Thoughts From a Research Career by Dr Jack H. Dean,the 2017 Mildred S. Christian Career Achievement Award Winner

Introduction

Firstly, I want to thank Dr Matt Bogdanffy, president of the Academy of Toxicological Sciences (ATS) and the awards committee for my selection as the 2017 Mildred S. Christian Career Achievement Award recipient. A special thanks to my longtime friend Dr Jim Popp for nominating me. I was surprised and honored when Matt called to tell me I was selected as this year’s recipient. It is a huge honor and humbling experience to be recognized by your peers, colleagues, and friends from an organization as prestigious as the ATS.

In addition to telling the story of my research career and decisions that help shape it, I will also focus on some of the events and people that have contributed to my success during 44 years of research in immunobiology, immunotoxicology, toxicology, and drug development. My advice to young scientists is to study and work hard, be willing to take risks, make well-informed career decisions, do research in an area that really excites you, and, if possible, define a research niche for yourself. Don’t be afraid to collaborate with scientists your equal or smarter, always recognize and acknowledge the contributions of others, build lasting friendships, help others achieve their goals, and stay humble because you will find many smarter than you. Many members and friends in the Academy have had well-focused research careers with great success. In contrast, mine has had several different paths, possibly because I needed a new or different challenge every few years.

Life and Career Phases

Childhood

I was born in Joplin, Missouri and raised in a small lead mining town across the state line in the Southeast corner of Kansas (Galena = lead sulfide). I had loving parents: my mother had grown up in that area, was one of 6 children, a housewife, and woman of great faith; my father was a supervisor at an electric generating plant on Spring River. He came to that area as a construction supervisor to build the plant and stayed on to help run it. As a kid, I spent most summers riding my bicycle, playing games, or swimming with my friends. When I was 10, I got a power lawn mower and earned money cutting grass. Unfortunately, my dad developed chronic lymphatic leukemia when I was 11 and died during my sophomore year in high school. During his illness, he was frequently in the hospital, which is probably where my interest in medicine and science was nurtured. I was the only kid in Galena who knew the normal range for a complete blood count or the different types of leukemia. My interest in toxicology developed when I lost an uncle to lead poisoning from working in the local smelter. Galena later became a Superfund cleanup site.

College

Upon graduation from high school, it was clear I would need to support my own college education, so I moved to California to live near my older sister to establish residency for in-state tuition. I got a job as an orderly in the emergency department at a local hospital and enrolled the next year at California State University at Long Beach (CSU-LB) as a microbiology major. Since I couldn’t afford a car like many students I rode a bicycle to campus and work.

During my junior year in college, I experienced my first life-changing event when I met this cute, smart, and sweet new graduate nurse while working part-time in the emergency department. Suellen has been my best friend, wife, and soul mate for 54 years and helped support us through graduate school. She has given us 3 wonderful sons (Carl, John, and Matthew) who have produced 6 exceptionally smart grandchildren.

Medical Technology Career Phase

Upon finishing my bachelor of science degree in microbiology, I applied to a medical technology training program at our hospital. At the end of the traineeship, I was licensed by the American Society of Clinical Pathology and the State of California. This provided the extra income to go on to graduate school. During my rotation through the microbiology laboratory, our consultant, a professor at CSU-LB, encouraged me to consider graduate school. Dr Russell was the first transformative force in my career, and without her influence, I might have retired as a medical technologist since I enjoyed clinical laboratory medicine.

Graduate School

I returned to CSU-LB and completed a master of science degree in medical microbiology (1967) working with Dr Russell, who then encouraged me to apply for doctoral programs that were not yet offered at Long Beach.

I was accepted for doctoral studies at 2 schools, but chose the University of Arizona, because of an interest in medical microbiology and immunology. I soon requested a year’s extension, since I was given the opportunity to set up and manage a clinical laboratory for Kaiser Permanente at a hospital they had just acquired in San Diego. I had worked for them 3 years as a part-time medical technologist while at CSU-LB. We spent 1 year in San Diego and both worked for Kaiser to save some money.

In July 1968, we moved to Tucson. It was 110° in July on the day we arrived at married student housing; Suellen was pregnant with our second child and we both were wondering why we left cool San Diego. I became a graduate student in the microbiology and molecular biology department at the new medical school and soon learned the focus was primarily immunology and molecular biology. My research was in immunology studying the response of mouse lymphocyte subpopulations to T- and B-cell mitogens and evaluating their ability to make immune (γ) interferon. My advisor Dr David Lucas and I published 5 papers from that work.

Tumor Biology and Immunology Career Phase

Upon graduating, at what I considered the old age of 31 (1972), I accepted a research position in the Tumor Biology and Immunology department at Litton Bionetics in Bethesda to work on multiple National Cancer Institute (NCI) contracts. My alternative was a postdoc at Stanford working with an interferon expert. This was one of life’s difficult decisions since our families lived in California, while the position in Bethesda had the strongest research interest. I worked on NCI programs with Dr Lloyd Law on tumor biology and immunology in mice and with Dr Ron Herberman studying immune function in patients with cancer. I was soon invited to Dr Law’s monthly Friday afternoon “seminar,” which I discovered was a golf outing with the senior folks in his laboratory. I learned a lot of tumor biology during those outings, although my golf game didn’t improve. My laboratory in Bethesda worked to evaluate immune function in tumor-bearing mice and determine whether they had an immune response to extracts of their autologous tumors. ¹ In patients with breast and lung cancer, we studied immune competence and if they had an immune response to a tumor extract of their autologous tumor or various tumor cell lines. ² During my 7 years in Bethesda, collaborating with these very productive and bright groups, I had the opportunity to publish and coauthor 85 publications and more importantly learn a lot about immune function and tumor biology in both mice and man. ³ In 1976, I became the department head when Dr James McCoy moved to the NCI’s Frederick Cancer Research Center.

A Career Change in the Making

In 1978, I was asked to organize a 2-day symposium on immunotoxicology at the Gordon Research Conference on Drug Safety in New Hampshire that summer. I had never heard the term immunotoxicology and had always wanted to attend a Gordon Conference, so I headed to the National Library of Medicine where I found a recently published paper by Dr Jeff Vos entitled “Immune suppression as related to toxicology.” ⁴ Jeff was a young Dutch pathologist who had been working at the National Institute of Environmental Health Sciences (NIEHS) with Dr Jack Moore, chief of the Comparative Biology Branch. Jeff and I later became good friends and collaborated. From the references, I identified the names of other scientists to invite to the first meeting organized on immunotoxicology. The attendees were primarily head of toxicology from the pharma, consumer products, and petrochemical industries. Presenters were Drs J. Moore, M. Luster, L. Koller, R. Sharma, and myself. I introduced the concept of a tiered testing paradigm for evaluating immunotoxicity in rodents at this meeting. ⁵

That fall, Dr Moore called and invited me to consider a position at the NIEHS to establish an immunotoxicology section in his branch. I accepted and we arrived in Chapel Hill, North Carolina in July 1979 with our 3 sons. I started at NIEHS and Suellen worked in the clinics at the University of North Carolina Hospital. Dr Moore became the next major force in my career development and actively supported the development of immunotoxicology as a subdiscipline of toxicology.

Immunotoxicology Research Phase (1979-1988)

At NIEHS, Dr Mike Luster and I established the immunotoxicology section and developed a great collaboration and friendship studying methods to assess immune suppression in rodents as well as identifying environmental chemicals that produced an immunotoxic effect in rodents. Mike had studied immunochemistry during graduate school and developed an immunoassay for dioxin. Our team at NIEHS, which included Drs Gary Boorman and Bob Lubke, produced 38 publications on the standardization and refinement of the immunotoxicology tier assays and studies with a variety of xenobiotics. ⁶ Dr Luster went on to complete the validation of the National Toxicology Program's tier panel for immunosuppression in rodents and its use for quantitative risk assessment. ⁷ While there, I also monitored the immunology and health effect studies contracted with Drs Selikoff and Bekasi at Mount Saini Hospital on the Michigan Farmers accidentally exposed to polybrominated biphenyls. At Dr Moore’s request, we developed contract proposals for standardizing and validating immune suppression assay in rodents. Two contracts were awarded (1981) to Drs A. Munson and P. Morhan at the Medical College of Virginia and to Dr P. Thomas at the Illinois Institute of Technology Research Institute. These contracts were significant in assay refinement and educating young scientists in this newly developing discipline.

My office at NIEHS was near Dr Bob Dixon’s office, who became a good friend. During his Presidency of the Society of Toxicology (1982-1983), he encouraged me to petition the SOT Council to establish an Immunotoxicology Specialty Section (ISS). After getting 50 names on the petition, it was approved and the first meeting was at the SOT Annual Meeting in 1985 where I was elected the founding ISS president. Immunotoxicology became my niche and allowed me to integrate the science I knew, immunology, and immunobiology, with toxicology, a science I had to learn.

Chemical Industry Institute of Toxicology

In 1982, Drs Bob Neal and Jim Gibson recruited me to set up an immunotoxicology laboratory at the Chemical Industry Institute of Toxicology (CIIT). I accepted the position, since the postdoctoral positions offered at NIEHS had been frozen when President Reagan took office in 1981. Chemical Industry Institute of Toxicology provided a wonderful environment with great leadership, a talented faculty, and excellent postdoctoral fellows. While there, I was the advisor to 2 PhD students (Ken Hastings and Robert House) and 6 postdoctoral trainees (Drs Marc Pallardy, Joel Cornacoff, Michael Murray, Linda Thurmond, Christine Babiuk, and Ted Ward). My laboratory team at CIIT was smart, hardworking, and very creative, and all went on to develop successfully scientific careers. We had several lab trips to the North Carolina beaches together.

My contribution in the field of immunotoxicology included introduction of the immune suppression tier testing paradigm that later became the NTP testing scheme, introduction of tumor and host resistance models, the use of human lymphocytes for studying immunotoxicity, and promoting this science through organizing several national and international meetings. We also contributed data on several chemicals to the NTP Tier Panel Interlaboratory Immunotoxicology validation effort. In collaboration with Dr Burleson, we demonstrated altered viral resistance following dioxin exposure in rodents.

While at NIEHS and CIIT, my associates and I studied a variety of xenobiotics, including diethylstilbestrol, benzo(a)pyrene, 7,12-dimethylbenz[a]anthracene, phorbol myristate acetate, ethylene glycol monomethyl ether, 2,3,7,8-tetra-chlorodibenzo-p-dioxin, formaldehyde and aflatoxin B2, which resulted in more than 78 publications during the CIIT period. ^{8 –11}

In 1987, I realized I missed extrapolating rodent data to human participants as I had done in Bethesda. During that summer, I received a job offer to head the Toxicology Laboratory at Pharmatalia in Milan, Italy. During discussions with my friend Bob Dixon, who had joined Sterling-Winthrop (SW) as vice president (VP) of Drug Safety, concerning the position in Italy, he invited me to interview for a position to head the toxicology department at SW in Rensselaer, New York. I interviewed and took the position.

Drug Safety Assessment Phase

I arrived in Albany in January 1988 to a record cold winter and just as the company was being acquired by Eastman Kodak and merged with Eastman Pharmaceuticals. This was probably my riskiest career decision since I came with no experience in industrial or pharmaceutical toxicology. Bob encouraged me that “I was smart and would figure it out”.

Dr Dixon was another major force in my career and great mentor, as was the decision to join him in pharma. He was a great scientist, passionate about doing good research, and taught me the importance of a sense of humor. He believed that toxicology in pharma was “just doing experiments with the drug candidate to better understand the underlying toxicities and that much of the observed toxicity was high-dose pharmacology”. My experience has proven him correct.

My first year in pharma was overwhelming because I had to learn GLP, to write and review toxicology reports, prepare INDs and NDAs, and understand quality assurance and regulatory guidelines. After a year and a half of working with Bob, he was diagnosed with advanced liver cancer and died within a few months. This was a difficult period since my pharma mentor and good friend was gone and I still had so much to learn. I doubled down and after first declining to be interviewed for his position due to lack of experience, I later asked to be added to the candidate list and became the VP of Drug Safety with global responsibility for toxicology/pathology, laboratory animal resources and metabolism, and pharmacokinetics. In July 1990, the new president of research from Eastman Pharmaceuticals (Dr Gene Cordes) asked me to take a second job as the site director of our laboratory in the castle town of Alnwick, Northumberland, United Kingdom, to “broaden my knowledge in drug development”.

The Alnwick Centre was a site of 225 scientists that represented most of the commonwealth and all preclinical departments. The quality of the staff was excellent and I had the opportunity to experience drug development up close across many disciplines. I would later recruit several outstanding scientists from Alnwick to the United States, including Dr Ernie Harpur to head regulatory compliance within toxicology. The 2 years we lived in England were brilliant with walking in the Cheviot Hills on the weekends and holiday travel to Europe. When we returned to the United States, we immediately moved from Albany to the Philadelphia area where SW had just completed a new research center in Collegeville. I was elevated to executive VP of development to manage the clinical, nonclinical, and regulatory departments. Knowing that I needed a strong Global Head of Toxicology, I reached out to my good friend at CIIT, Jim Popp to join us. He provided great scientific leadership to the global toxicology departments for several years.

In 1992, SW formed a joint development alliance with Sanofi and I was appointed to the joint Development Coordinating Committee. Abruptly, in 1994, Eastman Kodak announced it was selling the pharma business and Sanofi acquired the ethical drug business. I was asked to stay on to manage the US R&D and soon was given additional responsibilities by Sanofi to lead Global Preclinical Development. This turned out to be the most interesting and challenging experience of my career: managing scientific issues with my team across all 7 global development departments (chemical development, analytical sciences, pharmaceutical sciences, drug metabolism/pharmacokinetics, toxicology/pathology, animal resources, clinical trial supplies). For the next 12 years, I traveled to Europe monthly for the Development Coordination Committee, Research Management Committee and Drug Safety Committee. This position provided an opportunity to review toxicology and development issues, participate in developing strategies for regulatory filings and scientific discussions at the Food and Drug Administration and EMEA, and work with exceptionally talented and experienced scientists.

The most memorable lesson on the behavior of a superior leader came from our French CEO (Jean-Francois Dehecq) who was the co-founder of Sanofi (1973) and developed it into the second largest pharma company globally by sales when I retired. In addition to being very smart and hardworking, Mr Dehecq’s secret was his passion for the company and its people, and his ability to make everyone feel important and appreciated. My immediate boss, the global head of research (Dr Gerard LeFur), was a talented CNS pharmacologist. He was sure the drugs he had discovered were not toxic and would frequently remark “Il est clair qu’ils ne sont pas toxiques”. Gerard and I frequently disagreed on this topic.

I am most proud that during my 18 years with Sanofi and legacy companies, I played a small role in the development of 12 drugs for the United States and global markets, including Plavix (antiplatelet agent which became #2 global drug behind Lipitor); Eloxatin or oxaliplatin (second-line therapy for colorectal cancer); Avapro (an angiotensin receptor blocker for blood pressure control), and my favorite, Ambien SR (sleep aid). We underwent 3 pharma mergers (SW, Synthelabo, and Aventis) in which I participated in the global and United States reorganization and integration of preclinical department. As most know, it is more difficult to publish in industry and papers produced are generally descriptive ¹² or result from a scientific advisory committee activity. ¹³

To manage the 50+ projects in preclinical development, our management team met quarterly to review scientific issues, preform pre-IND and NDA readiness reviews, and prepare for regulatory meetings. I cherished these meetings because of the diverse scientific challenges that emerged and tried to convey we were “just doing research with our drugs”. Project teams developing the drugs get very passionate about their project and sometimes try to ignore toxicity signals and it becomes the responsibility of the toxicologist to add clarity.

When I retired in 2006, preclinical development had grown to over 3,300 scientists in 8 countries, on 19 sites, in 7 global departments. My proudest moment came shortly after I retired when the French Government awarded me “Chevalier” of the Legion of Honor, an award given for my “contribution to medical and pharmaceutical research” at a ceremony in Paris attended by my wife, sons and their wives, and many work colleagues.

Other Activities and Accomplishments

I served twice on the Society of Toxicology Council starting with the presidency of Dr Jerry Hook and then again in the Presidential Chain starting with Dr John Emmerson and served as president in 1995 to 1996. Serving on SOT Council was a special experience because of the energy, competency, and passion of Shawn Lamb, Clarissa Russell, and Council members.

I also served for 18 years on the Health and Environmental Science Institute (HESI) Board of Trustees (1994-2012), as HESI president (1999-2002), and twice as treasurer. The HESI is a unique scientific organization where scientist from industry, academia, and regulatory agencies come together to work on health-related issues.

Retirement Phase

In 2006, Suellen and I moved to Tucson and built a home. I promised Suellen that we would meet at our pool every evening at 4 pm for a swim possibly followed by a glass of wine. The second promise was that we would spend as much time together as possible with our sons and families and travel for fun. My good friends Drs Glenn Sipes and Terry Monks offered me adjunct faculty appoints at the University of Arizona to give a couple of lectures per year and stay involved in toxicology. I phased in my retirement over 10 years and, following advice from a colleague, to divide my retirement into thirds, 1/3 to give back, 1/3 with wife, family, and travel, and 1/3 doing things I found challenging, like lecturing on immunotoxicology or consulting on drug safety issues.

Conclusion

In summary, my scientific accomplishments are modest compared to many ATS members. I know that all that I achieved was because of the highly competent folks I worked with and the loving support of Suellen and our sons. I enjoyed every day that I spent doing research in cancer biology and immunology, immunotoxicology, and drug safety evaluation. I was blessed in my career, my marriage, and family and in making so many great friends along the way.

Finally, as stated in the beginning, successful careers require hard work, informed decisions, risk taking, passion for your work, good collaborators, acknowledging the contribution of others, maintaining a sense of humor, and building lasting friendships.