McNally-portrait-500Exploring the human genome makes good gene hunters of researchers. DNA trackers search for clues among the needle-in-the-haystack framework of the 25,000 genes in the human body to better understand and treat genetically caused diseases. Their perseverance, coupled with ongoing technological advances, has yielded quite a few “needles” in recent years. The use of genetic information to inform patient care, from cancer to neurological disorders, has personalized medicine for individual patients like never before. But more is still to come. Much more, according to Elizabeth M. McNally, MD, PhD, new director of Northwestern University Feinberg School of Medicine’s Center for Genetic Medicine.

An internationally renowned expert on the genetics of heart disease and muscular dystrophy, this experienced gene hunter or “huntress” foresees an entirely new era for genetic medicine. “A revolution in DNA sequencing is dramatically driving down costs and transforming how we practice medicine,” says the recently named Elizabeth J. Ward Chair of Genetic Medicine, who arrived at Feinberg in September. “The center is poised to take genetic medicine to the next level. Now more than ever, we have the opportunity to expand our understanding of genetic variations and link this information to clinical outcomes so that we may more effectively care for our patients.”

Dr. McNally fully understands the rewards of applying laboratory research to clinical care. Formerly at the University of Chicago, she founded the Institute for Cardiovascular Research as well as launched a Cardiovascular Genetics Clinic. One of a few of its kind in the nation, the clinic focused on diagnosing and treating patients with inherited forms of heart disease. At Northwestern Medicine, she will direct a clinical cardiac genetics program through the Bluhm Cardiovascular Institute. A new offering for Northwestern in the area of genomics and cardiovascular medicine, the program will take advantage of genetic counseling and testing to identify individuals at risk for hereditary heart disease and to plan appropriate treatment from devices to drugs.

TGF-caption

Dr. McNally and her group study the genetics of inherited muscle and heart disease (muscle fibers outlined in green). Using genetic methods, they mapped a gene that controls TGF-β signaling (red), as a major modifier of muscular dystrophy.

While her expertise will further advance Northwestern Medicine’s influence in genetic medicine, McNally envisions more. In her latest leadership role, she hopes to strengthen inter-institutional collaborations across the city to establish Chicago as a “mecca for genetics.” It may sound like a pipe dream but so was the physician-scientist’s goal to go after genetic modifiers some 15 years ago when genetic medicine was still in its infancy. Today, she counts among her most significant scientific accomplishments the identification of two gene modifiers that could change the destructive nature of muscular dystrophy: TGF-β binding protein involved in preventing muscle weakness and a newly identified modifier known as annexin A6 that sheds light on muscle cell injury and repair. McNally and colleagues are currently working on a novel therapeutic agent that modulates TGF-β activity to reduce tissue damage and fibrosis and be potentially applicable to a variety of diseases, including myocardial injury, radiation-induced injury and vascular disease.

MATERNAL INSTINCTS

The second oldest of five siblings, Dr. McNally credits two moms—her own and that of a boyfriend—for serving as key role models who helped shape her career.

“My mother raised us all, while at the same time earning her college degree in Spanish, English and education,” shares the Chicago native who spent her teen years in Platteville, Wis. “In my family, there was definitely a push for education from my mother because she knew education and advancement were tightly tied.” McNally attended Barnard College, Columbia University, in New York, where she earned bachelor’s degrees in biology and philosophy in 1983. While at college, she dated a guy whose mother happened to be preeminent scientist Ora M. Rosen, MD. (The late Dr. Rosen and colleagues at Memorial Sloan-Kettering were the first to clone the gene for the human insulin receptor in the mid-’80s.) “I was interested in research and medicine but wasn’t quite sure of my direction,” recalls McNally. “Ora took me under her wing and encouraged me to work in a lab while I was still an undergraduate.”

Shown is super-resolution imaging of a single muscle fiber after injury. A mutation in annexin A6 (green) inhibits muscle repair after injury by slowing annexin A6’s ability to reseal the injury site (red).

Dr. Rosen connected McNally with researcher Leslie Leinwand, PhD, a faculty member at Albert Einstein College of Medicine. A summer stint in Leinwand’s lab allowed the budding young investigator to not only clone her first bit of DNA, the myosin gene, but also find her research calling. A major motor protein found in heart and skeletal muscles, myosin mutations interfere with muscle contraction that can lead to disorders such as cardiomyopathy (weakness of the heart muscle) and muscular dystrophy. McNally has focused on both of these areas of investigation throughout and ever since completing the MD/PhD program at Albert Einstein in 1990. She even worked under the mentorship of Dr. Leinwand, who served as her dissertation advisor. McNally jokes, “I was the summer student who never went away!”

An internship and residency training in internal medicine, however, took McNally to Brigham and Women’s Hospital in Boston. There she also completed a fellowship in cardiovascular medicine in 1996 before going on to a research fellowship in genetics at Boston Children’s Hospital. She then joined the faculty at the University of Chicago, where her husband, Stephen Kron, MD, PhD, is currently professor of molecular genetics and cell biology. Twenty-eight years ago, the Oak Park, Ill., couple met at the Marine Biological Laboratory in Woods Hole, Mass., where McNally spent two summers as a teaching assistant. Coincidentally, it was also at this seaside haven for scientists that McNally first made the acquaintance of Rex Chisholm, PhD, vice dean for Scientific Affairs and Graduate Education, and the Adam and Richard T. Lind Professor of Medical Genetics at Feinberg. In 2000 he founded Northwestern’s Center for Genetic Medicine—the very one McNally looks forward to building upon.

Lisa Castillo is a certified genetic counselor who works closely with Dr. McNally, staffing the cardiovascular genetics clinic, where genetic testing is used to pinpoint the cause of inherited disease like cardiomyopathy, Marfan syndrome and inherited arrhythmias.

“I love what has been established at Northwestern,” she says. “The extensive research resources like the NUgene Project [one of the nation’s first DNA banking studies] and clinical services such as genetic counseling are not only fantastic but also necessary components of getting us to where we want to go in the future.”

AFFORDABLE GENOMES

When McNally began hunting genes decades ago she relied on Southern blotting, a molecular biology technique used to isolate and examine a single DNA fragment from an individual. “We would get just one nucleotide at a time to study—one out of three billion base pairs in a human genome,” she explains. “Today with whole genome sequencing technology, we can look at all three billion bases in many different individual genomes and begin to search for both common and rare genetic variations that link to disease in populations of people.”

In 2003, the Human Genome Project completed the sequence of the first human genome. The international effort cost upwards of $3 billion and took 13 years to be declared a success. Last year, the average price tag for whole genome sequencing was $10,000. In January, biotech company Illumina introduced a new machine that can sequence an entire human genome for $1,000 in about 24 hours. This exciting development will extend whole genome sequencing to many more patients, providing richer and more robust genetic data that will dramatically change health care.

Muscle with mutations in Dysferlin and the related protein Myoferlin develop fat accumulation within muscle (red).

Muscle with mutations in Dysferlin and the related protein Myoferlin develop fat accumulation within muscle (red).

“Lower cost sequencing technology will allow us to better classify diseases. That’s already been happening in the cancer field, cardiology and neurosciences,” explains Dr. McNally. “In cardiology, we tend to lump conditions into broad categories—the group of heart failure, the group of cardiomyopathy. What we are learning is that there are many different diseases within these groups, and many times there is a strong genetic influence. If we can understand the effect of specific gene mutations on disease progression, we will have a better sense of when to intervene with medical and surgical treatments for each and every patient.”

The growing field of personalized medicine relies on the ability to tap into DNA codes. Dr. McNally has both hunted and gathered revealing biological data for many years in her quest to improve care for her heart patients and generations of their families. “In our clinic, we’ve already been doing personalized medicine to deliver more precise therapies, minimize side effects and improve outcomes,” she says. “Cardiovascular genetics has grown at an amazing rate and demonstrated the importance of using genetic information in the practice of good medicine in cardiology and across other areas of medicine as well.”