When it comes to easing, if not curing, what ails us; the study of how drugs work in living organisms establishes pharmacology as one of the most clinically relevant of scientific disciplines. So it’s fitting that Northwestern University Feinberg School of Medicine’s recently reimagined Department of Pharmacology has an inaugural leader who specifically trained as a physician to pursue a research career—and a stellar one at that.
“Pharmacology is a basic science discipline that is highly translatable to clinical medicine,” says Alfred L. George Jr., MD, a renowned expert in the field of ion channel proteins who joined Northwestern in March as the Magerstadt professor and chair of pharmacology and director of the new Center for Pharmacogenomics. He was most recently at Vanderbilt University where he held a named professorship in medicine and was professor of pharmacology, chief of genetic medicine and director of the Institute for Integrative Genomics. “While I no longer consider myself a clinician, I still have a clinical perspective and that can only serve as an asset in this field.”
The medical school’s Department of Pharmacology became a standalone academic unit in early 2014. Established with members from the former Department of Molecular Pharmacology and Biological Chemistry, this new entity will expand the discipline at Northwestern Medicine through research, training and drug discovery, and help to further strengthen collaborative efforts on the Chicago and Evanston campuses. Dr. George envisions a department that will meld classic pharmacology topics with emerging areas of pharmacogenomics, drug discovery and translational pharmacology. The resulting research programs will have direct relevance to human diseases, including cardiovascular and neurological disorders—areas in which George has already contributed a great deal. His own body of work focuses on conditions such as cardiac arrhythmia and epilepsy, both caused by genetically disturbed ion channel function.
George’s father was a physician in private practice and his homemaker mother was involved in politics in Batavia, New York. Interested in science, George graduated with honors from the College of Wooster in Ohio in 1978 with a bachelor’s degree in chemistry. While he had no plans to become a practicing physician, his familiarity with the field of medicine—thanks to his dad—prompted him to enter medical school at the University of Rochester as a means to a different end. He explains, “I went into medicine with the intention of conducting research.”
With that mindset, he completed his residency in internal medicine at Vanderbilt followed by a fellowship in nephrology at the University of Pennsylvania. Then a visiting postdoctoral fellowship in Switzerland took George, wife Jackie and toddler son William (now 29) to Europe for a year. (The couple has another child, Lindsay, 25.) Once stateside again, he returned to Penn as a research fellow. There he began studying the genetics of ion channels—specifically, voltage-gated sodium channels responsible for generating electrical impulses or “action potential” that drive neural activity and evoke contractions of muscles including the heart.
In the late ‘80s, little was known about genetic defects in sodium channels and connections to disease except for a “small shred of evidence published in a very specialized journal,” according to Dr. George. A German research group had reported a possible relationship between an abnormal muscle sodium channel function and rare familial neuromuscular disorders causing periodic paralysis, or myotonia. This was evidence enough for George that his chosen research focus had endless possibilities.
“If I had been advising a graduate student on whether to pursue study based on this limited finding, I probably would have said, ‘Do something else!’” he remarks. So why did he do it as a young investigator? George admits, “It was incredibly interesting.”
The Heart of the Matter
Cloning a human heart sodium channel to study genetic disorders seemed like a good idea. Scientific evidence was beginning to show that genomic defects in ion channels might be linked to cardiac and neurological conditions.
“It was human and was in the heart,” he recalls about his early work at Penn. “We thought it had to be good for something, although we didn’t know what. That something turned out to be gold.”
George and others used the clone to better understand inherited heart rhythm disorders, such as congenital long QT syndrome (LQTS). Causing rapid, erratic heartbeats, this condition can lead to fainting and sudden death, often in children and young adults. In 1995, a Utah geneticist discovered a family with a history of LQTS with a mutation in the very same sodium channel that George had genetically mapped. A Vanderbilt faculty member at the time, Dr. George quickly set out to investigate the functional consequences of the mutation as a first step to understanding the cause of irregularly beating hearts. In a matter of six weeks, he and his colleagues submitted their results to the journal Nature, which published the findings two months later. The investigators were first to link an ion channel anomaly with an inherited arrhythmia. “It was gratifying to know we were on the right track from the very beginning,” shares George.
This groundbreaking finding revealed a subtle but life-threatening mutation in the heart sodium channel that disrupts the heart’s electrical stability. The observation has gone on to become an important one for pharmaceutical companies: some are now targeting the activity of this sodium channel in the development of drugs to control heart rhythm. In recent years, the NIH-supported George lab has investigated extreme forms of LQTS that occur early in life—even in utero.
“We’ve helped to make the connection between congenital LQTS and sudden infant death syndrome,” he explains. “Some 10 to 20 percent of SIDS cases are estimated to be related to inherited cardiac arrhythmias. Genetic testing might help determine which families are at risk for SIDS.”
The majority of sodium channel genes are expressed in the central nervous system. Given his success with the heart, George soon turned his attention to a different organ. He says, “We often thought there might be genetic mutations in brain sodium channels and pondered the potential consequences.”
In 1998, his laboratory collaborated with investigators in Australia to publish the first identified mutation in a human brain sodium channel gene associated with epilepsy. Later in 2001, his lab uncovered a surprising discovery while studying mutations in SCN1A located on human chromosome 2—the most mutated gene among genetic forms of epilepsy. His lab found that the same type of functional defect in heart sodium channels responsible for causing irregular heartbeats in congenital LQTS was the same culprit observed for certain brain sodium channel mutations causing a form of genetic epilepsy.
“There are only so many ways to break a sodium channel,” explains Dr. George. “This subtle defect is one of them.”
Currently, his lab is testing novel pharmacologic agents in a mouse seizure model to develop effective anticonvulsive drugs to control epilepsy. Dr. George will continue this exciting work at Feinberg with the assistance of mouse geneticist and epileptologist Jennifer Kearney, PhD, who left Vanderbilt to join Northwestern’s faculty in July.
Advancing Personalized Medicine
Genetics dictate how patients will react to any given medication. A rapidly emerging area of study, pharmacogenomics strives to understand how genetic determinants affect drug responses (both good and bad), which, in turn, allows for patient care that is truly personalized. In the area of oncology, for example, clinicians have already been tailoring drug therapy to specific tumor types determined by genetic testing.
“Of all the genetic discoveries that can be interpreted to the care of patients who have common disorders, pharmacogenomics—alongside cancer—is among the best examples,” says George. He helped to establish Vanderbilt’s expertise in genetic medicine by founding its first division in 1999 and the Institute for Integrative Genomics in 2004. At Feinberg, he looks forward to building a multidisciplinary center “without walls” focused on pharmacogenomics. An early emphasis of the center will be to study ways to implement testing and interpretation in the clinical setting. Over time, he plans to explore the development of basic research programs in drug metabolism as well as help to recruit more pharmacogenomics faculty to Northwestern.
“One day, doctors will be able to test preemptively for genetic susceptibilities and know which medications will work best for their patients, whether they should back off on the dosage or change drugs entirely,” says Dr. George. “There are great opportunities in the future to advance personalized medicine with pharmacogenomics.”