Interview with Curtis D. Klaassen, PhD
Curtis D. Klaassen, PhD, was the recipient of the 2017 Career Achievement Award in Toxicology from ASPET. His career spanned 45 years at the University of Kansas, where he served as chair and University Distinguished Professor of the Department of Pharmacology, Toxicology and Therapeutics in the School of Medicine. During his faculty tenure, Dr. Klaassen mentored over 120 graduate and postdoctoral students. He also serves as the director of the Mid-America Toxicology Course that has helped over 3000 scientists prepare for certification in toxicology.
Dr. Klaassen’s research has focused on how chemicals reprogram the liver to deviate the path of toxicity. This research interest originated from his doctoral dissertation studies 50 years ago when Dr. Klaassen noted that chemicals known to increase the cytochrome-P450 enzymes in the liver can also increase the biliary excretion of some drugs and chemicals. Over the past five decades, he and his trainees have demonstrated that this phenomenon was due to the ability of these chemicals to activate transcription factors and the subsequent synthesis of transporter proteins that move chemicals into and/or out of liver cells. Dr. Klaassen refers to this phenomenon as “reprogramming the liver”. Similar to a computer programmer that programs a computer through software, the chemical reprograms the liver to increase the synthesis of transporter proteins to eliminate the toxic chemical. They showed that the heavy metal cadmium can reprogram the liver to decrease its toxicity by enhancing transcription of metallothionein protein, which bound cadmium and decreased its distribution to cadmium-sensitive proteins in the liver. During the past few years, he and his students have demonstrated that plant derived natural products can activate the NRF2 transcription factor to induce transporter proteins, in addition to the synthesis of phase-II metabolism enzymes for chemical conjugation and detoxification.
His successful career in toxicology education and research has earned him a reputation as an internationally renowned superstar toxicologist. The Division for Toxicology was grateful for his enthusiasm to share his experience with us for this article, and to two of his previous students, Drs. Nathan Cherrington and Lauren Aleksunes, for providing the perspective of their training with Dr. Klaassen.
Q: What sparked your interest in toxicology?
A: As an undergraduate student, I majored in biology and minored in chemistry at Wartburg College in Waverly, Iowa. Most students with this educational background and at that time in history went to medical, dental, or veterinary school. None of those occupations enticed me, so I decided to go to graduate school in a discipline that blended biology and chemistry. I asked my undergraduate mentor whether biochemistry might be such a discipline, and he informed me that biochemistry was much more chemistry than biology, but my interests were vice-versa. Fortunately, my older brother at the time was going to pharmacy school, and when I told him my desires, he said, “what you are looking for is pharmacology.” I quickly researched the discipline, applied and became a graduate student at the University of Iowa. This proved to be an excellent graduate program as many of my colleagues became successful toxicologists and some even became president of the Society of Toxicology (SOT): Bob Dixon, Gabriel Plaa, Jim Gibson, Jerry Hook, Mike McClain and myself. When I first arrived in Iowa City, I was given one week to select a mentor, who was Gabriel Plaa, an internationally-known toxicologist. Thus, I became a toxicologist because of luck, rather than a long-term, intellectual plan.
Q: How has toxicology research changed over the course of your career?
A: Toxicology has changed tremendously over the last 50 years. This is largely due to the advances in all areas of the biomedical sciences as well as the techniques that have developed over this time interval. When I started graduate school in 1964, our laboratory had only two pieces of equipment: a colorimeter and a centrifuge for separating blood cells and plasma. There was also a high-speed centrifuge, i.e., ultracentrifuge that was shared equipment for the department, and a spectrometer, but available for students only on weekends. Many instruments and techniques that are in common use today were unknown back then such as: HPLC, mass spectrometry, immunoassays, cloning, mRNA assays, polymerase chain reaction, DNA sequencing, transgenic mice, knock-out mice, metabolomics, proteomics, epigenetics, etc.
Q: In your opinion, what are the greatest impacts of your research program on how toxicology is conducted today?
A: My accomplishments have been in research, education and service for the toxicology community. In the studies on “how to program the liver”, we realized that liver functions were not static and could be altered by chemicals, which helped us to understand molecular mechanisms that are important in toxicology, such as transporters that regulate the concentration of chemicals in cells, binding proteins that protect more sensitive macromolecules in cells, phase-II enzymes to detoxify chemicals, and anti-oxidative enzymes to decrease oxidative stress, mechanisms by which chemicals can be made less toxic. Our research has been supported by an average of three NIH-R01 grants each year. My students accepted the philosophy of “publish and prosper”, and our publications have been numerous and have made an impact in the toxicology field. Together, we have published more than 600 peer-reviewed manuscripts, which averages one per month over my academic career, and more than 90 review articles and chapters in books.
In regard to education, I have had the pleasure to mentor over 120 PhD and postdoctoral fellows, of which five (Mike Waalkes, David Eaton, Lois Lehman-McKeeman, Nathan Cherrington and Lauren Aleksunes) have received the Achievement Award from the Society of Toxicology, and three (David Eaton, Lois Lehman-McKeeman and Peter Goering) have served as president of the Society of Toxicology. As chair of the department and due to obtaining a mentoring grant from the National Institutes of Health (NIH), I had the fantastic opportunity to hire and mentor over a dozen young scientists to enable them to obtain their first NIH grants and become independent investigators. I have been editor since 1980 of the leading toxicology textbook, Casarett and Doull’s Toxicology: The Basic Science of Poisons, and was author of the toxicology section of Goodman and Gilman’s Pharmacological Basis of Therapeutics from 1980 to 2005. I have presented over 450 lectures around the world. Many toxicologists may recognize my contribution as the organizer of the Mid-America Toxicology Course, which was designed to help scientists prepare for the certification exam in toxicology.
I have served the toxicology community by being the inaugural Editor-in-Chief of Toxicological Sciences. I was associate editor of the Journal of Pharmacology and Experimental Therapeutics for 24 years, and Toxicology and Applied Pharmacology for 10 years. I have served on over 100 national and international committees, and was elected by my peers to lead many national and international offices, including president of the Society of Toxicology in 1990-91, as well as president of the International Union of Toxicology from 1992-95. As a result of my accomplishments in research, teaching, and service, I have been the recipient of over 40 national and international awards.
Q: What do you think is the most significant challenge facing toxicologists today?
A: The future of toxicology in academia will have many of the same problems that it has always had, but they appear to be becoming more severe. One problem academic toxicology has always had in the US is that there are very few or no toxicology departments in universities. Most toxicologists are located in departments of pharmacology or pathology in medical schools, pharmacology in pharmacy schools, or occupational health in schools of public health. With the lack of departments of toxicology, there are very few toxicologists who can become chairs of these various other departments, and thus opportunities for toxicologists to be hired in academic institutes are sparse. Secondly, the availability of money has always been a rate-limiting step in research. While the NIH has been generous in supporting research (about $100 per US citizen), the cost of doing research has increased exponentially due to the equipment necessary to do state-of-the-art research, the cost of reagents and supplies, animal care costs and personnel costs. My first NIH grant was for $19,900 a year in the early 70’s with minimal overhead costs, while grants today are about $250,000 a year and $125,000 overhead. In the era in which I started in academia, many universities paid most if not all the salary of the faculty. However, today most faculty are expected to pay for a third to a half of their salary from grant(s). Graduate students received a stipend of $200 a month when I was a student from 1964 to 1968, but now it is more than $2,000 a month. In addition, tuition has increased from $500 to $25,000 a year over this time interval. Part of the increase in costs over the years for a university is the implementation of many federal regulations, and they are costly in money and time for the scientist. These regulations have decreased scientific productivity.
Q: What has been your perspective on/approach to mentoring the next generation of toxicologists? As one of the most recognized toxicologists in the world, what advice would you give to young scientists who seek to become recognized leaders in the toxicology field?
A: I don’t think that the education of the next generation of toxicologists is that different than it was 50 years ago. First of all, we need to recruit students who are intelligent, have an appropriate educational background, desire to learn and work hard, and have good judgement and high ethical standards. Toxicology is an extremely broad discipline and thus one should have knowledge in biochemistry, physiology, pharmacology, histology, pathology, statistics, computer science, and of course toxicology. These courses (except computer science) were taken by me and my colleagues 50 years ago, and advances have been made in all these disciplines, including much more molecular biology in biochemistry and the addition of computer science. When I went to graduate school, there was one computer at the University of Iowa, and only because of the excellent Space Physics Department, while today we all have a computer in our pocket (smart phone), in addition to the one on our desk; computer skills are indispensable today. I did not take neuroscience or immunology courses, but wish I had when I was a student. While additional coursework is desirable for the education of toxicologists, unfortunately there is a trend in graduate education to decrease coursework.
The mentor needs to make sure the student has taken the appropriate coursework, but most importantly the mentor has the responsibility of introducing the student to working in the laboratory, guiding him/her to completion of their dissertation, and obtaining an appropriate post-doctoral position. The student needs to be treated as one’s child rather than as an employee. I usually assigned a rather small project as the first set of experiments for an incoming student to perform in the laboratory. The purpose of the project was to make sure the student learned the culture of the laboratory, such as the location of various supplies, how to handle animals, use pipettes, use various instruments, collect data, read the appropriate literature, do appropriate statistical tests on their data set, draw graphs and write the manuscript. It was when this was completed that we discussed what project they would like to do for their dissertation. I gave my students a considerable amount of freedom in selecting what hypothesis they would like to test for the first project of their thesis, and when the first project was nearing completion, the student would suggest what hypothesis they thought should be their second project, which we discussed in detail. We usually repeated this process until they completed four manuscripts, and this became the heart of their dissertation. The one-on-one meetings with the students as well as the weekly laboratory meetings are very important in not only covering topics from the laboratory and current research articles, but also the historical and ethical aspects of toxicology. A yearly one-hour seminar given to the departmental faculty was an excellent mechanism for the students to organize their thoughts and data, as well as obtain experience in presenting to a large group and answer questions while on their feet. The training of toxicologists should also provide opportunities for students to present their research at national meetings, in which they will not only learn to organize their data and present it to the scientific community, but also meet and talk to other scientists in their area of research. All of the above points are important to build a solid foundation for a career in toxicology. However, toxicology and the other basic sciences continue to advance, and thus to be a success, one has the pleasure to continue learning for the rest of one’s career.
Interview with Nathan Cherrington, PhD
Nathan Cherrington, PhD, was a postdoctoral fellow in Dr. Curtis D. Klaassen’s laboratory before landing an assistant professor position in the Department of Pharmacology and Toxicology at the University of Arizona in 2002. He is now a professor of pharmacology and toxicology, director of the Center for Toxicology, director of the Southwest Environmental Health Science Center, and associate dean for research and graduate studies at the University of Arizona College of Pharmacy. He was recipient of the 2011 Achievement Award from the Society of Toxicology.
Q: What year were you in Dr. Klaassen’s laboratory and what was the laboratory like then?
A: I was there from 1999-2002. We had an active lab with approximately 8 graduate students and 8 postdocs and research faculty. I think there were 3 to 4 NIH R01s and a training grant available to support the lab. The cadmium research project was just coming to an end and Dr. Klaassen was making a wholesale shift toward drug transport and disposition. There were weekly lab meetings and numerous individual and small group meetings for updates, strategy and planning, as well as late afternoon sessions that turned into advice and stories. It was a very vibrant, diverse, and stimulating environment.
Q: Why did you choose to receive training in Dr. Klaassen’s laboratory instead of other laboratories?
A: I’d like to say that I was the one who made that choice since it was perhaps the most meaningful decision of my career. However, I think the credit should go to Dr. Klaassen himself for identifying me and rescuing a wayward research career.
Q: What did you learn the most from Dr. Klaassen?
A: There are only 168 hours in a week. While we can disagree about how many hours someone should spend in each of the important categories of life (sleep, personal hygiene, family, church, etc.), your decisions regarding time management largely determine the degree of success you want to achieve. Hard work beats talent, when talent doesn’t work hard.
Q: What kind of research you are doing now? How is what you learned in Dr. Klaassen’s laboratory related to what you do today?
A: My research is similar to the principles that I learned in Dr. Klaassen’s lab. I can’t say things like “30 years ago we observed that… Now we’ve determined the molecular mechanism…” But then again, not very many people have been so successful for so many years to see the technology and capacity of research change so much.
Q: Anything else you’d like to share about Dr. Klaassen?
A: Curt is guided by an intense sense of right and wrong. At the core of his work ethic, his training of students and postdocs, and his contributions to our society is a commitment to doing what is right. Students do not benefit from low expectations, so he requires extra effort. And no matter how much effort you put in, he will not be outworked, and he will make sure that you are rewarded for your effort. There is nothing that hard work and good minds can’t accomplish.
Interview with Lauren Aleksunes, PharmD, PhD, DABT
Lauren Aleksunes, PhD, is an associate professor at Rutgers University Ernest Mario School of Pharmacy. Dr. Aleksunes joined Rutgers in 2009 after completing a 2-year fellowship with Dr. Klaassen. She is now the director of the Joint Graduate Program in Toxicology at Rutgers University. In 2016, she was recognized with the Achievement award from the Society of Toxicology. She is a past secretary-treasurer of the Division for Toxicology at ASPET.
Q: What year were you in Dr. Klaassen’s laboratory and what was the laboratory like then?
A: I was in Dr. Klaassen’s lab from 2007-2009. The lab and department had just moved into a state-of-the-art facility in Kansas City that provided us with access to outstanding technology and expertise. The lab was large, predominantly postdocs with a few graduate students. This made for a dynamic learning experience since we all had different backgrounds and were able to learn from each other as well as from Dr. Klaassen.
Q: Why did you choose to receive training in Dr. Klaassen’s laboratory instead of other laboratories?
A: I had the opportunity to visit Dr. Klaassen’s lab on a few occasions as part of a collaboration with my predoctoral mentor. Each time I visited Kansas City, I was excited by the diverse projects, amazing scientists and excellent environment that I encountered. Dr. Klaassen always made time to meet with me and discuss my project. Dr. Klaassen had an outstanding track record of trainees and scientific accomplishments that made me want to join his research team.
Q: What did you learn the most from Dr. Klaassen?
A: Science is fun! Dr. Klaassen would always exclaim ‘Wow! Isn’t this exciting?’ when lab members discussed their research findings. This enthusiasm was infectious and helped you get past the failed experiments. I also learned from Dr. Klaassen to always publish your very best work in your Society’s journals such as ASPET and SOT. This helps elevate our field.
Q: What research you are doing now? How is what you learned in Dr. Klaassen’s laboratory related to what you do today?
A: I still work in transporters largely because of a 96-page review article that Dr. Klaassen and I published in Pharmacological Reviews in 2010. As we navigated the field at that time, I was able to identify many areas that required further investigation. As a junior academician, this served as a roadmap for me to develop my research laboratory.
Q: Anything else you’d like to share about Dr. Klaassen?
A: Klaassen alums remain part of the Klaassen family even after leaving Kansas. Dr. Klaassen continues to send us interesting news items, an annual holiday letter, and hosts get together events at national meetings. Despite entering different fields of toxicology, Klaassen alums often continue to work together on research and professional activities, further strengthening this family bond.