Howard Nash: 40 Years of Collaboration Continued Nash, PNAS 1975 John Hays, recombination colleague Oregon State University Reminiscences about Howard I was trained as a physical chemist and then membrane biochemist. Thus, as an Assistant Professor of Chemistry at the University of Maryland Baltimore County in 1973 very much interested in the molecular biology of homologous recombination, I didn’t know how to get started. Fortunately, I happened to make contact with Max Gottesman and Howard Nash, and subsequently joined the rest of the regulars at the infamous weekly “Lambda Lunch”. Howard soon told me that he had also been interested in homologous recombination, but that “he had his hands full with site-specific recombination” and would “help me any way he could”. In fact, he became my mentor in molecular biology, substantially altering the course of my scientific career I recall here two of my favorite “Nashisms”. First, in response to a question about statistical analyses of my data he said “John, if a molecular biology experiment demonstrates less than a 3-fold effect, write it in your notebook and forget about it”. Second, when I asked him whether the 18.125 µl of reagent specified in one of his protocols (apparently scaled down 8- fold from a previous recipe) could be 18 or even 20 µl he told me “Well, I don’t know about that, but I always follow the protocol exactly”. Baseball also appealed to Howard’s quantitative instincts, and we enjoyed often discussing and occasionally watching the Baltimore Orioles together. I hope that his future includes plenty of time for baseball. Nancy Kleckner, DNA recombination friend and colleague Harvard University I started my scientific life studying bacteriophage lambda in all of its complexities, including its several recombination systems. I grew up immersed in genetic analysis of the system, beginning with the Campbell model and continuing through the identification of mutants defective in Int protein and the genetic definition of "attachment sites" and their unusual properties. Howard burst onto this scene virtually unannounced (at least to those of us outside of the NIH) with his seminal 1975 paper describing Int-promoted recombination in vitro. The ensuing studies comprise a remarkable intellectual tour. Howard has three special strengths as a scientist. First, he always chooses deeply important, cutting-edge research areas, e.g. lambda integration and the basis for anaesthesia. Second, he is willing to develop new ways of tackling problems that are not only uniquely powerful for the issues at hand but also require that he develop expertise in entirely new disciplines, e.g. biochemistry and genetics respectively. Third, he is always committed to thinking very hard about the complex issues that arise. In many cases these complexities result from his own contributions. This seriousness of purpose, manifested in every aspect of his scientific life, is one of Howard's most endearing qualities. I got to know Howard quite well through his published work before ever meeting him. His research is always logical and carefully reasoned with respect to the overall sequence of experiments as well as their design and execution. His presentation of results in published form exactly mirrors his underlying logic, making it possible to hear him thinking through the written word. The same clarity of thought and expression illuminates Howard's several commentary articles. In person, Howard turned out to be exactly the same person who had emerged from the printed page. At meetings in the field of site-specific recombination and transposition, his clarity of thought and reasoning provided constant beacons of understanding. He advanced the field via probing questions, both in public and in private. Equally importantly, Howard's leadership was critical in making the field a haven for pure intellectual pursuits. The focus was primarily on the science and inter-personal relationships that, while not always perfect, were nonetheless grounded fundamentally in mutual respect and scientific accomplishment. That atmosphere is apparent even to this day. The biannual "Workshop on Site-specific Recombination and Transposition", started by Howard in 1990, has this year reached its 20-year anniversary, with many of the same participants as on the very first occasion, albeit with some evolution in their areas of research. Indeed, as my own research began to include new areas, I discovered with great shock and disappointment that most scientific fields do not meet this standard and, correspondingly, what a remarkable and unique environment Howard's influence created. Not surprisingly in light of the above considerations, when Howard decided to switch to studying anaesthesia, his old field went into mourning. We understood his decision. We vigorously applaud his new successes. We are happy that a new community now has the benefits we used to enjoy from Howard's membership in ours. And we know that we are all better scientists, and people, for having shared his sphere of influence. Nonetheless, we all still miss Howard a great deal, more than he would probably guess. It is wonderful that this Symposium offers an opportunity to rectify that deficit, to let Howard know how much his old community appreciates him still. Griffith & Nash, PNAS, 1985 chocolate soccer ball Tall: Steve Goodman, Howard, Drew Granston Short: Anca Segall, Carol Robertson, Sue Nicholson; circa 1990 Nancy Craig, postdoctoral fellow 1980-1984 Johns Hopkins University Howard has a remarkable facility to learn something from virtually every experiment he contributes to. This ability derives from his talents in experimental design and careful data analysis. Thus, there are few experiments that "don't work". Another characteristic of Howard's scientific acumen is that he also has a terrific sense of what his experiments don't show. To a degree not seen with many other scientists, he is also willing to say "I have no information about that". I have greatly benefited from these core "Nash" phenotypes and have tried to transmit them to my trainees. Anca Segall, postdoctoral fellow 1989 – 1994 San Diego State University As I was finishing my graduate work in bacterial genetics of chromosome rearrangements, I decided that I had to learn biochemistry in order to understand chromosome structure more deeply. Howard had recently published a review article in Nature with Marty Gellert on site-specific recombination that had impressed me and I asked to join his lab. Despite my complete lack of biochemistry background, Howard took a chance on me. He later seriously questioned his decision after an unproductive first couple of years, after which he suggested that I consider leaving experimental science and joining the Center for Scientific Review. Nevertheless, we both hung on in there. During those years, a few of the lessons I learned from Howard were: 1) that making models is extremely useful, but you have to be willing to challenge them ruthlessly (refuting his own four-stranded DNA recombination intermediate model is one example), 2) that serious criticism should be welcomed and not be taken personally, and 3) to be adventurous and pursue truly novel lines of inquiry, not to be held back by trivial constraints. As a mentor, his advice was thoughtful, spare and no- nonsense. He was extremely generous, especially so with young scientists. At the Site-Specific Recombination Workshops, a meeting that he had helped start, he made a point to visit almost all the posters being presented and get to know all the junior scientists presenting them - he gave graduate students as much time as he gave his senior colleagues, and remembered them through their careers. The seriousness with which Howard tackles anything - experiments, meetings, singing in choirs, lunch - was daunting but also sometimes amusing. He is the only scientist I have ever met who “studies” before going to meetings. On occasion, in a genuine scholarly spirit, Howard would remind another senior colleague during discussion at a poster of their own results shown in a past paper that contradicted their data now being presented. At the lambda lunch seminar, Howard nearly always brought a sandwich and an apple, in a paper bag. After he finished the sandwich, he used the paper bag as a cutting board for the apple, the thwacks heard around the room, then methodically folded the rustling bag away. Just another example of Howard precision. Howard has an incredible ability to convert any complex problem into its simple mathematical expression. I still strive to achieve Howard’s clarity of thought and focus of purpose, and while failing frequently, the trying pushes me to be a better scientist. Among the most impressive, to me, of Howard’s traits is his deeply felt sense of obligation to challenge himself to perform the kind of cutting-edge, “blue-sky” science that is difficult to pass through grant reviewers on study sections. Howard expressed his belief that NIH’s uniqueness as a relatively protected environment is an exhortation to explore new “weird and wonderful” avenues, and his career continues to reflect this belief. Jeffrey Gardner University of Illinois, Urbana-Champaign Howard and the Prairie Chickens Faculty members who go on sabbatical always hope to have a transformative experience but are usually disappointed. In my case, this hope was actually realized when I went to Howard’s laboratory. I had done fairly well with a genetic approach toward studying site-specific recombination, but Howard introduced me to biochemistry in a way I had not experienced before. My year in Howard’s laboratory was the most important year of my career. The experience changed my way of doing research, which has carried over to my more recent work on Bacteroides conjugative transposons. I was so happy with my experience in Howard’s laboratory that I asked him more than once to come to Illinois to give a seminar on his work.