A history of firsts for Wake Forest University School of Medicine. (Wake Forest Centennial).

PROGRESS IN MEDICINE rarely happens because of a sudden event or dramatic breakthrough. Rather, it moves forward incrementally, with each advance building on multiple observations and insights by the clinicians and researchers who came before. Every now and again, medicine reaches a milestone, another first, that often grows more important with the perspective of time than it seemed when it happened. In many ways, what happens after the milestone, how it advances the diagnosis, care, or treatment of patients, is of far more significance than the milestone itself Such is the case with a series of milestones, including some national firsts, achieved over the years at Wake Forest University School of Medicine.

Now celebrating its 100th year, the medical school has been built by entrepreneurs and innovators dedicated to excellence in education, patient care, and research. In 1941, for example, after moving from the town of Wake Forest to the city of Winston-Salem as a newly expanded 4-year institution, the School of Medicine created a department of medical genetics, the first in the nation, building on a $50,000 research program made possible by the Carnegie Foundation. Today, that legacy lives on through the school's Center for Human Genomics, an integral part of new research and treatment. In 1958, the medical school held a faculty retreat considered the first of its kind in the nation, building on a spirit of interdisciplinary cooperation and collegiality that exists to this day.

The important thing is that the institution attracted open and inquisitive minds, adventurous physicians, educators, and scientists who were ready, willing, and able to play significant roles in moving medicine into the 21st century. The medical school lays claim to important firsts in such diverse areas as atherosclerosis, cancer, cardiology, radiology, stroke, surgery, ultrasonography, and urology. Some milestones from each of these areas, and their significance to the advancement of medical practice, provide the basis of this article.

At the bottom of it all, though, has been a commitment to work with community physicians to bring tertiary care to patients in the region. So it was on that June day in 1965, when the phone call came from a surgeon in nearby Mount Airy, North Carolina, a town perhaps better known as the model for the fictional community of Mayberry. A man's hand had been cut off. Could someone in Winston-Salem put it back on?

REATTACHING A HUMAN HAND

The patient was a 26-year-old inmate whose left hand had been accidentally but cleanly severed just above the wrist while working on a road gang. The lay public at this time was fascinated by the ability of modern medicine to reattach human limbs. There was a story in Time magazine in late 1962 about a 12-year-old Little League pitcher whose right arm had been reattached after a train-related accident near Boston. In 1964, the magazine had reported of some Chinese surgeons who had successfully reattached a man's hand. Now, as Time would report in July 1965, Jesse H. Meredith, MD, director of the surgery research laboratory at the then Bowman Gray School of Medicine, was presented with the opportunity to become the first United States surgeon to reattach a human hand.

By current standards, the surgical tools at Meredith's disposal might be considered crude. But his techniques were leading-edge for the day, if not radical; innovations intuitively built on his experiences and insights from the laboratory. The first step was to use 2 rods to stabilize the ulna and radius to the proximal forearm. The severed arteries were repaired and unclamped, the hand perfused with blood before the veins were rejoined, nerves and tendons repaired, and the skin sewn up. Some of his approaches were considered inappropriate--using tension sutures to unload the nerve repairs, as well as early postoperative motion--but are common practice today.

At the time, however, there was little appreciation of the significance of the surgery; Meredith's wife did not learn what he had done until she read about it in the newspaper, and the patient himself died the following year from injuries sustained in an automobile accident. What was clear, though, was that both the medical school and North Carolina Baptist Hospital, its teaching facility, were committed to carrying forward with a tradition of trauma management and surgical innovation in the name of patient care.

Twenty years after the successful replantation, the new thing was arthroscopy. And almost by accident, at an international meeting devoted to the knee, a society for arthroscopic surgery of the wrist would emerge. During a discussion, Gary G. Poehling, MD, of the medical school, and 2 colleagues from Virginia and Canada, discovered that each had been experimenting with cadavers to show that arthroscopes could be used in surgery of the wrist. Because many older academic leaders in orthopaedics had resisted the introduction of athroscopic knee surgery into clinical practice, the 3 were determined to avoid a similar fate. After more than 6 months of planning, 52 leading wrist experts met in Winston-Salem in January 1986 to lay the foundation for training the new generation of wrist arthroscopists.

Today, that tradition of innovation and excellence in surgery of the hand and wrist lives on at the medical school, with leading-edge work in the use of arthroscopic techniques to improve the treatment of distal radius fractures.

PIONEERING STUDIES OF KIDNEY STONES

Meanwhile, others at the medical school were on their way to firsts of their own in the diagnosis and treatment of disorders of the kidney, prostate, and gallbladder. When William Boyce, MD, came to the Winston-Salem medical school in 1952, communications were improving, air transportation was making possible the cross-pollination that comes from attending seminars and scientific meetings, and research funding from government sources and private foundations was opening doors to better understanding and treatment of such endemic regional problems as kidney stones.

A prevailing view of the time was to sacrifice a diseased kidney that threatened the entire urinary system, because the intricate procedures could make corrective surgery far too involved; a patient could function with only one good kidney, also. The earliest surgical procedures demanded that a surgeon get in and get out of this vascular organ as quickly as possible to avoid problems associated with excessive blood loss. Intrigued by reports of a Chicago woman who "froze to death" on the street but was revived when her body temperature rose, Boyce developed a procedure in which the kidney was cooled in situ with an ice bath during surgery. The technique, known as anatrophic nephrolithotomy, became standard procedure for removing large staghorn stones, which were commonplace at the time, that could result in a complete cast of the drainage system of the kidney.

Boyce, however, did not stop with his pioneering work in the treatment of kidney stones and the development of the anatomy of the blood vessels and blood supply to the kidney. In 1969, with the assistance of William M. McKinney, MD, a medical school pioneer in diagnostic imaging, he became the first in the nation to use ultrasonography to detect prostate cancer.

David L. McCullough, MD, succeeded Boyce as urology chair, and he, too, has helped to advance clinical practice. In 1986, the school was the first in the nation to use lithotripsy to break up stones in the common bile duct. At the time, surgery for common bile duct exploration and removal of stones was done in open fashion and had a mortality rate of about 8%. McCullough, as head of the American Urological Association's Committee on Lithotripsy for 6 years, helped to establish the guidelines for training in the process that helped the minimally invasive procedure take hold in this country.

In addition, the school had the first laser in the South and the second prototype in the country that was used for breaking up stones in the urinary tract and also for breaking up stones in the biliary tract. McCullough also reported the use of a different kind of laser to destroy prostate tissue in dogs with benign prostatic hyperplasia, and later was the first to use the laser to treat this condition in men. Finally, in 1991, McCullough reported a new technique for earlier detection of cancer by taking biopsies from 5 different regions of the prostate.

ULTRASONOGRAPHY ACROSS SUBSPECIALTIES

Ultrasonography has grown up with the medical school, and made possible clinical and research advances not only in urology, but in virtually every subspecialty. The key has been a willingness to incorporate the technique as a clinical and research tool for all departments that wanted it, rather than making it the sole province of any one. In keeping with this custom, the Center for Medical Ultrasound has trained more than 28,000 people, and a text by its director, Frederick W. Kremkau, PhD, is considered the "bible" of ultrasonography.

The medical school's expertise in ultrasonography is rooted in a tradition of excellence in physiology under the leadership of the department chair, Harold D. Green, MD, DSc, which led to the development of the first blood flow meter in 1955, and pioneering use of the square wave flow meter in 1956. Using these devices, Adam B. Denison, MD, and Merrill P. Spencer, MD, both in the physiology department, and Frank C. Greiss, Jr., MD, now professor emeritus of obstetrics and gynecology, performed research that led to a better understanding of blood flow to the uterus, and improvements in the use of spinal and epidural anesthesia during pregnancy.

One of the first published applications of ultrasonography was the imaging of carotid arteries. In 1983, the medical school was the first in the nation to use transcranial Doppler ultrasound to measure atherosclerotic buildup on the walls of the carotid artery and to image arterial circulation in the brain.

The medical school's federally funded Stroke Center relied heavily on ultrasonography in landmark studies of asymptomatic atherosclerosis in the carotid arteries. The idea was to noninvasively identify the earliest anatomic evidence of atherosclerosis in the artery wall, where the process begins, rather than the lumen, and to correlate this to incidents of stroke or heart attack in 16,000 randomly selected men and women, aged 45 to 64 years, and an additional 5,886 subjects aged 65 years or older. The results showed that, as the thickness of the arterial wall increases, so does the relative risk of having a stroke and the relative risk of having a heart attack.

Since those pioneering studies in the United States, the medical school's Division of Vascular Ultrasound Research has written the protocols for the sonography and for the reading of these sonograms for additional studies involving more than 60 leading medical centers across Europe.

FIRSTS WITH COBALT, THEN AND NOW

Isadore Meschan, MD, joined the medical school faculty in 1955 as chairman of the Department of Radiology, and 2 years later began performing the first cobalt treatments in North Carolina. He also introduced the Meschan applicator, a radioactive device that was temporarily inserted into the vagina to treat cancer of the cervix. Meanwhile, as the medical school was succeeding at being among the first in the nation to acquire new, leading-edge imaging devices and to research and report their diagnostic and clinical applications, Meschan was writing more than 20 textbooks, including the definitive work, An Atlas of Anatomy Basic to Radiology. It was just something that had to be done to make the new technology widely available to patients and their community physicians.

In that regard, the medical school was instrumental in pioneering the clinical use of a radioactive material known as technetium Tc 99m, developed in the 1960s and still widely used today. With a half-life of only 6 hours, the substance was ideal for imaging studies. It could be safely administered to patients in larger quantities because it decayed so rapidly, and that helped to make for clearer imaging. More important, because the substance could be easily generated from a parent isotope with a half-life of several days, community hospitals around the country could have easy access to a very useful, short-lived radioactive material. The energy level of technetium Tc 99m was ideal for detection by devices in use at the time, particularly the gamma camera, and the medical school used it to label albumin for one of the first lung scans ever to detect pulmonary emboli.

Ironically, as technology has evolved and employed different forms of radiation for cancer diagnosis and treatment, the medical school has come full circle with cobalt. Gamma knife stereotactic radiosurgery, using the only Elekta Gamma Knife (Elekta AB, Stockholm, Sweden) unit in North Carolina since 1998, focuses 201 narrow beams of cobalt 60 to treat a variety of brain lesions or vascular malformations.

THE COMPREHENSIVE CANCER CENTER

The gamma knife program is just one of the significant firsts associated with the medical school's multidisciplinary Comprehensive Cancer Center, 1 of only 7 in the Southeast and 40 nationwide that the National Cancer Institute designates as meeting strict criteria for research, collaboration, and access to advanced technologies.

Last year, the physicians at the Cancer Center were the first in the world to treat a brain tumor with the GliaSite Radiation Therapy System (Proxima Therapeutics, Inc, Aipharetta, Ga), newly approved by the United States Food and Drug Administration, which targets cancerous tissue with a liquid source of radiation delivered through a balloon catheter. The Cancer Center also was 1 of 10 sites nationwide last year that began testing the use of a live virus known as ONYX-015, which is genetically engineered to selectively kill cancerous cells in the brain while sparing normal cells. And it is one of only 6 sites in the country that offers treatment for unresectable liver tumors using TheraSphere (MDS Nordion, Ottawa, Canada). The device, delivered through a catheter, has millions of microscopic glass beads permanently embedded with yttrium 90 that are released into the branch of the hepatic artery feeding the liver tumor.

In addition to these and other high-technology treatments in use, on trial, or under development, the Comprehensive Cancer Center of Wake Forest University has 3 pilot projects that are related to prostate cancer and are funded in part by the National Center for Complementary and Alternative Medicine. One involves using fish oil to test the effect of vitamin D dietary supplements on prostate-specific antigen (PSA) levels in healthy men; another attempts to determine whether an active ingredient of beeswax (caffeic acid phenylethyl ester) that has anticancer properties in mice enhances the effectiveness of radiation in killing tumor cells; the third measures the effect of lycopene, a tomato extract, on patients with recurrent prostate cancer.

ATHEROSCLEROSIS: THE FIRST LAUNCHING PAD

Studies of diet and nutrition and their impact on health and disease have a long history at the medical school, starting with a research observation first published in 1959: White Carneau pigeons have naturally occurring atherosclerosis. This discovery was significant in 2 important regards. It provided the first animal model (later, monkeys would be used because of their similarity to humans) for studying hardening of the arteries, a leading cause of death from heart attack or stroke, and it started the school down a 45-year trail of research that continues to change the way physicians around the world treat cardiovascular disease--particularly among women.

The school's ongoing research into atherosclerosis has yielded 4 seminal findings:

* Lowering plasma cholesterol concentrations results in a substantial regression in coronary artery atherosclerosis. This observation led to the diet and heart claims of the American Heart Association, and the push to develop hydroxymethylglutaryl co-enzyme A reductase inhibitors (statins) to lower cholesterol levels.

* Postmenopausal estrogen replacement is associated with primary inhibition of coronary artery atherosclerosis in monkeys. Estrogen deficiency was the primary modulator of coronary artery atherosclerosis, and replacing deficient estrogen inhibited the progression of coronary disease by about 70%. Giving estrogen replacement therapy to women aged [greater than or equal to] 65 years who already had coronary heart disease, however, would make their condition worse.

* Providing estrogen when a premenopausal subject needs it has a bigger impact on atherosclerosis than providing estrogen for postmenopausal monkeys. Therefore, it is important to begin treatment during the perimenopausal transition, when the ovary becomes dysfunctional and the average amount of estrogen declines.

* Estrogens in soybeans (isoflavones) might be useful in postmenopausal women in conjunction with hormone replacement therapy by reducing the occurrence of breast tumors and the incidence of breakthrough bleeding.

BEING FIRST WHERE IT COUNTS

There have been many other milestones at the medical school, including the first toll-free hotline in the nation providing information about epilepsy (1979); pioneering of laryngeal framework surgery, plastic surgery of the larynx to fix "broken voices" (1984); the first center in the nation to implant a vagal nerve stimulator to control intractable seizures in a patient with epilepsy (1988); the first research team in the nation to show that human immunodeficiency virus (HIV) and herpesvirus can reproduce simultaneously in the same white blood cell, providing a possible explanation for the activation of dormant HIV (1988); the first cardiologists in North Carolina to open a blocked artery using a laser (1990); the first facility in the world to incorporate geriatric acute care, transitional care, psychiatry, and rehabilitation under one roof (J. Paul Sticht Center for Aging and Rehabilitation in 1997); the first community-health resource center in North Carolina to be located in a shopping mall (1999); and t he first live Internet broadcast of surgery for implantation of a deep-brain stimulator for symptoms of Parkinson's disease (2002).

In each case, a medical school clinician or researcher rose to the occasion of providing care or advancing scientific knowledge. As rewarding as it is to achieve milestones, what matters first at Wake Forest University School of Medicine is training physicians and scientists who can help people live better, longer, and healthier lives.

Acknowledgments: I would like to thank M. Gene Bond, PhD; William Boyce, MD; Thomas B. Clarkson, DVM; Robert Conn; Adriene Cunningham; Bill Glance; Frank C. Greiss, Jr, MD; John W. Hammon, Jr, MD; L. Andrew Koman, MD; William C. Little, MD; C. Douglas Maynard, MD; David L. McCullough, MD; William M. McKinney, MD; Jesse H. Meredith, MD; Isadore Meschan, MD; Gary G. Poehling, MD; Karen Richardson; Jonnie Rohrer; Stephen B. Tatter, MD, PhD; James F. Toole, MD; and Frank M. Torti, MD, MPH for their time and efforts in the preparation of this manuscript.

RELATED ARTICLE

"The reasons for embarking upon a medical career were undoubtedly as numerous in 1902 as they are today. Perhaps some men were drawn to Wake Forest because of the proximity of 'the capital of the State,' which the 1902 catalogue boasted 'affords many of the advantages without the moral dangers of city life.' Dr. Taylor reported to the trustees in 1898 that there were demands among the students planning to become missionaries that a medical department be established. At least one member of the class of 1903 reported that he had decided to begin the study of medicine when his fiancee had refused to be a farmer's bride. For whatever their reasons, thirteen medical students began their careers at Wake Forest College in the fall of 1902."

Coy C. Carpenter, MD

The Story of Medicine at Wake Forest University

From the Office of Public Relations and Marketing, Wake Forest University Baptist Medical Center, Winston-Salem, NC.

Reprint requests to Michael P. Massoglia, Office of Public Relations and Marketing, wake Forest University Baptist Medical Center, 2200 Cloverdale Ave, Winston-salem, NC 27157.