Vanderbilt University

The First Forty Years

Origins in Biochemistry
The history of the Center is the history of people, and the key person in the formation of the Center was the late Dr. Frank R. Blood. Frank Blood had dealt with questions about safety assessment at DuPont, where he worked after obtaining his M.S. The story then moves to the Department of Biological Chemistry at the University of Michigan, where Frank Blood and William F. Darby overlapped as graduate students of Dr. H. P. Lewis in the late 1930s. Bill Darby moved on to Vanderbilt University School of Medicine, in the Department of Biochemistry.  Frank Blood went to the University of Denver, where he taught biochemistry and did research.  In the course of his work there, he encountered an undergraduate chemistry student named Robert A. Neal. Bill Darby became Chairman of Biochemistry at Vanderbilt in 1949 and hired Frank Blood on the Biochemistry faculty.

The 1950s
In the 1950s problems with aflatoxins and other mycotoxins in food began to surface.  Bill Darby and several of the Vanderbilt Biochemistry faculty had longstanding interests in nutrition and food safety issues, which now tied into the formative field of toxicology. Frank Blood had done early studies on the toxicity of irradiated foods in experimental animals (an issue which surfaced again in 1998). Bill Darby became interested in food safety issues at the federal level and served as Chairman of the Food Protection Committee for the National Research Council.  Frank Blood was on one of the subcommittees. Dr. Wayland J. “Jack” Hayes, who would later join Vanderbilt, was on another. Bill Darby also served as chief advisor on food safety for the World Health Organization. Dr. Benjamin J. Wilson was teaching at David Lipscomb College in Nashville and doing research on mycotoxins, and he was also recruited to join the Biochemistry faculty at Vanderbilt. Thus toxicology, particularly related to foods, became a focal point of interest, and the program acquired a national reputation.

The 1960s
In the 1960s, the food toxicology activities of the National Research Council committee had become a major interest of several faculty members in the Department of Biochemistry at Vanderbilt. There was a need for better information on analytical methods and risk assessment.  Bob Neal had gone on to graduate school in Biochemistry at Vanderbilt at the advice of Frank Blood. He received his degree in the area of nutritional biochemistry under the direction of Dr. William Pearson. Following his graduation, he did postdoctoral research on pesticide toxicology with the eminent toxicologist Dr. K. P. DuBois at the University of Chicago. He accepted an offer to return to Vanderbilt on the Biochemistry faculty in 1964.

Frank Blood was the first editor of the series Essays in Toxicology. By this time he had acquired a national reputation in toxicology, and for many years the Society of Toxicology annually recognized the best paper published in its journals with the Frank R. Blood Award. Frank Blood was also surrounded by a group of other faculty with toxicology interests in the Department of Biochemistry. The newly created National Institute of Environmental Health Sciences (NIEHS) awarded a Center grant to Vanderbilt in 1967, with Frank Blood as Director. The Vanderbilt Center (ES000267) was one of the first six centers in this program, along with Harvard University, New York University, the University of Rochester, the University of Cincinnati, and Oregon State University. The original group of investigators in this program (termed the Division of Toxicology in the Department of Biochemistry) included Drs. Frank Blood (Director), Bob Neal, and Ben Wilson. Major issues of focus were pesticides and mycotoxins. In the late 1960s Jack Hayes was hired from the Centers for Disease Control. Others included in the late 1960s were Drs. Arthur Schulert and Harold Sandstead. The Center had begun to develop and began using the name “Center in Environmental Toxicology,” with the acquired funding from the NIEHS.

The 1970s
Frank Blood served as the first Director of the Center from 1967 until his untimely death in early 1971, at which point the direction of the Center became the responsibility of Bob Neal. Following service as Acting Director of the Center, he was named Director in 1973. Dr. Neal had become quite prominent in research and on the national toxicology scene, serving as Chairman of the NIH Toxicology Study Section and on numerous national advisory panels. In the 1970s he built the Center at Vanderbilt into an organization with an enhanced reputation. An NIEHS training grant was acquired in 1975 and has been continuously funded to this day. Other faculty involved in the Center in Environmental Toxicology in the 1970s (not already mentioned) included Drs. Mark Jones, Raymond Harbison, Samuel DiMari, William Vaughn, Myron Holscher, Thomas Burka, William Mitchell, Timothy Macdonald, Martin Houston, and Lamar Field. In the period from 1967 to 1980 the format of the NIEHS Center was such that it was similar to a program project, with funding utilized to support research projects and faculty salaries. During the 1970s, the NIEHS program was expanded to include centers at the University of California, Berkeley (Bruce Ames, Director) and the Massachusetts Institute of Technology (Gerald Wogan, Director). Interests at Vanderbilt developed in metal toxicology, biochemical pharmacology, veterinary pathology, and chemical mechanisms of toxicology. Also, during the 1970s, the composition of the Center was expanded to include faculty in departments other than Biochemistry.

In 1975, Dr. Fred Guengerich accepted a position on the Biochemistry faculty at Vanderbilt and became an Investigator in the Center in Environmental Toxicology. Fred Guengerich had received his Ph.D. from Vanderbilt in 1973 and did postdoctoral research for Dr. Minor J. Coon at the University of Michigan. When he returned to Vanderbilt, he continued his work with cytochrome P450.

The 1980s
In the summer of 1980 Bob Neal accepted an offer to become President of the Chemical Industry Institute of Toxicology (CIIT) in Research Triangle Park, North Carolina. Fred Guengerich agreed to serve as Acting Director of the Center, and following an external search, was offered the position as Director of the Center in Environmental Toxicology. By the time Dr. Guengerich became Director in 1981, the NIEHS had changed the center format from one that was primarily project-oriented to that of a “core” grant, in which center resources are focused in particular areas, or components called cores. The new structure required centers to utilize several different types of cores to accomplish scientific goals: 1) facility cores – analytical service facilities that house instrumentation and provide technological expertise to investigators; 2) research cores – a mechanism for grouping similar research activities; and 3) administrative cores – units with allocations to cover business administration of the center, outreach activities, and awarding of pilot project funds. The transition to the new format was challenging but ultimately successful.
           
When Dr. Guengerich became Director, one of his first moves was to add some senior Vanderbilt faculty to the Center to develop the program. Dr. Lubomir Hnilica was the Stahlman Professor of Cancer Research at Vanderbilt, with a primary appointment in Biochemistry and secondary appointment in Pathology. He had long-standing interests in chromatin and cancer and became an important part of the Center in Environmental Toxicology. He had spent considerable time on various NIH advisory committees and was well acquainted with NIH policy and various funding mechanisms. His accidental death on Easter Sunday 1986 was a complete shock and a great loss. The Center now holds a Lubomir S. Hnilica Lecture each year, at which the graduate students in the Toxicology program select a seminar speaker and host the visit.
           
The other addition to the Center in 1981 was Dr. Thomas M. Harris, of the Department of Chemistry. Dr. Harris provided insight into the chemical side of toxicology, which became a significant strength of the program. In the early 1980s, Dr. John Essigmann, then a junior faculty member at the Massachusetts Institute of Technology, was invited to give a seminar on his new work with site-directed mutagenesis using defined oligonucleotides. Tom Harris was fascinated with all of this and, over the next few years, completely changed the focus of his research to DNA-carcinogen interactions. In 1988 he and his student Steven Baertschi developed a synthesis of aflatoxin B1 epoxide, which completely changed basic aflatoxin research here and everywhere else. Dr. Harris served many years as Deputy (Associate) Director of the Center and has been a valuable part of its development.
           
In 1981 there were some glaring deficiencies in the program, including a lack of strength in cellular and molecular biology (which were relatively new areas at the time). The Department of Biochemistry recruited two new assistant professors to help build this area in toxicology, Drs. Michael Meredith and Stephen Lloyd. Steve Lloyd was highly instrumental in setting up core laboratories and teaching other faculty how to apply the new methods, and his research on DNA repair developed rapidly. He remained with the Center from 1983-1992, when he was recruited by Dr. Samuel Wilson to the University of Texas/Galveston. During the late 1980s, Dr. Robert Briggs was also a Center Investigator and supervised the Cell Biology Facility Core.
           
In the early 1980s Vanderbilt was generally deficient in instrumentation and service facilities, which posed a significant problem for investigators in the Center (and in other programs on campus). Strong science is driven by more than clever hypotheses, and an institution must possess the means to carry out relevant experiments. Thus, a priority of the Center became the acquisition and application of analytical and other facilities. The Center helped acquire the first super-conducting NMR spectrometer on campus in 1984, a 400 MHz Brüker machine that is still in operation (now with a new console). Over the years the Center helped considerably in developing the NMR program at Vanderbilt, which includes 200, 300, 400, 500, 600, and 800 MHz instruments. These instruments have been valuable in many aspects of research and particularly in elucidating structures of DNA-carcinogen complexes. Dr. Michael Stone and, later, Markus Voehler, have been very important in developing this program.
           
Another critical need in 1981 was mass spectrometry. At that time each department or center with a need for mass spectrometry at Vanderbilt had its own instrument, a simple gas chromatograph/mass spectrometer. All of these instruments did the same things, but a revolution in methodology began to occur with the new softer ionization methods. The only way to develop an effective mass spectrometry operation at Vanderbilt seemed to be to pool resources and have a system with specialized instruments for different purposes. Dr. Ian Blair was recruited from London in 1983 to direct this effort and was one of the Center Investigators until 1997, when he left to direct the Clinical Cancer Pharmacology program at the University of Pennsylvania. Ian Blair improved the program over the years, particularly in the area of drug and eicosanoid analysis. He also developed his own research interests in DNA adduct research.  The mass spectrometry program is now under the direction of Dr. Richard Caprioli, who joined the Center and the Department of Biochemistry in 1998. Richard Caprioli has considerable experience in mass spectrometry of peptides and proteins and has introduced a new dimension to the program at Vanderbilt. In addition, Dr. David Hachey has done an excellent job in training and working with individual investigators and their trainees on complex mass spectrometry problems. More recently, Dr. Daniel C. Liebler returned (he had been a graduate student at Vanderbilt) as a Center Investigator and Director of the proteomics component of the mass spectrometry program.
           
One of the philosophies in this Center involves the importance of interacting with other centers and departments on campus. Several Center Investigators have developed in ways that have led to significant responsibilities in other programs. For instance, Prof. Raymond F. Burk came to Vanderbilt in 1987 as Chief of the Gastroenterology Division and an Investigator in the Center in Molecular Toxicology. His research interests are in the area of oxidative stress, and he became Director of the Clinical Nutrition Research Unit (an NIH-sponsored center) from 1995-2004. Dr. Lawrence J. Marnett joined the Center in 1989, filling the Stahlman Chair in Cancer Research that Lubosh Hnilica held previously. Dr. Marnett’s research in eicosanoids, oxidative damage, and DNA adducts has been an important part of the Center. Dr. Marnett was also instrumental in developing the NIH-sponsored Cancer Center in 1994, in which he served as Director of Research. In 2001, he was involved in the creation of the Vanderbilt Institute of Chemical Biology and currently serves as Director for that program.

Coordination of activities with the Cancer Center, the Diabetes Center, and other centers and programs at Vanderbilt has enabled the investigators to avoid overlap and share resources towards achieving common goals. With the acquisition of new faculty and increasingly advanced facilities, the Vanderbilt Center developed significantly during this period. In the mid-1980s as the program continued to evolve, the name was changed to the Center in Molecular Toxicology to better reflect the scientific focus.

The 1990s
In the 1990s the NIEHS Core Centers program continued to expand with the addition of new centers across the country. Over the course of the next few years, the total number of core centers increased to 26 (including four smaller centers focused on marine toxicology). During this period the Vanderbilt Center in Molecular Toxicology continued to develop and expand, as well. A number of prominent scientists were recruited to Vanderbilt over the next several years. In 1992 Dr. Mike Waterman was recruited from University of Texas/Dallas as Chair of the Department of Biochemistry. Dr. Richard N. Armstrong was recruited from the University of Maryland in 1995. Dr. Armstrong had developed a reputation as an outstanding enzymologist with interests in the conjugating enzymes generally involved in detoxication. His research has been seminal in the areas of glutathione transferase and epoxide hydrolase structure and function, and his arrival spurred a renewed interest in applications of kinetics. Dr. Jennifer A. Pietenpol had been a graduate student in Cell Biology at Vanderbilt with Dr. Harold Moses and later did postdoctoral training with Dr. Bert Vogelstein at Johns Hopkins University. She is interested in the tumor suppressor protein p53 and its role in DNA damage recognition and cell cycle regulation. In late 1997 Dr. Ned A. Porter accepted an offer to join Vanderbilt as a Stevenson Professor of Chemistry and became Chair of that department in 2002. Ned had done important studies on the chemistry of lipid peroxidation at Duke University and was Larry Marnett’s thesis advisor there.

2000-present
The Center in Molecular Toxicology continued to expand, with the addition of new Center Investigators, further development of analytical facilities, and modifications to the Center’s administrative structure. In 2002 Drs. Ray Burk in the Department of Medicine (Division of Gastroenterology) and Carmelo Rizzo from the Department of Chemistry were appointed as Co-Deputy Directors of the Center to replace Dr. Thomas Harris, who has since retired. The rationale behind these appointments was largely based on the different research strengths of each: Dr. Burk provides a link to more biological and clinical areas with his interests in nutrition and oxidative damage, while Dr. Rizzo represents a chemical and physical research emphasis with his focus on DNA damage and mutagenesis. Their involvement has created a balanced and well-integrated administrative structure from the top down.
           
In 2003 Dr. Dan Liebler was recruited to the Vanderbilt Department of Biochemistry from the University of Arizona where he had been Director of the Southwest Environmental Health Sciences Center. He became an Investigator in the Vanderbilt Center and directed the development of the (then) new Proteomics Facility Core. During this period the Center also experienced significant expansion in the area of structural biology with the increasingly sensitive technologies of NMR spectroscopy and X-ray crystallography. A number of investigators with extensive expertise both in structural biology and DNA damage have joined the Center in recent years, including Dr. Mike Stone from the Department of Chemistry (the Director of the Center’s Structural Biology Facility Core), Dr. Walter Chazin from the Department of Biochemistry (and Director of the university-wide, shared structural biology facility), Dr. Martin Egli in the Department of Biochemistry, and Dr. Brandt Eichman in the Department of Biological Sciences.
           
Other Center Investigators added during this period were Dr. David Cortez, recruited to the Department of Biochemistry, and Dr. Bill Valentine in the Department of Pathology. Dr. Cortez’s research efforts focus on signaling pathways involved in cellular response to genotoxic stress. Dr. Valentine’s work is in the area of neurotoxicology, particularly the cellular processes responsible for axonal degeneration. Another important addition to the Center in the area of neurotoxicology came about in 2004 when Dr. Michael Aschner was recruited to the Vanderbilt Department of Pediatrics from Wake Forest University. Dr. Aschner has been a key player in a number of different Center initiatives, including his roles as 1) Co-PI on the Advanced Research Cooperation in Environmental Health (ARCH) with Meharry Medical College, 2) PI on the proposed Superfund Basic Research Program with Oak Ridge National Laboratory, and 3) PI on the Manganese Health Research Program funded by the Department of Defense.

The Center in Molecular Toxicology has maintained a successful and vital program over the years, largely due to the ability of Center leadership to anticipate and adapt to changes in direction at the NIEHS. In 2005, the previous Director of the NIEHS, Dr. Ken Olden, was succeeded by Dr. David Schwartz, who implemented a number of significant modifications to the Core Centers program. As a result of this shift in focus, the Center in Molecular Toxicology has evolved to focus efforts accordingly. Effective in 2006, the Center was no longer organized in terms of specific research cores (historically required components within any core center). The five areas of focus continue as major strengths of this Center (oxidative damage, DNA damage and genetic instability, enzymatic biotransformation and reactions of electrophiles, neurotoxicity, and maintenance of genomic integrity), but a less restricted organizational structure is allowing investigators to move into a number of new directions, including biomarker development and clinical research.
           
Clinical and translational investigations have become a critical element in the Core Centers program. Beginning in 2005, the Center began to take an increasingly integrated translational approach to the science of environmental health, incorporating both basic and clinical research activities into the scope of the Center’s mission. As a result several clinical faculty have been added as Center Investigators since 2005:

  • Dr. Jason Morrow, Director of Clinical Pharmacology at Vanderbilt: Dr. Morrow has made some significant breakthroughs in the area of oxidative damage, particularly in biomarker development, utilizing isoprostanes as indicators of oxidative injury.
  • Dr. Nancy J. Brown, Professor of Pharmacology and Associate Dean for Clinical and Translational Scientist Development: Dr. Brown’s work focuses on the role of oxidative stress in human vascular disease.
  • Dr. Tina Hartert, Associate Professor of Medicine in Pulmonary and Critical Care, Director of the Clinical Epidemiology and Outcomes Research Program in the Center for Health Services Research, and Director of the Medical Scholars Program: Dr. Hartert’s research is aimed at identifying modifiable environmental factors (including oxidative stress) as well as genetic factors that predispose individuals to atopic diseases, such as asthma.
  • Dr. Alp Ikizler: Associate Professor of Nephrology, Director of the Master of Science in Clinical Investigation. Dr. Ikizler studies the role of oxidative stress and inflammation in the progressive loss of kidney function, endothelial dysfunction, and accelerated development of cardiovascular disease.
  • Dr. Judy Aschner, Professor and Chief of Neonatology: Dr. Aschner’s work focuses on manganese neurotoxicity both in adults and in infants.

Another clinical effort in the Center in Molecular Toxicology has been the creation of a new facility core, Integrative Health Sciences. This core (a new requirement of all NIEHS Core Centers) was established in 2006 in collaboration with the Vanderbilt General Clinical Research Center (GCRC) in consultation with the GCRC Director, Dr. David Robertson, and current Center Investigators, Drs. Burk and Morrow. It should be noted that the GCRC was recently incorporated into the newly funded Clinical and Translational Science Award (CTSA), and Dr. Robertson now directs the Participant and Clinical Interactions Resources (PCIR) unit of the CTSA. The Integrative Health Sciences Facility Core is directed by Dr. Ginger Milne with input from Dr. Morrow. This facility has fostered an emphasis on the development and application of biomarkers for use in clinical problems related to several diseases with environmental etiology, particularly oxidative stress and neuroscience.

As technology continues to evolve, many tools commonly used in research may become obsolete over time and must be either modified or abandoned altogether to make use of superior methods. Over the Center’s history, facility cores are created to fill particular scientific niches, and some continue to thrive and develop, while others must be discontinued due to decreased usage or shifts in scientific focus. For example, in the past several years three facility cores have been phased out, including facility cores in Protein Chemistry, Molecular Recognition, and (most recently) Cell Culture. The Center’s Community Outreach and Education Core was also discontinued in 2006 in response to changing guidelines at the NIEHS. The Center in Molecular Toxicology currently has four facility cores, Mass Spectrometry, Proteomics, Structural Biology, and Integrative Health Sciences.

In 2006 the Center in Molecular Toxicology expanded into a more comprehensive organization that administers several units under a common “umbrella,” as part of the 5-year strategic plan distributed in 2006 by Vanderbilt’s Associate Vice-Chancellor for Research. Historically, the Center consisted of two major programs: the P30 EHS Core Center grant (NIH P30 ES000267) and the affiliated Training Program in Environmental Toxicology (NIH T32 ES007028). Today the P30 EHS Core Center and training programs continue to provide much of the research and training infrastructure for the Center in Molecular Toxicology, but several other programs and initiatives are now included under the Center’s administrative umbrella:

  • Advanced Research Cooperation in Environmental Health (ARCH) with Meharry Medical College (S11 ES014156)
  • Manganese Health Research Program funded by the Department of Defense
  • Patient-Oriented Career Development Program (NIH K12 ES015855) that provides support for environmental health science scholars
  • A pending NIEHS T35 short-term summer research and training program for medical students
  • A proposed NIEHS Superfund Basic Research Program with Oak Ridge National Laboratory focusing on mechanisms of susceptibility to mercury toxicity
  • A proposed institutionally-sponsored program in mechanisms of drug-induced cellular toxicity

In April 2007, the P30 EHS Core Center celebrated its 40th year of continuous funding from the NIEHS with an anniversary symposium featuring “Advances in Mass Spectrometry: Basic and Clinical Research and Applications in Environmental Health Sciences.” While this is certainly an impressive milestone, researchers in the Center never lose sight of the primary mission: to improve human health through a better scientific understanding of chemical and physical agents in the environment. Although the Center continues to support excellent scientific programs, new research challenges will continue to emerge. By adapting to new developments the Center continues to maintain an intellectual atmosphere that encourages scientific excellence from all affiliated faculty and trainees.