Professional Information

Dr. Hatfield received his Ph.D. in the Genetics Foundation at the University of Texas at Austin under Dr. Hugh S. Forrest, and did postdoctoral work on protein purification in Dr. James B. Wyngaarden’s laboratory at Duke University Medical School; on genetic coding and protein synthesis in Dr. Marshall Nirenberg’s laboratory at the National Heart, Lung, and Blood Institute, NIH, Bethesda, MD; and on bacterial genetics in Dr. Jacques Monod’s laboratory at the Institut Pasteur, Paris, France. He then came to the National Cancer Institute (NCI) where he has continued a lifelong interest in genetic coding and protein synthesis.

Dr. Forrest was Dolph’s most important mentor. They have remained lifelong friends. Dr. Forrest was born in Scotland and came to the US after obtaining two PhDs and has remained a full-fledged Scotsman his whole life. A photo of Dr. Forrest and his three children are shown (see photo).

Research at the NCI
Role of Selenium in Cancer and Human Health

The major aims of the section of the Molecular Biology of Selenium Section (MBSS) were to understand 1) the molecular mechanisms by which selenium and selenium-containing proteins (selenoproteins) provide essential roles in development and human health and 2) the means by which selenium is incorporated into protein as selenocysteine (Sec), the 21st amino acid in the genetic code.

Selenium has been shown to have roles in preventing cancer and heart disease, delaying the aging process and the onset of AIDS in HIV positive patients, inhibiting viral expression and supporting mammalian development, male reproduction and immune function.

Dolph’s laboratory devised various mouse model systems to examine the role of selenium and selenoproteins in health and development. Since the knockout of the Sec tRNA gene is embryonic lethal, loxP/Cre technology was used to generate a conditional knockout of this gene in targeted mouse tissues and organs. His lab targeted liver, breast, T cells, macrophages, epidermal and dermal tissues, endothelial cells and cardiac muscle. Selenoprotein expression was specifically altered using these mouse models providing a means of assessing the biological roles of selenium-containing proteins in numerous diseases and in development. These studies in the MBSS demonstrated that the targeted removal of selenoprotein expression in heart muscle resulted in cardiac failure at 10-12 days after birth providing the first evidence at the molecular level that this protein class has a role in preventing heart disease. The MBSS also discovered roles of selenium and selenoproteins in immune function, liver cancer prevention and skin development.

Dolph’s laboratory also generated a mouse line that carried mutant Sec tRNA transgenes which produced Sec tRNA lacking the highly modified base, isopentenyladenosine, in its anticodon loop. The mutant mice manifested reduced translation of numerous selenoproteins in a protein- and tissue-specific manner. This study provided the first example of mice engineered to produce functional tRNA transgenes. The response of these selenoprotein-deficient mice to a variety of stress conditions such as viral infection, specific cancer driver genes, or selenium-deficient diets yielded important insights into the roles of selenoproteins in health, including their ability to serve as anticarcinogenic agents.

Bradley A. Carlson, who worked in Dolph’s laboratory for more than 20 years, prepared most of the above mouse models. Brad published almost 160 scientific articles in Dolph’s lab, a record at the NIH for anyone having Brad’s job description. This record will likely stand forever.

The MBSS in collaboration with Dr. Vadim Gladyshev’s laboratory at Harvard Medical School, determined the entire biosynthetic pathway of Sec in eukaryotes and archaea. Selenocysteine was the last known amino acid in the genetic code in eukaryotes whose biosynthesis had not been resolved. Dolph and Vadim have published more than 120 scientific articles together.

The MBSS also targeted the knockdown of thioredoxin reductase 1 (TR1) in a mouse lung cancer cell line and found that many of the malignant phenotypes were reversed in the resulting TR1 deficient cells to those more characteristic of normal cells. This study provided the best evidence at the time of its publication of a direct role of selenium and a selenoprotein, TR1, in cancer promotion. Furthermore, the MBSS demonstrated that knockdown of TR1 in a number of mouse and human cancer cell lines altered malignant phenotypes and that the resulting TR1 deficient cells have a defect in DNA replication.

Dolph’s CV

Dolph’s Bibliography