Contributions to medicine of students of Mario Capecchi, Ph.D. based on evolution.
Physician-scientist students of Capecchi’s have made great strides in the understanding and treatment of human diseases as a result of their studies in his lab on fundamentals–the evolution, the genetic structure, and the cellular disease process. To name one, Anne M. Moon, M.D., Ph.D., manipulated the genetic structures of mice with targeted mutations in the Fgf8 gene. The initial study mice died from heart, glandular, craniofacial, and brain deficits. Dr. Moon, as a clinician, recognized their deficits as resembling those in human patients with 22q11 deletion syndrome. Over the next ten years she discovered that a deficiency in a gene called crkl, which is required for Fgf8 function, contributes to many defects that afflict these patients. Symptoms commonly include heart disease, cleft palate, and immune deficiency. The disease is not rare; it occurs once in every 2,000-4,000 live births. The mouse models created in the Capecchi laboratory have proved useful to the understanding of the biology of this and other human diseases. The work is an integral part of the study of evolution on a cellular/genetic level.
E. Dale Abel, M.D., PhD., associate professor of internal medicine and biochemistry, and chief of the Division of Endocrinology, Metabolism, and Diabetes is investigating heart disease in diabetics. Hearts need a large, continuous supply of energy to function, and that energy is supplied by mitochondria. In diabetics, with cardiac hypertrophy, mitochondria perform poorly. Abel, working with Capecchi’s gene markers in his cellular biology lab, recently discovered that a protein, phosphoinositide-3 Kinase (P13K), is required for mitochondria to synthesize energy efficiently in the heart. Abel and his students are working on ways to activate P13K.
Dean Y. Li, M.D., Ph.D., associate professor of internal medicine and oncological sciences, uses his evolution and cellular biology knowledge to treat human vascular diseases. Li determined how mutations in the elastin gene trigger the inherited disease Supravalvular Aortic Stenosis. The disease causes arteries to narrow, which, if left untreated, can lead to heart failure. Using elastin-deficient mice, Li found that the gene instructs vascular smooth muscles (VSMCs) to maintain the integrity of arterial walls. In the absence of elastin, VSMCs divide and migrate, blocking the arterial lumen. Li said, “Human genetics told us that the gene was important for vascular development, but the mouse told us why. Knowing that allowed us to make a medical device.”
H. Steve White, PhD., professor of pharmacology and toxicology, works in the University of Utah’s ADD program, specifically with mutations associated with various forms of epilepsy by making clinically relevant mouse models. Robert Fujinami, PhD., professor of neurology, found that genetics play an important role in the level of brain damage and seizure susceptibility observed following infection with Theiler’s virus. Such information is critical when trying to design and develop new therapies for various forms of epilepsy. Since 1974, the ADD program has evaluated 28,000 investigational drugs for the treatment of epilepsy. 10 drugs from that investigation are on the market, and another 18 are in various stages of clinical development.
Stephen Lessnick, M.D., PhD., treats and investigates sarcomas such as Ewing’s Sarcoma–deadly childhood cancers–using Capecchi’s investigations on how sarcomas work and developing mouse models to test new treatments. The existence of five fusion genes that include the Ewing’s sarcoma gene (EWS) provides a way of improving the diagnosis of the disease and understanding how the lethal cancer starts. All of these advances owe their progress to the pioneering evolutionary molecular biology work of Mario Capecchi.
D.R. Beckler, et. al., studied the rpoB gene known to be involved with resistance to the tuberculosis drugs, Rifamycin and Rifabutin. Using the methodology from their evolution studies on gene mapping, they were able identify mutations in rpoB gene that resulted in resistance to the drugs. Testing in the Beckler lab can now evaluate tuberculous drug effectiveness, and this molecular approach is now able to serve as a model for other drugs used for the treatment of tuberulosis and other related mycobacterium avian paratuberculosis (MAP) diseases.
Medical clinicians and investigators work regularly with the effects of evolution in the form of bacterial and viral resistance to antibiotics. Only by understanding the processes of evolution, have physicians been able keep ahead of the mutational changes that cause the resistance.
Julie R. Korenberg, M.D., PhD. of the University of Utah, has studied Down’s syndrome for more than 30 years and William’s syndrome for more than 15. She has become one of the world’s leading researchers in the genetics of William’s syndrome. She created a color-coded guide to the human genome by tagging thousands of fragments of DNA with different colors that can be seen with fluorescent light under a microscope. Using the colors as a guide, Korenberg was the first person in the world to identify fluorescent markers that spanned the entire human genome. Work in her lab on GTF21 and GTF21RD1 genes revealed them to be linked with visual-spatial processing and proved that GTF21 plays a role in social behavior and GTF21RD1 contributes to visual spatial performance. Further work is underway to utilize this basic genetic/evolutionary knowledge to help not only William’s syndrome patients, but others with retardation and/or social behavioral deficiencies to have richer lives.
Using a new technique that allows a genome-wide scan of millions of genetic mutations, researchers, Gerald G. Krueger, M.D., and Kristina C. Duffin, M.D., professors of dermatology at the University of Utah, have identified four new genetic “hotspots” that affect the risk for psoriasis, an autoimmune disease of the skin that adversely affects 75 million Americans. They identified 438,670 genetic mutations. After identifying 18 DNA sites with the highest associations with psoriasis, the researchers expanded their study to include about 5,000 psoriatic patients with 5,000 controls. This work identified 7 sites as potential serious mutation points for psoriasis. The clinical implications include the potential for identifying individuals likely to develop psoriasis before they develop frank skin changes, and in the future, perhaps to apply gene therapy to prevent the onset of the painful, disfiguring, and socially devastating disease.
Tatjana Piotrowski, PhD, assistant professor in the Department of Neurobiology and Anatomy at the University of Utah School of Medicine, pursues lessons from evolu-tion to help people with hearing loss. Evolution is the progressive change of heritable traits, but the changes are not always for the better. Dr. Piotrowski noted that the ability to hear is one example of an evolutionary decline in a trait. Lower vertebrates including frogs, fish, and some birds, can regenerate hair cells in the inner ear that enable hearing. After mammals branched off the evolutionary tree, this enviable trait was lost. Humans experience a broad array of causes of hair cell death and the result is that hearing loss is one of the most prevalent disabilities in people. Dr. Piotrowski was awarded a grant to study and compare the regeneration process between zebrafish and mammals with the strong hope that the information gained will teach us at which step the regeneration process is disrupted in humans and eventually how to circumvent that adverse evolutionary consequence.