied and published on responses against these stages in mice and people, and our current work on human immune responses during treatment, reinfection, retreatment and reinfection, over and over again, in occupationally exposed car washers, is focused on determining the mechanisms that correlate with reinfection vs. resistance to reinfection. However, the main areas involving vaccine work that I have been associated with have been two attempts to move vaccine discovery to vaccine development. The first was the Task Force for Schistosome Vaccine Development, funded by the Edna McConnell Clark Foundation from 1987-92. The second was the USAID-funded Schistosome Vaccine Development Program from 1999-2003. I was asked to be director of each of these, probably because I cared about it, but had no horse in the race, i.e., I did not have a candidate vaccine that I had discovered or was promoting. The TFSVD was primarily turned over to the WHO/TDR program in 1990, and the SVDP came to the end of its funding in 2003.
My role inn these two endeavors was sort of as a granting agency, trying, with the help of advisory boards, etc., to move vaccine discovery (which is a basic science enterprise) into the realm of vaccine development (which is very different from discovery, and is essentially an industrial process, with all its rules and regulations, and with hard-core Go-No Go decision making). In basic science we are taught to accept failure (often) and turn it into good questions. Therefore, either success or failure (if you have done the right controls) often leads to more (and hopefully better) questions. In developmental science one has to learn to abandon most failures at any step along the developmental path. These are fundamentally different processes, both essential, neither being right or wrong, just different. Currently, there are no vaccines against schistosomiasis that are being tested in humans. Professor Andre Capron and his colleagues have one (Sh28, GST) that has made it through Phase II trials, but to my knowledge has yet to get into Phase III trials, which are very expensive, and in schistosomiasis are also challenging to properly design and control (Todd and Colley, Amer. J. Trop. Med. Hyg., 66:348-358, 2002). Still, most people believe that a vaccine could be an important part of the armamentarium against schistosomiasis, in conjunction with praziquantel treatment programs, and water and sanitation development.
Evan Secor, Diana Karanja and I think that our studies in western Kenya have demonstrated interesting resistant and susceptible phenotypes in heavily exposed adult men, and we even think we may have induced a degree of resistance (immunity we hope) in people through repetitive patterns of treatment and reexposure (Karanja, et al., Lancet, 360:592-596, 2002). We hope that these studies will reveal, in part, what immune responses correlate with resistance or susceptibility. Eventually, these might tell us the responses a schistosome vaccine should/could invoke, but it is a long range goal.
Along with doing short range science that answers specific, well defined hypothesis-driven or observational questions, I highly recommend also having long range goals – such as understanding immunoregulation, or knowing what a vaccine needs to do. Who knows, even if you never actually get there, someone you trained may do so, or someone they train may do so. Fortunately, this type of sequential daydream can go on infinitum, sort of like idiotypic networks.