Dean's Newsletter

Archive of previous newsletters

Medical Student Research

December 20, 2006

In the world of research, scientists strive to publish their best work in the best journals. Like it or not, the perception of "best" among journals is influenced by its "impact factor," which is calculated as a function of the frequency with which articles in the journal are cited by others. In the area of biomedical research, the journal with the highest impact factor is Nature Medicine (28.9). Few faculty members in any medical center get to publish their work in Nature Medicine. When this occurs—and I'm pleased to report that it does so on a regular basis at Rochester--it represents a deep sense of accomplishment for all connected with the work. Imagine our pride, then, when we recently learned that one of our medical students, Anthony Petraglia (Class of 2007), was co-first author of a paper in the November, 2006 issue of Nature Medicine (2006;12:1278-85) on the potential protective effects of activated protein C (APC) in stroke.

One of the goals of this newsletter (and a fun part for me) is to identify individuals in our SMD community with extraordinary accomplishments, and to tell their stories along with the story of their work. This newsletter is about Anthony Petraglia and his work on APC. I will get to this in a moment, but to place the topic in context, please allow a short historical aside on medical student research at Rochester.

Medical student research has had a long and rich tradition here. The earliest notable example is one of fundamental import: the discovery of progesterone by medical student Willard Allen. An account of this story by Dr. Allen based on his published reflections (Gynecologic Investigation 1974;5:142-82) may be of some interest and amusement: "My part in the progesterone story began in September 1926, when I walked into the Dean's office at the University of Rochester seeking admission to the Medical School. I had no appointment, I had made no formal application, and classes had already commenced. The Dean was kind enough to have me interviewed by the Admissions Committee. The next person I saw was George W. Corner, Professor of Anatomy. After a few more interviews, I returned to the Dean's office to learn my fate. George Hoyt Whipple, the Dean, said that he had made a few phone calls and that I was now a medical student. Late in my first year Dr George Corner invited me to become a fellow in anatomy and do research with him."

Willard Allen then proceeded with Dr. Corner to conduct a series of studies on a progestational substance in ovaries, first reported in 1929 (Am J Physiol 1929;88:326–399), when Allen was still a medical student. This paper described experiments in which "alcoholic extracts of the corpus luteum, freed from phospholipids, contain a substance which when injected into castrated adult female rabbits induces a characteristic alteration of the endometrium identical with the progestational proliferation previously shown to be due to the presence of corpora lutea in the ovaries... It appears that extracts of the corpus luteum contain a special hormone which has for one of its functions the preparation of the uterus for reception of the embryos by inducing progestational proliferation of the endometrium." After finishing medical school, and while taking clinical training in obstetrics and gynecology, Dr. Allen continued his work, naming the hormone "progestin," demonstrating its fundamental importance for uterine implantation of the embryo, and reporting its chemical structure.

Today we continue to provide opportunities for medical student research, through programs such as the academic research track (ART), the MD-PhD program, and the long-standing "year-out" program for research, which Anthony put to good advantage.

Anthony Petraglia grew up in northern New Jersey. During high school, his main interests were athletics, playing varsity football and golf. He chose to attend the University of Chicago because of its reputation for academic excellence and the chance to spend four years in Chicago. Anthony received his B.A in June, 2002, with specialization in neuroscience and Honors in the Division of Biological Sciences. As an undergraduate he conducted multiple sclerosis research, resulting in an honors thesis, two published abstracts, a poster presentation at an international meeting and a manuscript published in the Journal of Neuroimmunology. He was inducted into Sigma Xi Scientific Research Honor Society. In addition to his research, Anthony was an active member of his fraternity, Phi Delta Theta, and played intramural football, soccer, and softball. Several orthopaedic injuries occurred along the way, the silver lining of which was the solidification of his decision to become a physician, with a likely specialty of orthopaedics. He was attracted to Rochester for medical school because of its reputation and proximity to home, and entered in August, 2002 with the Class of 2006.

Continuing his interest in orthopaedics, Anthony sought the opportunity to do musculoskeletal research in the summer between his first and second years. He found a position in the lab of Randy Rosier, MD, PhD, Chair of Orthopaedics, where he developed mouse and avian models of osteoarthritis. His job was to establish and characterize an osteoarthritic phenotype in two animal models and to further explore the cellular mechanisms underlying the disease through cell culture work. The work resulted in two abstracts, a presentation and 2 papers (one under review and another in preparation).

At the end of the second year of medical school, Anthony had a fateful cup of coffee with Web Pilcher, MD, PhD, Chair of Neurosurgery. In that conversation, Anthony realized that his true calling was to neuroscience and to neurosurgical patients. Web remembers it this way:

"From the beginning, Anthony struck me as a very bright and committed individual who was giving very careful consideration to his choice of a career path; a young man who was looking for a challenge. I had been impressed with him in his role as a leader of the Medical School Surgery Interest Group and I was very happy to help him when he asked for advice regarding a possible research experience in Neurosurgery. Little did I know at that moment that Anthony would turn his "medical student research experience" into a tour de force of translational research and incredible personal accomplishment."

This conversation over coffee with Dr. Pilcher led Anthony to change the direction of his interest from orthopedics to neurosurgery. In Anthony's words: "During my third year of medical school, I spent a month on the Neurosurgery service and fell in love with it. In Dr. Paul Maurer and Dr. Pilcher, I found amazing clinical mentors. I saw a lot of what I always envisioned my future career as a physician to be like in them. After doing my sub-I in Neurosurgery here at Rochester in July, 2005 and an away Neurosurgical rotation at Columbia, I then decided to take a year out to immerse myself in the basic science side of Neurosurgery."

Anthony decided to work in the lab of Berislav ("Betza") Zlokovic, MD, PhD (see newsletter July 8, 2004). His initial interest, born of his athletic background, and interest in athletic-associated brain injuries, was to study the effects of neuroprotection strategies in animal models of closed head injury. He approached Dr. Pilcher for Department support to purchase a cortical impact device which was essential to the production of focal brain injury in the studies he had proposed. When he realized that this device was back-ordered and wouldn't be available for several months, Anthony approached Dr. Zlokovic and asked him if he could help with another project while awaiting delivery of his equipment. One of the projects in Betza's lab, which Anthony joined, was exploration of the potential role of activated protein C (APC), a systemic anti-coagulent and anti-inflammatory factor, in the management of stroke.

Each year, about 700,000 Americans have a stroke. Stroke is now the third leading cause of death in the nation, and has become the most common cause of long-term disability. A stroke is the sudden death of a portion of the brain cells due to a lack of oxygen. This occurs when blood flow to the brain is damaged, as by blockage or rupture of an artery to the brain, resulting in abnormal brain function. However, the long-term damage from a stroke occurs not only because of the deprivation of oxygen and other nutrients. Rather, the Zlokovic lab has been exploring the influx of white blood cells and the overall role of inflammation in the after-effects of stroke. Indeed, while brain damage from stroke initially occurs from a lack of blood flow, the Zlokovic lab has been exploring the hypothesis that the damage is extended and increased by a cascade of reactions, including the overzealous attempt by the body's own immune system to "fix" the damage. Even when blood flow is restored, brain cells undergo apoptosis, or cell death, for hours or days, because the cellular damage has reached the point of no return.

In research led by Dr. Zlokovic and published in a 2003 article in Nature Medicine (2003;9:338-42), it was discovered using a mouse model that APC protects the brain from ischemic injury by acting directly on brain cells, in addition to its anti-coagulant and anti-inflammatory properties. Specifically, APC directly prevents apoptosis in hypoxic human brain endothelium through cellular receptors (EPCR and PAR-1). APC acts on these receptors to inhibit a molecule known as p53, which otherwise in low-oxygen conditions would orchestrate a cell's biochemical downward spiral and apoptosis.

The only medical treatment available for stroke is the thrombolytic agent tPA (tissue plasminogen activator), approved for use by the FDA in 1996. Overall, however, tPA is used in only about 3% of those who might benefit from it, because it must be administered within 3 hours of the onset of symptoms. It is rare for patients to get to the hospital soon enough to receive the tests needed to proceed with treatment. Moreover, although the benefit-risk ratio favors the use of tPA if the patient is seen in time, there are some toxic effects of tPA, including the potential prolongation of a stroke due to extended neuronal death and its promotion of hemorrhage as a major complication of its use.

This is where Anthony's work comes in. tPA can promote brain hemorrhage by activating matrix metalloproteinase-9 (MMP-9) in brain endothelium, which degrades the vascular basement membrane and the proteins associated with the blood-brain barrier, allowing blood to seep out of vessels into brain tissue. In Anthony's Nature Medicine paper, he (along with co-first author Tong Cheng, senior author Zlokovic, and others) shows that APC may be able to temper this effect, perhaps leading to an increase in the window of opportunity for tPA treatment beyond three hours, and perhaps leading to primary use of APC as a treatment for stroke. In this paper, it is suggested that APC may improve thrombolytic therapy for stroke by reducing tPA-mediated hemorrhage through a mechanism involving the inhibition of the MMP-9 pathway through protease-activated receptor 1.

When he began in the lab in September, 2005, Anthony's first job was to learn how to perform the delicate surgical procedure in mice that produced the model of transient middle cerebral artery occlusion. This involves first making a midline incision and skeletonizing the carotid arteries. Then, using 6-0 prolene suture with a blunted tip, he advances the suture 10 mm in a manner that occludes the middle cerebral artery to create the stroke model. After many experiments, sufficient data accumulated to write the paper submitted to Nature Medicine. The paper was originally submitted in December, 2005. The reviewers asked for more experiments, which Anthony accomplished over the next several months. The paper was re-submitted, and was accepted for publication in September 2006.

Many individuals influenced Anthony's progress in the lab and in his decision to pursue neuroscience as a career. He credits his scientific mentor, Dr. Zlokovic, for opening his eyes to the excitement of research. The admiration is mutual: "In my opinion," Betza states, "Anthony is a most capable, energetic, motivated and talented medical student. In terms of his research abilities, he ranks among the highest 5% of trainees I have had over the years, including many neurosurgery residents who are now associate or full professors at major academic institutions. He is extremely well organized, dedicated and highly motivated in developing and promoting new translational therapies for nervous system injuries, including both stroke and brain trauma."

In addition to his mentorship in the laboratory, Anthony is particularly appreciative of the guidance he has received from Ed Vates, MD, PhD, Assistant Professor of Neurosurgery: "Dr. Vates is the epitome of the physician scientist here at the U of R. He has served as a role model to me and an invaluable source of career guidance. In addition, he has taken it upon himself to expose the medical students at the U of R to this side of neuromedicine – regardless of their ultimate career choice. He has guided many medical students in both basic and clinical science papers/projects, getting them into labs, etc. He also has taken upon himself to see that the students are able to get down to the ORs to see the clinical side as well if they wish. He has truly become the go-to guy for medical students when it comes to any interest in Neuromedicine."

Overall, Anthony describes his experience as extremely satisfying, because the work he did at the bench could alter the way we practice medicine, and ultimately improve outcomes at the bedside. Additionally, in his words again: "I love using my hands and performing technically challenging procedures. It felt great to push myself so hard and to have such a great outcome. All in all I have found fantastic clinical role models, an outstanding department that has been extremely supportive of my work, and a great basic science mentor in Dr. Zlokovic. The year out also gave me an opportunity to get involved with clinical research projects as well."

Anthony is now completing his fourth year of medical school and applying for residency programs in Neurosurgery. Something tells me that he will do just fine in the match. Meanwhile, a clinical trial that in part flows from the results of Anthony's trials has commenced. Neurologist Curtis Benesch, M.D., M.P.H., director of the Strong Stroke Center, will lead a $3.4 million safety clinical trial of APC use in stroke. During the next five years, he will work together with collaborators at the University of California at Irvine, Washington University in St. Louis, Mt. Sinai Hospital in New York City, and Rochester General Hospital to enroll 72 people in the study. Participants will be people who have had a stroke within six hours but who have not received tPA.

Talk about translational research!

Meliora,

David S. Guzick, MD, PhD
Dean, School of Medicine and Dentistry