Journal of Interferon & Cytokine ResearchVol. 42, No. 12 Guest EditorialFree AccessA Personal Perspective on My Scientific CareerHoward A. YoungHoward A. YoungAddress correspondence to: Howard A. Young, Senior Investigator, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA E-mail Address: younghow@mail.nih.govCenter for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.Search for more papers by this authorPublished Online:12 Dec 2022https://doi.org/10.1089/jir.2022.29046.editorialAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail My research career started when I was offered a summer position by Dr. Charles D. Cox, who was chair of the department of microbiology at the University of Massachusetts (Amherst). My mother had wanted me to work on a kibbutz in Israel that summer, but I felt the opportunity to work in a laboratory was too exciting to pass up. I helped his graduate students with their studies on Leptospira sp. I have always remembered the first time I got a clear result from an experiment as I was able to demonstrate that the bacteria needed vitamin B12 to grow. They also used the fatty acids present in Tween 80 as a carbon source.I continued to work in the laboratory during my senior year as well as the summer after I graduated. Although Dr. Cox told me that I could get my PhD in 3 years if I stayed at UMass, I applied to several schools, including UMass, University of Illinois, UCLA, and the University of Washington (UW) for graduate school. I got accepted by all of them and was urged to go to the UW by a new UMass professor (Dr. Tom Lessie) who had done his postdoc research there. I accepted his recommendation, and my next career step began as I drove from Amherst, MA, to Seattle, WA, in my mother's old Ford.My PhD thesis project started off slow, as I began to characterize the RNA polymerases in the dimorphic fungus, Mucor rouxii. I wanted to know whether there were changes in the enzyme when the fungus went from a yeast phase to mycelial growth. My advisor, Dr. Helen Whiteley, had never had a project like this, so she left me to develop enzyme purification protocols, assays, etc. I was her first official graduate student because, up until then, nepotism rules prevented her from being on the faculty because her husband was a staff member of the zoology department.If I had started graduate school a year later, I might well have ended up as a plant biologist because in my 2nd year, the laboratory of Gene Nester began its pioneering work on genetic alteration of plants, a field that has significantly changed agriculture. I will take some minor credit for generation of the first genetically engineered vegetable, the “Flavor-Saver” tomatoes. These were developed by a fellow graduate student who told me that he would never have come back to graduate school after serving in Vietnam if he had not received a letter from the department asking him to return. I had urged the department administrator to send him that letter and the rest is history, although the tomato was not a big seller.For my own project, I remember watching my data unfold at the scintillation counter in an experiment assaying enzymatic activity and I felt discouraged as I only saw very weak activity. However, a faculty member was passing by, and he said that by the time I am finished I will be seeing very strong activity. Thankfully he was correct, and the project worked out well and resulted in my thesis and 2 published scientific articles (Young and Whiteley, 1975a; Young and Whiteley, 1975b).I was an active graduate student as I served as the representative for the graduate students on the faculty committee for a year. One of the quirks of the program was the master's bypass examination. If you passed that examination, you could go on toward your PhD. I pointed out to the faculty that someone could be here for 5 years and if they suddenly have to leave, they would have nothing to show for their time in the department. This led the faculty to change the system such that if you passed the examination, you would be awarded an MS degree. I might have been the first graduate student to get that degree before my doctorate.When I took my qualifying examinations for my doctorate, I did not do so well on 1 part of the written examination, but I did okay on the oral examination so I was cleared for my PhD. The 1 committee member I was most anxious about fell ill at the last minute and did not participate in the oral examination, but he said he knew I would pass. Needless to say, I was relieved.When I started to look for a postdoctoral position, I first wrote to David Baltimore, but he was not interested in me. My UMass laboratory mentor, Richard Henneberry, was then located at the National Institutes of Health (NIH) in Bethesda, MD. He recommended me to his boss, Dr. Robert Lazzarini, who without meeting me then recommended me to Dr. Edward Scolnick at the National Cancer Institute (NCI). A year or so later I asked why he recommended me sight unseen and he told me that if Dick Henneberry recommended me, that was good enough for him.I visited the Scolnick laboratory and at the end of the visit, he said “let me know what you decide” without actually making me an offer. When I got back to Seattle, I talked to Dr. Whiteley about this, and she said to accept it as an offer. I did so and that was the direction my career next took. I had interviewed with Dr. Purnell Chopin at the Rockefeller Institute, where my father had worked as a laboratory technician. When I interviewed, all the men wore ties while working in the laboratory and everyone went upstairs to a formal lunch. It was impressive but a bit intimidating, especially compared with Seattle. At the end of the interview, he made me an offer but said that I would need to apply for grant support. However, when I got back to Seattle, he sent me a letter indicating that he had funding for me. If I had chosen that position, my career might have been very different since Dr. Chopin was a virologist. Dr. Chopin went on to become head of the Howard Hughes Medical Institute and Dr. Scolnick went on to become director of research at Merck.I left Seattle in May of 1974 and went straight to the laboratory of Drs. Edward Scolnick and Wade Parks. Their laboratory was in a small building on Research Blvd. in Rockville, MD, not on the NIH campus. One half of the building was a monkey colony (sometimes we would hear an announcement “Monkey loose in ceiling!!”) and the other half had a laboratory and a big undeveloped room. My first desk was in that room. I learned that I was the first “official” NCI postdoc in the laboratory and I was paid $11,000 per year: $8,000 came from an American Cancer Society fellowship and the other $3,000 came from a contract with Meloy laboratories. I am not sure how I survived on that sum but I did so without too many problems.I was very fortunate in that I was able to write an article 3–4 months after I first arrived in the Scolnick/Parks laboratory, on the glucocorticoid steroid induction of mouse mammary tumor virus, and it was published by the Journal of Biological Chemistry (Young et al, 1975). In the 5 years I was with them, I authored/coauthored a number of articles, including being a coauthor on the cloning of the RAtSarcoma viral oncogene (Ellis et al, 1981). In my 4th year, I was hoping for a more permanent NCI position, but it was not to be. One of the people in the laboratory when I was there was Dr. Doug Lowy, coinventor of the human papilloma virus cancer vaccine. He has also been acting director of the NCI 3 times.Fortunately, I did not really have to look hard for a job after learning that I would not get a more permanent NCI position, as I was offered a position at the new NCI laboratories on the Fort Detrick campus in Frederick, MD. President Richard Nixon used these laboratories to start his “War on Cancer” as they had previously been used by the U.S. Army for biological warfare research. The laboratories were run by a contractor and the research director was Dr. Ray Gilden. I was given a technician and shared laboratory space with Drs. Nancy Rice and Maurice Cohen.My work went along okay as I continued to publish articles on the Ras oncogene, but after 2 years, I felt that I was not being very creative and began to look for other opportunities. At the time, it might have been the right move as I later learned that 1 of the 3 of us was going to have to be let go due to budget cuts in the contract. Although it had not been decided who was going to be cut, my leaving made life easier for Dr. Gilden.The job I took in 1981 was with a company that created reagents for the newly emerging field of molecular biology, Bethesda Research Laboratories (BRL). I was hired to be director of technical services where I was responsible for product quality control, serve as editor of the newsletter, and be the public face of the company. People had told me that I had an entrepreneurial spirit, and the company was growing by leaps and bounds, so I thought I would be a good fit for the job. Little did I know that the fiscal management of the company was almost nonexistent. With the help of other employees, we did set better standards for product QC and built a loyal customer base. I talked to >3,000 customers during the 2 years I was there.I also created a useful newsletter and even initiated and developed a novel product. However, as I said, fiscal control was lacking, and on 1 afternoon, I was told that I was going to have to tell 8 employees that they were being immediately let go. It was very traumatic and not the only round of layoffs. I had very mixed feelings about this (ie, glad I still had a job but sad that my colleagues lost their jobs). Beginning the next day, I had to answer every call that was not an order or asked for someone by name. It was very stressful but because we always helped our customers, many continued to order from the company.Those loyal customers and the intervention by a fiscal “White Knight” saved the company at that time. In fact when hiring began again, former employees were offered jobs and many accepted. BRL eventually merged with Gibco, was later bought out by Invitrogen, which itself was later acquired by the giant company, ThermoFisher. When Invitrogen acquired the company, it closed the Gaithersburg laboratory and that created a boycott by many NIH scientists because former NIH staff had jobs there. Eventually the company came back to Maryland, but it was thought that the boycott had been very effective, based on some surveys that Invitrogen conducted.My trip back into research started again when I had an interview with Drs. Joost Oppenheim and Ron Herberman who were starting the Biological Response Modifiers Program (BRMP) in Frederick, MD. Dr. Oppenheim needed someone who knew something about molecular biology, since everyone there at that time was a cellular immunologist. I could not even give a seminar during my interview because I had not been doing any research during the previous 2 years. Nevertheless I was offered a cancer expert position that was a 1-year appointment to bring specific expertise in molecular biology into the NCI.Given that I did not know much about immunology, I asked whether I could have 2 years. Dr. Oppenheim agreed and he even wanted to start me as a section head. I declined that position since no one there knew me, and I felt I first had to prove myself to the existing staff. Dr. Oppenheim encouraged a new postdoc, Dr. Elizabeth Kovacs, to work with me and we began to compliment the cellular immunology research with molecular data. I remember that Dr. Oppenheim wanted me to clone the Interleukin-1 gene, but when I asked him whether he had an antibody or an amino acid sequence, he replied “no” to both requests.I asked him how I was supposed to clone it and he said I should figure it out since I was the molecular biologist. However, I heard that the IL-1 gene had already been cloned in Boston and in those early days of molecular biology, being second to clone a gene was not of much value. Thus, I did not try to clone IL-1 and instead began to work on the interferon-gamma (IFNG) gene, a topic to which I have devoted almost all of my subsequent research efforts.During my many years in the BRMP, I worked with many excellent research scientists, including John Ortaldo, Luigi Varesio, Bob Wiltrout, and Craig Reynolds, among many others. With their help, I was able to be very productive and I asked Dr. Oppenheim whether I could try to get tenure. He agreed, and with the support of NCI Division Director, Dr. Bruce Chabner, I was granted tenure in 1989. Interestingly, during my tenure discussion meeting, I was told that someone asked whether I was a Ronald Reagan supporter, since it was right at the end of his second term and there was a controversy at that time about political appointees being converted into permanent government positions. The committee was reassured that this was not the case with me.Currently, I am a senior investigator in the cancer innovation laboratory, Center for Cancer Research, NCI in Frederick, MD. I will not go into great detail about my research over the years at the NCI. Suffice it to say that I had a lot of collaborations and some very outstanding postdocs. I never had a big laboratory group, and my scientific accomplishments would go through peaks and valleys. My laboratory identified several ways in which IFNG mRNA expression is induced or inhibited, the transcription factors involved in the induction of the IFNG gene, and the role of DNA methylation on RNA expression.We also studied natural killer cells and how cytokines regulate IFNG expression in these cells. In the later years we focused on a mouse model we created, where IFNG protein was expressed in the serum at chronic, although low levels (Hodge et al, 2014) (Fig. 1). We replaced the adenylate-uridylate-rich elements in the 3′UTR with random nucleotides and this resulted in a very stable IFNG mRNA. This mouse has turned out to be the best model for the disease, primary biliary cholangitis, because it matches the human disease with the female bias better than any other mouse model. It is now being studied in a number of liver research laboratories around the world. We believe that this mouse strain is also a new model for ovarian failure syndrome and for early stages of lupus.FIG. 1. Howard discussing data with student Brittany Reichelt and former Staff Scientist, Deborah Hodge.We are investigating therapeutic approaches to monitoring and treating these autoimmune diseases as well as identifying the basis of disease initiation and progression. Furthermore, my laboratory is studying how cancer progresses in the context of an autoimmune host background. Thus, I approach the end of my scientific career knowing that we have contributed to bettering human health, at least in a small way, as this mouse model may well result in new treatments for these diseases.As I indicated previously, I had many productive collaborations throughout the years, including a very interesting collaboration with the army. Army scientists infected 18 monkeys with Ebola virus and then sacrificed 3 per day for 6 consecutive days. At the time, it could not have been done anywhere else in the world and it was the most complete analysis of the course of Ebola virus infection in a nonhuman primate. I obtained the white blood cells from these animals after the virus had been inactivated and looked for cytokine/chemokine RNA expression.For these studies and many other collaborations, my laboratory had mastered a technique named multiprobe RNA protection analysis (Young et al, 2003). It was technically difficult, but we streamlined the procedure and when other NIH laboratories heard that we were running this assay on a regular basis, we got many requests to test their RNA samples. By my calculations, we assayed samples from 30+ different laboratories. The company that made the reagents for the assay told me that we ran more samples than any other laboratory in the country. It was a very useful assay but eventually got replaced by the newer quantitative PCR technology.My career at the NCI has involved more than just research. I have participated on numerous NCI and NIH committees and have received 3 NIH/NCI director's awards for mentoring. I am very proud to have organized/co-organized a number of research events in Frederick, including the Spring Research Festival, the summer intern seminar series, the summer intern poster day, and the NCI-Frederick Green Team. I also helped the library with its yearly summer intern jeopardy tournament. I started a plant swap where employees could bring excess plants from their home gardens and either exchange them or just give them away to other employees.For many years I was the master of ceremony (MC) for the laboratory of experimental immunology holiday party where, after getting funds from the other senior staff to buy prizes, I would ask attendees for different items (eg, a parking ticket) and the first one to show the item would win the prize. That made the party a lot of fun. I am most proud of helping to start the Werner Kirsten (WK) Student Intern Program where high school juniors apply for a laboratory position, and if selected, they work for 8 weeks during the summer after their junior year and then at least 3 h per day during their senior year. Over 1,000 students have gone through this program in many different NCI-Frederick laboratories and some now have their own laboratories. Throughout my career, I hosted many summer students in my laboratory (Fig. 1), and before the COVID-19 pandemic, I usually had 2 WK student interns every year.I have been very active in the NIH immunology community, having twice chaired the immunology interest group (IIG) steering committee. I moderate the IIG ListServ and started the IIG newsletter. I have also been elected as the only permanent IIG steering committee member. In addition to the IIG, I cofounded the NIH Cytokine Interest Group (CIG) and twice served as chair of the CIG steering committee. Over the years I have also spent time organizing various research symposia in Frederick and at the NIH Bethesda campus that have covered a broad range of scientific subjects, from autoimmunity to cancer to the coronavirus.In addition to my various contributions to the NCI and NIH, I was also an active member of several scientific societies, including the American Society for Microbiology (I chaired the immunology division for 1 year), the American Association of Immunologists and the American Association for the Advancement of Science (AAAS). I am most proud of my involvement with the International Society for Interferon and Cytokine Research [now known as the International Cytokine and Interferon Society (ICIS)] that I first joined in 1983. The first meeting I went to was in Clearwater Beach, FL, where out of ∼300 attendees, I knew only 1 person.Over the years, I tried to attend every annual society meeting and that has taken me to many great locations: for example, Vienna, Paris, Torino, Oxford, Nice, Tokyo, Melbourne, Cairns, Kyoto, Florence, Geneva, Amsterdam, Seattle, San Francisco, San Diego, and Boston. During the Kyoto meeting, I was the second speaker in the meeting and I had a slide made in Japanese, thanking the organizers for inviting me. After I read the Japanese wording, there was a brief moment of silence and then the audience burst into applause. I tried the same thing in other countries but never got quite that response (the French smiled and the Italians laughed). I also served as president of the ISICR (2004–2005), and our annual meetings when I was president were held in San Juan and Shanghai, both great locations.As I already indicated, the society meant a lot to my scientific career because several colleagues in the society wrote letters to support my NCI tenure and promotions. As a way to repay my colleagues for their support for my career, I have made an effort to be a very active society member. I initiated the society newsletter 25 years ago (which I still edit today), have served on the Society Governing Council, and have chaired and served on a number of society committees. I am still an ad hoc advisor to the society executive director and have been honored with 3 society awards: the first distinguished service award (corecipient with Dr. Sidney Pestka), the honorary lifetime membership award, and the first society mentoring award.As my career is now starting to approach its final experiments, I know the privilege of being a research scientist would not have been possible without the help, support, and collaboration from many colleagues, both within and outside of the NIH. It has been an honor to have a career at the NCI as it has always been much more than just a job for me. I only hope that my efforts throughout the years made the Fredrick research community and the NIH immunology and cytokine research communities a little bit better.ReferencesEllis RW, Defeo D, Shih TY, et al. The p21 src genes of Harvey and Kirsten sarcoma viruses originate from divergent members of a family of normal vertebrate genes. Nature 1981;292(5823):506–511; doi: 10.1038/292506a0 Crossref, Medline, Google ScholarHodge DL, Berthet C, Coppola V, et al. IFN-gamma AU-rich element removal promotes chronic IFN-gamma expression and autoimmunity in mice. J Autoimmun 2014;53:33–45; doi: 10.1016/j.jaut.2014.02.003 Crossref, Medline, Google ScholarYoung HA, Scolnick EM, Parks WP. Glucocorticoid-receptor interaction and induction of murine mammary tumor virus. J Biol Chem 1975;250(9):3337–3343. Crossref, Medline, Google ScholarYoung HA, Subleski JJ, Krebs SM. Multiprobe ribonuclease protection assay for simultaneous measurement of mRNA expression. Curr Protoc Immunol 2003;Chapter 10:Unit 10.29; doi: 10.1002/0471142735.im1029s54 Crossref, Medline, Google ScholarYoung HA, Whiteley HR. Deoxyribonucleic acid-dependent ribonucleic acid polymerases in the dimorphic fungus Mucor rouxii. J Biol Chem 1975a;250(2):479–487. Crossref, Medline, Google ScholarYoung HA, Whiteley HR. Changes in the levels of DNA-dependent RNA polymerases during the transition of the dimorphic fungus Mucor rouxii from yeast-like to mycelial growth. Exp Cell Res 1975b;91(1):216–222; doi: 10.1016/0014-4827(75)90160-3 Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Volume 42Issue 12Dec 2022 InformationCopyright 2022, Mary Ann Liebert, Inc., publishersTo cite this article:Howard A. Young.A Personal Perspective on My Scientific Career.Journal of Interferon & Cytokine Research.Dec 2022.597-600.http://doi.org/10.1089/jir.2022.29046.editorialPublished in Volume: 42 Issue 12: December 12, 2022PDF download
Search from 250 M+ research papersSearch from 250 M+ research papers
Open Access
Mar 15, 2024
Jie Jiang + 7