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Medical investigator turns genetic research into clinical practice
Medical research is meant to effect change and improvements in real-world practice. Translating findings to the clinical setting is the point of medical research. At the forefront of turning scientific breakthroughs into regular practice is Helen H. Hobbs, MD, this year’s winner of the Endocrine Society’s Gerald D. Aurbach Award for Outstanding Translational Research.
Hobbs, who is an investigator for the Howard Hughes Medical Institute and the director of the McDermott Center for Human Growth and Development at the University of Texas Southwestern in Dallas, has made important discoveries about genetic contributions to cardiometabolic diseases and helped improve treatment of high cholesterol levels. She spoke with Endocrine Today about how she set out on her career path, her breakthroughs, current research endeavors and her affinity for the literary character Isabel Archer.
What was the defining moment that led you to your field?
Hobbs: I was chief resident in internal medicine at the University of Texas Southwestern and had every intention of becoming a practicing endocrinologist. The course of my life was changed completely by Dr. Donald Seldin, chief of internal medicine. He strongly encouraged me to obtain rigorous scientific training in the laboratory of Dr. Michael Brown and [Dr.] Joseph Goldstein. My respect for Dr. Seldin and longstanding interest in science led to me following his advice.
At the age of 30, I entered the Brown and Goldstein laboratory, having never held a pipetman. Brown and Goldstein had just cloned the gene encoding the low-density lipoprotein receptor (LDLR), and my first project was to identify structural mutations in LDLR in their collection of skin fibroblasts from individuals with homozygous familial hypercholesterolemia (FH). I started by examining the alleles that produced no LDLR protein or LDLR mRNA. I noted that almost all these individuals were of French Canadian ancestry and discovered that they all were homozygous for the same deletion in the LDLR gene. In collaboration with Dr. Jean Davignon in Montreal, we found that approximately 60% of French Canadians with heterozygous FH were heterozygous for the deletion. This contrasted with our experience in the United States where we found that practically every unrelated person with FH had a different LDLR mutation. We went on to provide genetic evidence that was consistent with the hypothesis that the high frequency of the LDLR deletion in Quebec province was due to a founder effect. The paper describing these results was published in The New England Journal of Medicine.
I found it intoxicating that the story of the migration of a group of individuals to the New World could be deduced from the pattern of bands on a Southern blot using DNA from a few individuals.
What area of research in endocrinology most interests you right now and why?
Hobbs: I remain interested in the reasons why individuals have different levels of lipids in the blood and other tissues and the impact these differences have on cardiovascular and metabolic diseases.
Early in my career we studied the genetic underpinnings of differences in plasma levels of cholesterol. These studies led to the discovery of loss-of-function mutations in PCSK9 that cause reduced plasma levels of LDL cholesterol and a marked decrease in the risk for coronary atherosclerosis.
More recently our focus has been on plasma and tissue levels of triglyceride, and specifically on the role of two members of the angiopoietin-like (ANGPTL) family of proteins, ANGPTL3 and ANGPTL8, in triglyceride trafficking in response to food intake. We have also discovered genetic variations that contribute to susceptibility and to fatty liver disease as well as other variants that protect from progression of both nonalcoholic and alcoholic fatty liver disease.
The overarching paradigm of our laboratory remains the same. We use genetics to discover alleles of medical importance in humans and then elucidate the functional underpinnings responsible for the observed associations using a variety of scientific approaches, extending from structural studies of proteins to physiological studies in mice.
What is the best career advice you’ve received?
Hobbs: The best career advice I received was from Dr. Donald Seldin; he told me to always train with the best. When he first encouraged me to obtain laboratory training, I proposed a laboratory other than the Brown and Goldstein laboratory since I was not particularly interested in lipid metabolism. Dr. Seldin was emphatic that this would be a grave mistake. Always go for the best.
I also got excellent career advice from Brown and Goldstein. After I went on faculty, they told me to “just say no,” especially to travel. My success would be defined by what I did in the laboratory, not by talks I gave in foreign lands.
What was the last book you read and what did you think of it?
Hobbs: The last book I read was Mrs. Osmond by John Banville, which is a sequel to one of my favorite books, Portrait of a Lady by Henry James. I can never get enough of Isabel Archer, the heroine of Portrait of a Lady, who is one of the most appealing and interesting women in English literature. Despite being a person of great intellect, intuition and courage, she manages to make a total mess out of her life by repeatedly misreading people and situations. Banville’s book successfully captures the spirit and ambiance of James’ masterpiece and my interest in Ms. Archer was sustained until the very last page.
What’s up next for you?
Hobbs: I have no plans to change the complexion of my life in any significant way. I plan to continue to focus on my science while continuing to teach and take care of a small number of adults with genetic diseases. At UT Southwestern, I am lucky to work among a terrific community of excellent, highly interactive scientists. I cannot imagine a better environment to work in. My outside activities will continue to include promoting the development of physician-scientists, contributing to selection of individuals for grants and awards and serving on a board of a pharmaceutical company.