Environmental Factor, August 2007, National Institute of Environmental Health Sciences
Endocrinologist Lectures as Second Scientific Director Candidate
By Eddy Ball
NIEHS continued its search for a Scientific Director on July 24 in Rodbell Auditorium with a lecture and question-and-answer session featuring Evan Simpson, Ph.D. Simpson, whose talk was titled "Sex, Fat and Cancer," is a professor of Biochemistry at Monash University, lab director of the Victorian Breast Cancer Consortium and head, Sex Hormone Biology, Prince Henry's Institute.
The candidate's research interests include breast cancer, locally produced estrogen metabolism, osteoporosis and gene expression of aromatase, the enzyme that converts testosterone to the most potent estrogen, estradiol (E2). His group is working to develop a breast tissue-specific aromatase inhibitor for use as a first-line alternative to current therapies and as an adjuvant and neoadjuvant therapy for estrogen-dependent tumors.
Simpson is also interested in the roles of phytoestrogens and potential endocrine disrupting compounds in the pathogenesis of breast cancer, the effects of sex steroids on cognition, personality and energy homeostasis, and the relationship between obesity and breast cancer risk.
According to Simpson, estrogen-dependent tumors occur in about 75% of postmenopausal breast cancer cases. "What we believe is happening [in these cancers] is that the adipose tissue [in breast] actually picks up the function of producing estrogen after menopause, when the ovaries cease to do so," he explained - with aromatase playing an essential role in localized production of the hormone.
In the 1980s, Simpson performed cDNA cloning of aromatase and, a decade afterward, developed the aromatase knock-out (ArKO) mouse. He and his lab characterized the ArKO phenotype in order to study the physical effects of inhibiting the enzyme. In addition to inhibiting aromatase, the scientists found that this phenotype resulted in spermatogenic arrest and failure of ovarian follicular development, as well as increased adiposity, reduced energy expenditure and sluggishness, obsessive compulsive behavior and insulin resistance.
Because of the side effects of this global inhibition of the enzyme, Simpson early on concluded that "it would clearly be of benefit to specifically inhibit the pathway of aromatase expression within the breast." His attention then turned to determining the best candidate among tissue-specific aromatase promoters to target.
Simpson ultimately identified breast tumor-derived factors such as prostaglandin E-2 (PGE2) as strong stimulants of aromatase expression via an alternative promoter, promoter II. He targeted the orphan nuclear receptor known as liver receptor homolog-1 (LRH-1) and its co-regulators as key players in modulating aromatase expression in breast adipose tissue. His group concluded that mutation of the nuclear receptor site could completely abrogate the action of LRH-1 in activating promoter II expression at the transcriptional level and inhibit the subsequent expression of aromatase in the breast.
In his search for LHR-1-specific inhibitors, Simpson and his colleagues are conducting computerized screening of the crystal structure of LHR-1 against potentially useful drug-like molecules to determine which ones show potential for selective binding at promoter sites. As promising as his discoveries are thus far, the candidate cautioned his audience that "this is very much a work in progress." Several promising compounds, he noted, have failed to demonstrate the degree of specificity required.
Simpson was the second of three candidates invited to lecture and interview with interest groups at NIEHS during the final phase of the selection process for this key position. Like the other two candidates, his talk was hosted by NIEHS Deputy Director Sam Wilson, M.D. As expected, Simpson attracted a variety of individuals from throughout the Institute interested both in his research and in whatever they could learn of the candidate's management style and philosophy.
Getting a Measure of the Candidate
When asked by David A. Schwartz , M.D., about his interest in becoming the new Scientific Director, Simpson cited personal and professionals reasons for wanting to join NIEHS and return to the United States. Although born and educated in Scotland, the candidate is an American citizen who has spent most of his professional life in this country and has family who live in North Carolina.
After eight years as director of Prince Henry's Institute, Simpson said, "I feel like I've done my bit... and I'm looking for something new to do, something challenging and satisfying." Simpson pointed to "so much exciting work going on here... much of it right up my alley."
Simpson emphasized the importance of obesity and related environmental health issues as he outlined the way he envisions the Institute's research mission developing in the future. "This is a global pandemic," he said, "and it may not be an issue simply of caloric intake." Like obesity, other environmental issues will also need to be addressed globally, and NIEHS is uniquely positioned to "spread the gospel of environmentalism" to emerging countries, such as China and India.
Asked to clarify his desire to leave the administrative demands of his current position only to face what appear to be similar demands in the role of Scientific Director, the candidate made a distinction between scientific administration, on the one hand, and the bureaucratic administration of dealing with state and federal regulators in Australia. "In terms of the administration of science, I really enjoy that," he said, "but [in my current position] I find myself doing more and more that isn't really related to science."
Toward the end of the question-and-answer session, Simpson underscored his commitment to the importance of basic research in the Institute's mission. "Integrated research and basic research should go hand in hand and feed back on each other," he explained.
The candidate described his management style as "horizontal" in response to a question from Senior Investigator Darryl Zeldin, M.D. "I believe in reaching decisions by consensus," Simpson said. "Decisions should be made by consultation, not by fiat."