Environmental Factor, August 2007, National Institute of Environmental Health Sciences
Blackshear Lecture Kicks Off Scientific Director Selection
By Lillian Gu and Eddy Ball
The Scientific Director Candidate Seminar Series commenced on July 2 in Rodbell Auditorium with a talk by Perry Blackshear, M.D., D.Phil., titled "The TTP Family of Tandem Zinc Finger Proteins and their Roles in mRNA Turnover." Blackshear, the first candidate under consideration, reviewed his lab's recent research on a group of proteins in the Tristetrapolin (TTP) family and potential novel clinical applications of the lab's findings.
The lecture series marks the beginning of the selection process for the next NIEHS scientific director. Blackshear is currently the acting scientific director, as well as the director of the Clinical Research Program and a principal investigator in the Laboratory of Signal Transduction Polypeptide Hormone Action Group(http://dir.niehs.nih.gov/dirln/home.htm). His lecture was hosted by NIEHS Deputy Director Sam Wilson, M.D.
Blackshear began with a brief overview of his lab's research on the tandem zinc finger protein TTP and TTP-like proteins over the past ten years. Much of the current understanding has resulted from his lab's development of TTP knockout (KO) mice, which were typically normal at birth, but rapidly developed severe arthritis, extreme emaciation and myeloid hyperplasia, a proliferation of blood cells in the bone marrow.
Experiments involving interbreeding and the injection of animals with Tumor Necrosis Factor-α (TNF-α) antibodies helped the researchers pinpoint the mechanisms linking TTP and symptoms in the KO mice. Blackshear and his colleagues postulated that the syndrome was due to an excess of TNF-α, a signaling compound that is implicated in autoimmune disorders such as rheumatoid arthritis and known to induce emaciation.
Following this line of thought, Blackshear's lab then experimented with stimulating KO mice macrophages, a main TNF production site, with lipopolysaccharide (LPS), a compound derived from bacterial cell walls. The result was production of more TNF-α protein as well as TNF-α messenger RNA (mRNA) than in wild type (WT) counterparts - reinforcing the hypothesis that TTP plays a role in either the transcription of TNF from DNA to mRNA or the stability of the mRNA.
In order to study the role of TTP in TNF expression, Blackshear exposed LPS-stimulated macrophages to the transcriptional inhibitor Actinomycin-D and tracked message decay. He found that the KO macrophages had a lower TNF-mRNA turnover rate than the WT macrophages, suggesting that the lack of TTP increased the stability of the message, increasing TNF production and producing the TTP-deficiency syndrome.
The investigator and colleagues suspected that TTP binds to the TNF-α transcript in an AU-rich region long known to be involved in mRNA destabilization. This AU-rich element (ARE) is highly conserved among mammals, and the lab found that single base mutations here are enough to block TTP and ARE binding.
According to Blackshear, greater understanding of the TTP pathway may lead to development of novel anti-inflammatory therapies with fewer side effects. Currently, the drugs that directly inhibit TNF are effective in only a handful of inflammatory and autoimmune diseases. In addition, these protein drugs are expensive and require injections. They also can result in the development of anti-drug antibodies.
By sequencing the TTP gene from a large number of subjects, Blackshear has associated variations in certain gene regions with rheumatoid arthritis and myositis. However, he points out that "while all of these [associations] are highly statistically significant, they need to be validated by secondary studies as well as by peer reviews."
Recent efforts in Blackshear's lab have involved finding new TTP targets with the help of RNA microarray analysis and studying other TTP family proteins such as ZFP36L1, ZFP36L2 and ZFP36L3. In addition, Blackshear has looked towards invertebrate species as an alternative to mammalian testing and found that their related proteins display similar RNA binding.
The series continued on July 24 and August 6 with lectures by the other two candidates for the position, whose talks will be reported in the September 1 issue of the eFactor. Evan Simpson, Ph.D., gave a talk titled "Sex, Fat and Cancer" on July 24 at 9:30 a.m. in Rodbell Auditorium. He is currently a professor of Biochemistry at Monash University, lab director of the Victorian Breast Cancer Consortium and head, Sex Hormone Biology, Prince Henry's Institute of Medical Research in Melbourne, Australia.
On August 6, Rudy Juliano, Ph.D., will give a talk on "Integrin-Mediated Control of Cell Signaling Events" at 9:30 a.m. in Rodbell Auditorium. Juliano is currently the Cary C. Boshamer Distinguished Professor in the Department of Pharmacology at the University of North Carolina at Chapel Hill.
One Candidate's Vision for the Division of Intramural Research (DIR)
During a question-and-answer session following his lecture, Blackshear was asked first about the role of the intramural research program at NIEHS. "I think our role should be that we undertake more high risk, potentially high yield research, that which may not be quite as predictable as what the extramural investigators are forced to do," he responded. "And I wish I could convince our BSC [Board of Scientific Counselors] that they should not rely quite so much on what I heard one reviewer refer to as 'sheer industriousness,' that is, large numbers of papers."
Blackshear also expressed the need for the scientific director to address the significant percentage of tenure-track investigators at NIEHS who have failed to get tenure, which he hopes to influence with increased "mentoring of these individuals at all levels - from their colleagues in their branches, their branch chief, to the scientific director, to everyone in the Institute." He pointed to the emergence of an activist tenure-track assembly as a promising development. "I think... we could also do more to mentor our postdoctoral fellows."
Recalling how important his undergraduate experiences were in his choice of a career, the candidate expressed his interest in finding ways to revitalize graduate and undergraduate programs. "I would like very much to revitalize the trainees' assembly by increasing the numbers of graduate students, medical students and undergraduates here, which have been traditionally low because of the obvious difficulties in connections with neighboring universities."
When asked about promoting clinical research among the rest of DIR, Blackshear expressed his high hopes for the bi-directional stimulus provided by communication between lab scientists and clinical researchers at the new NIEHS Clinical Research Unit. "I think we will have a very unusual opportunity for investigators to walk across the parking lot and extrapolate from their basic science into hands-on clinical research."
The candidate responded to a question about the need for more "informal, ad hoc discussions" between scientists in such venues as the cafeteria, where investigators have an opportunity to talk with people working in different areas. "I'd be open to suggestions as to other things," he concluded, "other than this very distant future of a campus [as envisioned in the Institute's master plan]."
Later that afternoon, Blackshear attended a question-and-answer session with the staff of the National Toxicology Program (NTP). Looking forward to a process of re-alignment with DIR, NTP scientists were naturally curious about how candidates envision the new role of NTP research at the Institute. The session was one of the first of several he would hold with interest groups throughout the Institute.