Abstract
To begin, I wish to thank the Academy of Toxicological Sciences for bestowing this honor on me. I have had a rewarding career in basic research and clinical medicine, beginning with research in high school and always planning on becoming a physician. I have had the good fortune of having outstanding mentors, wonderful parents, and a supportive and intuitive wife and family. This article provides a brief overview of some of the events of my career and individuals who have played a major role, beginning with the M.D./Ph.D. program at the University of Wisconsin, pathology residency and faculty at St. Vincent Hospital, Worcester, Massachusetts, a year as visiting professor at Nagoya City University, and my career at the University of Nebraska Medical Center since 1981. This could not have happened without the strong input and support from these individuals, the numerous students, residents and fellows with whom I have learned so much, and the more than 500 terrific collaborators.
Introduction
Above all else, I would like to thank the Academy of Toxicological Sciences and the Awards Committee for selecting me as the 2020 Mildred S. Christian Career Achievement Award recipient. Special thanks to Dr Roger McClellan for nominating me and to those who wrote letters of support. It is an honor to be recognized by one’s peers, especially for doing what one loves and enjoys during a career and lifetime. I have had the good fortune of knowing and working with innumerable, outstanding individuals, forming long, lasting friendships with many incredible people. I have also had the enormous good fortune to have had a loving and very supportive wife and family who have provided me not only with encouragement and support but have also kept me focused on what they and, ultimately I, considered important, even during some very turbulent, challenging, and difficult times. I mention several names, but am truly thankful to many more who played a significant role in my life. To the latter, please accept my apologies.
Childhood
I had the good fortune of having fantastic, loving parents who encouraged me and supported my pursuits, even when they did not always agree with them. I was born in Milwaukee, Wisconsin, the oldest of 5 children (Esther Lee, Dinah Meron, Linda Warner, and Donald Cohen), and grew up in Edgerton, a small town south of Madison, where we moved before I was 2. My father was a small town family practice physician, and my mother eventually became a realtor. There was no question in their mind that someday I would also become a physician. My father started taking me with him on house calls (for those of you who remember such things) when I was 4 years old, and at the age of 5, I began to accompany him on hospital rounds. Of course, such doings could not take place with today’s regulations, but this was long ago in a small town where everyone knew everyone. I also had the good fortune of having outstanding teachers throughout grade school and high school. I was particularly fortunate to have John Hamburg as my high school principal, an individual who, even though from a small high school, became president of the National Association of Secondary High School Principals. He supported my quest to complete high school in 3 years instead of 4, and blunted the antagonism of many of the teachers for such a “crazy” idea. Several teachers stimulated a voracious appetite for reading on a broad range of subjects. Unfortunately, my community was not as supportive of such “liberal” pursuits, leading to a “book burning” (banning of 5 books from the curriculum) during my last year in high school, a highly destructive period for the students, teachers, and school.
During my high school years I began to show interest in research, in addition to a career in medicine, not realizing at that time that one could do both. A history teacher, Mr Henry Ruszczyk, kindled my interest in history and especially encouraged my in-depth investigation of subjects. On the weekends, I would take a 30-minute bus ride to Madison to study various subjects at the University of Wisconsin (UW) Historical Library, one of the finest in the country. A common theme was Turner's theory about the role of the frontier in shaping the American character, a theme to be championed by President Kennedy with his Last Frontier. Those visits provided me with the opportunity to learn how to find information in depth (long before the days of Google), and also acquainted me with the beautiful UW campus where I ultimately matriculated.
Another aspect inspired by my life in Edgerton was my interest in travel, actively encouraged by my parents and supported by them and by part-time work. In 1960, I spent a week at the Colorado Springs American Boy Scout Jamboree, celebrating the 50th anniversary of Boy Scouts in America, where I had the opportunity to shake hands with President Dwight D. Eisenhower during his motorcade through the Jamboree. He was the first of 3 presidents with whom I have had the opportunity to meet and shake hands, but this was the only 1 of the 3 while he was in office (the other 2 were Obama before he became president and Carter after his presidency). The following year (1961), I traveled to the World Boy Scout Jamboree on Mount Carmel, just outside Haifa, Israel, meeting scouts from all over the world (as well as contracting Giardiasis, a quite unpleasant experience, given the lack of facilities). The 96 American Boy Scouts and 12 leaders spent an additional 2 and one-half weeks touring Israel, followed by a 2-week tour through Athens, Rome, Paris, London, and environs. I have been able to travel the world over and, more importantly, have met many wonderful people. One quickly learns that though there are numerous differences between societies and cultures, there are many more similarities. More importantly, one realizes that one culture is not better than the other, just different.
My scientific research interests were stimulated even more during the summer of 1962, when I spent 8 weeks at Howard University in Washington, D.C., as a National Science Foundation (NSF)-sponsored high school student. The NSF was trying to encourage young people to become interested in science after Sputnik alarmed Americans. My experience at Howard gave me the first opportunity to perform scientific research, not just history, as well as to meet and work with the other 47 program students from across the country. It was also an incredible experience being a minority on the campus of a traditionally African American university, just as the Civil Rights movement was gaining momentum.
University of Wisconsin (1963-1972)
The UW was enormous compared to my small-town high school (graduating class of 110). In 1963, UW had approximately 26,000 students, and it has grown ever since. The facilities and faculty were inadequate for the onslaught of the baby boomers into the college ranks, therefore, a strong effort was made to eliminate as many of the admitted students as possible, as early as possible. In those days, unlike today, efforts were made to get you out of the university rather than retain you. Only about a third of those admitted to UW in 1963 graduated by 1967.
The 60s was a particularly turbulent time for our nation and the world, especially on the UW campus. These were the days of the civil rights movement and the strong anti-war movement. There were several riots on the UW campus, culminating in August 1970, in the bombing of the physics building, which housed the Armed Forces Institute of Mathematics. More on that event later.
In the summer of 1964, I had a blind date with a young lady, Janet Olson, who had just graduated from high school, and soon we realized that we had many common interests, even though she had no interest in mathematics or science. She was very interested in people and incredibly intuitive and compassionate; she became an occupational therapist. By September 1964, due to a variety of circumstances, I needed a job to help support my college education. Jan happened to know someone, who knew someone, who knew someone who was willing to give me a job. That someone was Dr Jim Price in the Division of Clinical Oncology in the Department of Surgery at the Wisconsin Medical School.
Dr Price provided me with my first opportunity to work in a cancer research laboratory, initially researching the relationship of aromatic amines and urinary bladder cancer, and ultimately studying the carcinogenicity of 5-nitrofurans and other nitroaromatics. I’ve been studying bladder cancer ever since, both in basic research and clinically. One year later after starting working with Dr Price, he accepted a vice president position at Abbott Laboratories. I began working with his successor, Dr George T. (Terry) Bryan, under whose guidance I ultimately completed my PhD thesis research. Interestingly, both Dr Price and Dr Bryan were MD, PhD individuals; Terry Bryan continued to actively pursue both clinical work (oncology) and basic research. He served as the model I was to follow for the rest of my career.
In those days, internists had no interest in oncology, other than hematology, so the UW Department of Surgery began an oncology effort, primarily to evaluate the clinical efficacy of the anticancer drug, 5-fluorouracil, which had just been synthesized and patented by a UW faculty member, Dr Charles Heidelberger, at the McArdle Laboratories, which were world renowned for research on chemical carcinogenesis and other aspects of cancer research, such as therapeutics, viruses, and biochemistry. It turned out that Dr Heidelberger, an incredible chemist, had a strong interest in chemical carcinogenesis, especially as it related to polycyclic aromatic hydrocarbons, in addition to his interest in synthesizing anticancer agents. He ultimately was a member of my PhD supervisory committee.
The UW in the 1960s was an outstanding academic center in the sciences, medicine, and the nonsciences as well as in the political activism of the students and faculty. My major department was experimental oncology, which was housed in the McArdle Laboratories. The McArdle Laboratories had many outstanding faculty members including, in addition to Charlie Heidelberger, Henry Pitot, Jim and Betty Miller, Van Potter, Roz Boutwell, Bill Dove, and Nobel Prize winning Howard Temin. Most of the course work for the oncology PhD was in the departments of chemistry and biochemistry. Among my professors were Paul Bender, who discovered hydrazine as a rocket fuel and was one of the first to establish a common instrument facility in an academic department; Har Gobind Khorana, a Nobel Prize winner for his work on deciphering the genetic triplet code; and Hector DeLuca, who discovered the metabolism of vitamin D and its innumerable clinical applications. My academic life at the UW was stimulating and exciting and provided the model which I was to follow thereafter combining research and clinical medicine, trying to excel in both. It was like having 2 full-time highly gratifying and demanding careers.
Charlie Heidelberger had a conviction that one duty of a professor was to torture graduate students, and he had honed this skill to an outstanding level. Nevertheless, he also encouraged and provided strong support for the students and fellow researchers. One of his dictums, which he repeated many times, was that you must focus on important questions of biology and then develop the necessary skills and collaborations to perform research based on those questions. He emphasized that it was critical to learn a variety of technologies, but to not become infatuated with the technology except for what it could provide, with respect to solving the question at hand. This is the advice that today’s students should take to heart even more than when I was a student, as technology has become incredibly alluring and seductive. However, it is the use of these continually evolving technologies which helps us solve critical biologic questions that are the key to success. The other important dictum that I learned from my professors was that it was incredibly important to collaborate and most importantly to do so with outstanding individuals.
In January 1968 during my second year of medical school, Jan and I were married. Within a few weeks I was approached by Dr Henry Pitot, a pathologist at the McArdle Laboratories, to participate in the newly initiated Medical Scientist Program. This new program, funded by National Institutes of Health (NIH), strived to stimulate research interests in physicians, and UW was one of the first institutions to receive a grant for an MD, PhD program. Although I had significant reservations regarding the undertaking of such a prolonged and challenging effort, Jan had no doubts whatsoever and strongly encouraged me to sign up, which I did. After completing this second year of medical school, I spent 2 years doing research, continuing a program with which I had been involved since my undergraduate collaboration with Drs Price and Bryan. I then spent my third year in medical school devoted to clinical rotations, and then the last year finishing my thesis research and required clinical rotations.
In August 1970, a van full of dynamite was placed next to the physics building and was blown up at about 3
Worcester, Massachusetts (1972-1981)
The major reason I chose St. Vincent Hospital for my residency was that it allowed residents to spend time performing research, unlike most residency programs at that time. I was also able to obtain my first grant from the National Cancer Institute (NCI) in 1973. The National Bladder Cancer Project (NBCP) at St. Vincent Hospital was funded by NCI and was directed by the chairman of the St. Vincent department of pathology, Dr Gilbert (Gil) H. Friedell. Also, the University of Massachusetts Medical School in Worcester had just opened the year before, so the initial second-year pathology course was being taught when I arrived. This was the beginning of my teaching experience. I was given the task of teaching neoplasia to second-year medical students. My first postdoctoral fellow, Dr Masayuki Arai, arrived from Japan in 1974. During my residency, I focused primarily on learning diagnostic pathology, especially surgical pathology, but I also had sufficient time to do research.
The deputy director of the NBCP was Dr Robert (Bob) Greenfield, who had previously been deputy director of the National Institute of General Medical Sciences and also the NCI. He was one of the NCI scientist leaders who had been instrumental in developing and obtaining funding for the War on Cancer during the Nixon administration. He had intended to become a biologist but was forced by circumstances to instead become an MD because of World War II. Nevertheless, he ended up pursuing a career in research at NIH. He became my closest friend and mentor and continually provided guidance not only concerning my research but also for my career and my life. At his house, he had a pond with many very large frogs. My children called Bob “the frog man.”
In 1975, I completed my residency and passed the pathology board exams in 1976. In 1975, NIH began an effort to have American scientists travel to Japan and spend time in Japanese research laboratories. Jan, Bob, Gil, and Terry conspired to have me accept this offer from NIH and go to Japan, despite the fact that by the time we were to go, we would have 4 children all under the age of 5 (Sheri, Benjamin, Daniel, Erica). And thus, we were the first Americans to participate in this program. Jan’s enthusiasm and ability to manage this move were quite remarkable. I became a visiting professor in the laboratory of Dr Nobuyuki Ito at Nagoya City University. During that year, I formed many close friendships and connections with Japanese cancer researchers. Later on, I had the good fortune of having several Japanese postdoctoral fellows and a Japanese graduate student. The year in Japan was truly incredible and rewarding, both professionally and personally. Two of our children were blond and 2 were adopted and biracial. Living in a city of about 3 million Japanese triggered many interesting experiences, especially with the 2 oldest, ages 4 and 5, enrolled in the local school where no one spoke English.
In 1978, I was asked to serve on a week-long NCI site visit at the Eppley Institute at the University of Nebraska Medical Center (UNMC), then directed by Dr Philip Shubik. During the late 1970s, NCI was making a concerted effort to end contracts to universities, such as the one for Eppley, and to have universities compete for program projects and individual grants instead. Part of the site visit was to evaluate the various academic departments at the campus and their relationship to the Eppley Institute. At that time the Department of Pathology at UNMC was basically nonacademic, with no publications. In later years, Jan often reminded me of a comment I made to her over the phone during that site visit, stating adamantly that if there was one institution where I would never go, that would be UNMC. My lesson from that experience was “Never say never,” in medicine or in life.
In 1980, Dr David Purtilo, a faculty member at the University of Massachusetts Medical School and St. Vincent Hospital, with whom I had worked since 1973, accepted the position as Chair of the Department of Pathology at UNMC. Upon his return to Worcester, after having completed his contract negotiations, he called me into his office and asked if I would be interested in joining him as professor and vice chair. After 15 minutes of laughing, he convinced me that the administration and the state were willing to put their money where their mouth was in developing UNMC into a major academic medical center and I agreed to, at least, come and visit.
I was quite hesitant to move from Massachusetts to Nebraska, but both Jan and Bob felt strongly that it was best for my career. During Jan’s visit to Omaha in January, 1981, to look for a house, she was convinced enough that she actually put down an offer on a house before I even had a chance to see it. She also had the audacity to tell David that she had done so even before we had completed our contract negotiations. However, David was extraordinarily supportive and delivered even more than he promised.
University of Nebraska Medical Center, Omaha, Nebraska
I began my faculty position at UNMC on April 1, 1981, and have been there ever since. At first I served as vice chairman and from 1992, as chairman, after the untimely death of David from a massive brain stem stroke at the age of 53. By 1984, UNMC went from the indigent care hospital of Omaha to a major medical center with a world renowned cancer center and the second largest transplantation center at the time.
One day, between the acceptance of the offer from UNMC and the move to Omaha, Bob and I happened to be discussing our research at lunch at the St. Vincent Hospital cafeteria. Both of us were very frustrated, trying to figure out what our research results meant. Suddenly, Bob slammed his fists on the table, causing all of our dishes to fly into the air and ultimately to fall on the floor, loudly proclaiming that we needed to get in touch with Dr Leon Ellwein, Bob’s associate while at NIH. Leon had become a consultant in La Jolla. Leon, Bob, and I frequently met in Massachusetts, even late into the night in Leon’s hotel room near Boston’s Logan Airport, and later in Omaha. We strived to develop a model to mathematically describe the carcinogenesis process. I was able to convince Bob to become a part-time faculty member at UNMC and persuaded Leon to move to Omaha in 1983 for what became 9 productive years.
One of Bob’s major convictions, already when he was at NIH, was that it was critical for government, academia, and industry to work together to solve major medical and research challenges. This would have been a difficult cooperation even today. Nevertheless, Bob convinced me to accept partial support from the International Life Sciences Institute (ILSI) beginning in 1985 for our research on saccharin, a research effort that we had begun in 1973 with grant support from the NCI. The support from NCI and ILSI, along with funding from the State of Nebraska, continued until the mid-1990s. A major champion for us within ILSI was Dr Jim Emerson, who avidly believed in our efforts to model the carcinogenic process. Unfortunately, in August, 1985, shortly after we began working with ILSI, Bob died from cancer, the disease he spent his entire life studying. He was 65.
Our research focused strongly on demonstrating the role of increased cell proliferation and spontaneous errors occurring during DNA replication as a basis for carcinogenesis. This concept faced considerable opposition when we first proposed it, but various investigators have since extended it and it has become widely accepted. However, in 1981, when we first proposed this hypothesis, it was a time when genotoxicity was in vogue with many genotoxicity assays being developed, starting with the Ames assay. Interestingly, by 1990, Bruce Ames became one of our strongest supporters concerning the role of increased cell proliferation in carcinogenesis. Ultimately, our research demonstrated that saccharin produced bladder tumors in rats by a mode of action that is irrelevant to humans, resulting ultimately in the International Agency for Research on Cancer reclassifying it down from class 2B to class 3, and the National Toxicology Program removing it from the congressionally mandated List of Carcinogens.
International Life Sciences Institute has played an important role in my academic career, as I have served on numerous research committees, on the Board of Trustees (2007-2016), and as Chairman of the Board (2012-2015).
While winding down our research program on saccharin, we developed an interest in investigating the relationship between arsenic and bladder cancer. This began with a visit to my laboratory by Dr Michal Eldan, from Luxembourg Industries Ltd in Israel, concerning the development of bladder tumors in rats following the dietary administration of dimethylarsinic acid (DMA). This led to extensive investigations and collaborations with numerous researchers, including Dr Chris Le at the University of Alberta. Our research demonstrated that DMA produced bladder tumors in rats by a threshold, nongenotoxic mode of action that was irrelevant to humans at the expected levels of exposure. We then pursued research on the mode of action for inorganic arsenic carcinogenicity, which we also demonstrated to be a threshold process. Unfortunately, the issue of arsenic has become a major political morass rather than a scientific issue.
More recently, I have become interested again in the role of cigarette smoking and bladder cancer, showing that cigarette smoke by inhalation and nicotine itself when administered in the diet or in the drinking water produce urothelial cytotoxicity with consequent increased urothelial regenerative proliferation. When administered after pretreatment with N-butyl-N-(4-hydroxybutyl)nitrosamine, orally administered nicotine increased the incidence of bladder tumors in rats. This work is being performed with Drs Shugo Suzuki and Min Wei, former postdoctoral fellows of mine, now at Osaka City University.
Models and Human Relevance
The standard for the evaluation of chemicals for carcinogenic activity has been the rodent 2-year bioassay. Over time, scientists have become increasingly aware that numerous findings in animal models are not relevant to humans, either because of qualitative differences in mode of action, such as saccharin and bladder tumors in rats, or based on dose–response relationship and human exposure, such as DMA and bladder cancer in rats. By 2000, it was obvious that this was not going to be tenable for the investigation of a large number of chemicals to which humans are exposed. It is too costly, time-consuming, requires too many animals, and most importantly, it became apparent that applying the results to humans was questionable. Since then, I have been actively involved in attempts to develop alternatives to the 2-year bioassay.
In the late 1990s, I became involved with the International Programme on Chemical Safety (IPCS) effort to develop a framework for mode of action and human relevance evaluation. This effort resulted in a constantly evolving framework that has proven useful not only for regulatory science but also as a basis for research. In 2001, ILSI, with funding from the US Environmental Protection Agency (EPA) and Health Canada, extended the effort from the initial IPCS project concerning the mode of action, to a mode of action/human relevance framework. Numerous investigators from government, industry and academia participated in this challenging effort over a 2-year period, most notably headed by Dr Penelope Fenner-Crisp, formally from the EPA, but at that time, director of ILSI’s Risk Science Institute. I was asked to chair the committee, and Dr Jim Klaunig from Indiana University was asked to chair a subcommittee charged with applying the framework under development to a case study of peroxisome proliferator–activated receptor-α activators. Following intense discussions, frequently with active conflicts, the program ultimately led to a science-based, mode-of-action approach involving key events necessary for the development of some type of toxicity, which could be applied not only to carcinogenicity but also to noncancer toxic end points. Ultimately, IPCS again became involved and developed the framework further.
In the pharmaceutical industry, an effort began to replace the 2-year mouse study with a 6-month transgenic mouse assay. I was invited to participate in the project that was undertaken by the Health and Environmental Sciences Institute (HESI). This was a monumental project which involved hundreds of investigators from around the world, from academia, government and industry, to evaluate 6 different model systems as potential replacements for the 2-year rodent bioassay. Health and Environmental Sciences Institute’s 2-year project involved investigating 21 different drugs in all 6 assays, with standardized approaches for in-life procedures, histopathology, and statistics. Dr Jim MacDonald from Schering-Plough, chaired this massive effort, which cost approximately US$35 million. The outcome of HESI’s project served as the basis for the guidelines for carcinogenic screening of the International Conference for Harmonisation. Alternatives to the rodent bioassay continue to evolve, hopefully eventually leading to its demise.
I have been involved with various HESI projects since the 1990s and eventually became a member of their Board of Trustees (2002-2017), and Chair from 2006 to 2008. Jim MacDonald has been a strong supporter of my efforts with HESI and in research in general, as well as with my interactions with the pharmaceutical industry. Our association dated back to 1990 when he was at Merck and asked me to serve as a consultant to evaluate whether the mouse and rat liver tumors produced by simvastatin were relevant to humans. Thankfully, we concluded that simvastatin did not pose a carcinogenic risk to humans and were successful in convincing the Food and Drug Administration (FDA) of that. As a result of these efforts, the FDA approved simvastatin for treating high cholesterol levels, one of many statins now on the market. Since then, life experience as well as large-scale epidemiological studies involving hundreds of thousands of individuals have proven that our conclusion about lack of causal association between statins and human cancer was correct, as there appears to be no increased incidence of liver, or any other cancer, in humans who take statins.
Risk assessment efforts continue to evolve. One such effort is emanating from a HESI project, a program termed Risk21, chaired by Dr Tim Pastoor and Dr Michelle Embry. Risk21 is the culmination of efforts to modernize the risk assessment process. It is a problem formulation-based approach that is exposure-driven and reliant on employing all available data to assess risk. The threshold of toxicological concern (TTC) is used when appropriate. This continually evolving program has included hundreds of scientists from government, academia, and industry and is beginning to be used more frequently and actively for the assessment of risk from a variety of chemicals, including agrochemicals, food ingredients, and others.
I have also had the honor and pleasure of serving on the Expert Panel of the Flavor and Extract Manufacturers Association for the evaluation of the safety of flavoring ingredients. This is a small panel (8 members at any given time) of outstanding academic scientists from around the world, with expertise in various aspects of risk assessment, including chemistry, metabolism, toxicology, and pathology. I have been serving on the panel since 2002 and as chair since 2016. Small amounts of specific chemicals are used as flavorings, which led to the concept of congeneric groups, the Cramer classification, and the concept of TTC. The Expert Panel continues to use these concepts in its deliberations.
Career, Life, and the Mildred S. Christian Career Achievement Award
I am deeply honored by the Academy bestowing on me the Mildred S. Christian Career Achievement Award. Though I did not know Dr Christian in person, I am cognizant of her many accomplishments. She was a true visionary with boundless energy to implement those visions, including as a founding member of this Academy of Toxicological Sciences and the American College of Toxicology. I have been a member of the Academy since 2000, serving on its board of directors (2014-2017), and I am constantly impressed with the outstanding quality of its members. I would like to thank Roger McClellan for nominating me, and for the letters of support that he was able to garner, and the awards committee, on the decision to grant me this important award. The telephone call from Dr Michael Aschner conveying the award decision came as a very exciting surprise, at a time when I was facing many personal challenges. It helped to remind me how fortunate I am to be acquainted with so many outstanding individuals in academia, government and industry, with whom I worked and developed friendships over these past 55 years.
Thanks to the many students, fellows, and staff who have worked in my laboratory, and especially Lora Arnold, my right hand, who has directed and managed my laboratory since 1993. Lora has decided to retire this April and, in contrast to the concept that no one is irreplaceable, has led to my decision to close my laboratory after 47 years of continuous extramural funding. I will continue to perform research, utilizing equipment, supplies, and personnel in laboratories of my fellow faculty at UNMC. I would also like to thank numerous persons (more than 500) who have collaborated with me on a large number of projects and have served with me as co-authors on publications.
I am proud to be able to conclude that I stood up to the challenge and have been able to maintain an active clinical practice in diagnostic surgical pathology throughout my research career. Since I signed up for the MD, PhD program, I believed that basic research and clinical medicine together provide a perspective that is not available with one only. Involvement with clinical medicine has strongly influenced my approach to basic research. In each step of my research, I have asked, “What does this mean for humans?” and thanks to my clinical expertise, was able to evaluate research results from a practical point of view. With my experience at this point, I can say that combining research with clinical practice, especially with pathology, is much more than the sum of the two.
My belief in the combination of MD and PhD degrees led me to initiate the program at UNMC shortly after I arrived in 1981, and the program continues to flourish today. Of all my considerable involvement in medical and graduate education, the MD, PhD program is the one for which I am proudest. I thank my many students, residents and fellows for all they have taught me and for their stimulation to continue learning.
My advice to young people today is to focus your efforts on the science and do not be infatuated with the technology. Be patient and persevere in what you are doing and remember what George Box 1 stated more than a 50 years ago, “Models: All are wrong, but some are useful.” It is incumbent on us as scientists to make that distinction.
I always bear in mind David Purtilo’s criteria of finding good people at every level, whether students, residents, fellows, faculty, or staff: First of all, they have to have strong abilities; second, they need to have an energy and passion for what they’re doing; and third, they need to strive for excellence. To that I would add, that above all, it is important that they are quality human beings, with integrity and collegiality, who can work well with others. I have found many such individuals.
First and foremost, I had the good fortune to find the outstanding individual who became my wife, Jan. We met on a blind date in 1964, married in 1968, and over the years, had 4 children. We now have 8 grandchildren and 1 great grandchild. Unfortunately, Jan had numerous health problems, and in 2010 she was diagnosed with Lewy Body disease, a horrific neurodegenerative disorder which resulted in her early death at the age of 66, in 2011. Jan was an amazing person. She was supportive and loving, and had a sixth sense of what was worthwhile, and what was the correct path for us to take. I am also blessed with 4 great children who are supportive and loving, just like their mother, and my 8 grandchildren are a joy to overly indulge (we do not spoil them). I have been incredibly fortunate both professionally and personally. I wish you all well in your careers and life paths and thank you for the opportunity to tell my story.