Research centers in arteriosclerosis, stroke, and cancer at Wake Forest University School of Medicine. (Wake Forest Centennial).

WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE (WFUSM) has had the unusual distinction of holding simultaneous Center grants from the National Institutes of Health (NIH) in arteriosclerosis (begun in 1971), stroke (begun in 1965), and cancer (begun in 1972). Each was maintained for more than 2 decades, and the research directions they established have been maintained up to the present day. The purpose of this article is to provide a brief overview of the history and accomplishments of each of these areas of expertise at WFUSM.

PROGRESS IN CARDIOVASCULAR RESEARCH: ARTERIOSCLEROSIS

Cardiovascular research at WFUSM began in 1938, with the arrival of Camillo Artom from Italy. Artom taught first at the medical school on the old Wake Forest College campus, then moved with the medical school to Winston-Salem, where it was renamed the Bowman Gray School of Medicine (BGSM) in 1941. Artom was a creative and productive biochemist whose initial work centered on the structure and function of phospholipids, their role in the transport of lipid complexes, and how they are influenced by nutrition. (1)

In 1954, Artom recruited Hugh B. Lofland from Purdue University A giant in the field of cardiovascular research, Lofland's major contribution was in studies of the artery wall. An internationally known annual research conference on atherosclerosis bore his name and was active for many years, until it was incorporated into a larger conference in 1998.

Dr. Lofland supported the early research careers of Dr. Thomas B. Clarkson, a veterinarian who began BGSM's Animal Resources Program; and Dr. Robert Prichard, longtime chair of the Department of Pathology. Drs. Prichard and Clarkson observed the natural occurrence of atherosclerosis in a family of pigeons, and numerous publications documented the growing understanding of atherogenesis in that species. (2) Unique in the world, the pigeon model has elucidated connections between fats and the accumulation of arterial cholesterol plaque. Distant offspring of the original Show Racer and White Carneau pigeons are still housed at the Comparative Medicine Clinical Research Center, a 200-acre research complex created by Dr. Clarkson for animal-model research. This facility is an unsurpassed resource, containing purpose-built housing for rodents, nonhuman primates, and, at various times, other animal species used in experiments; state-of-the-art laboratories for measurement of experimental endpoints and preparation of diets; and surgical and necropsy facilities.

Perhaps the best-known activity of this research group is its use of monkey models to better understand atherosclerosis in humans. These studies began in 1963, when Drs. Clarkson and Lofland reported experiments on the effects of diet and genetics on lipid metabolism and atherosclerosis in squirrel monkeys. (3) This work documented the variability in individual responses to cholesterol feeding and lipid metabolism, an important concept underlying epidemiologic studies and public-health initiatives to this day.

A steady stream of novel experiments at the Comparative Medicine Clinical Research Center has been made possible by consistent success in obtaining NIH funding. If only one factor were chosen as the most influential in cardiovascular research at WFUSM, many would point to its holding the longest continuously funded training grant in the United States, funded by the National Center for Research Resources. In 1959, Dr. Harold Green, a pioneer in biochemistry and chronic-disease investigations, was named director of this training grant, and held this position for more than 2 decades. The purpose of the training grant was to train investigators--initially physicians, but, later on, other biomedical scientists--to conduct multidisciplinary research into cardiovascular disease. As such, it was the progenitor of numerous interdepartmental cardiovascular projects at BGSM. When Dr. Clarkson became its director, the program expanded to include the training of veterinarians in animal models of human chronic disease. The current director, Dr. Janice Wagner, is a veterinarian who trained at BGSM and then earned a PhD in molecular and cellular pathobiology through BGSM's graduate program.

In 1971, BGSM was designated a Specialized Center of Research (SCOR) in Arteriosclerosis by the National Heart, Lung, and Blood Institute (NHLBI) . The SCOR designation, with Dr. Clarkson as director, was retained for 25 years. The SCOR's initial research objectives centered on investigations of reductions in plasma cholesterol levels and regression of atherosclerosis, using the unique pigeon and monkey models. By the 25th year, the SCOR included new initiatives investigating mechanisms of lipoprotein metabolism. Ongoing research was then directed into 2 NHLBI-supported program projects. One, led by Dr. Lawrence Rudel, focused on biochemistry of lipoproteins, and the other, led by Dr. Clarkson, involved further investigations using cynomolgus monkeys. Ultimately, as many as 200 papers were published as a result of the investigations conducted over the life of the WFUSM SCOR.

New faculty recruited to BGSM in the 1980s provided a bridge between these comparative studies and parallel activities in clinical research. Drs. John Crouse III and William Hazzard were leaders in assessment of risk factors, lipoproteins, and the incidence of cardiovascular disease in human populations. Ground-breaking studies of the effects of estrogen in a monkey model of postmenopausal women have been carried out by anthropologist Jay Kaplan and veterinarians Michael Adams and Koudy Williams, in collaboration with cardiologist David Herrington, surgeon Randolph Geary, and veterinary pathologist J. Mark Cline, among others.

The work done by these scientists and their many collaborators and colleagues has laid the foundation for new research directions at WFUSM. Some of these new initiatives include studies of nutritional and pharmaceutical alternatives to estrogen therapy; genetic and molecular studies of the risk factors for cardiovascular disease; and neurobiologic and behavioral approaches to the diseases of aging.

THE STROKE CENTER: CEREBROVASCULAR RESEARCH AT WFUSM

Before the early 1960s, a diagnosis of stroke was essentially a death sentence; physicians believed that nothing could be done for such patients. In the early 1960s, the existence of transient ischemic attacks began to be recognized, and, with that knowledge, a sense that perhaps strokes could be treated, and maybe even prevented.

Meanwhile, at BGSM, 2 new faculty recruits were destined to play a large role in developing the institution's stroke programs: Dr. James Toole, who came from the University of Pennsylvania in 1962 to chair the Department of Neurology; and Dr. William McKinney, who in 1963 began the Sonics Center for the use of ultrasound for imaging the brain. Nationwide, the field of stroke research was energized by a report from the American Heart Association task force, chaired by Dr. Michael DeBakey. The report led to the initiation of the National Institute for Neurological Diseases and Blindness and thus to the establishment of national stroke centers.

When Dr. Toole arrived in Winston-Salem in 1962, BGSM had approximately 50 faculty members. Basic and clinical scientists had offices next to each other. The faculty would meet daily for lunch, and engage in brainstorming and discussions of each other's projects. The meetings were informal, never scheduled by appointments or held in a conference room.

Neurologists at BGSM in this period were cross-disciplinary before the term came into vogue. For example, unlike their colleagues elsewhere across the country, BGSM neurologists were performing arteriograms and electroencephalograms themselves, which was more efficient and produced more rapid diagnoses than procedures followed elsewhere. As a result, there was an early connection between these neurologists and members of the Department of Surgery because of their shared surgical expertise. Dr. Merrill Spencer along with Dr. Howard Green and Dr. Carlos Rapela, developed the electromagnetic flow meter and the first ultrasonic imaging system. Ultrasound imaging became a cerebrovascular diagnostic tool, used to visualize the brain and the arteries. The use of a retrofemoral technique for arteriograms was perfected by Dr. Richard Janeway, Dr. Henry Miller, and the Department of Anesthesia for patients who needed only local or regional anesthesia--a BGSM innovation that is still not the normal practice in other in stitutions.

These interlocking threads of expertise and personal interactions--the current term would be cross-talk--were the genesis of the multi-departmental Stroke and Neurosciences Study Group in 1964. The group assembled an application for the first announcement of funding for the national stroke centers, and, in 1965, BGSM became the third institution to be awarded a stroke center, with Dr. Toole as director.

By the l970s, the Stroke Center had assumed a national leadership role. In 1975, the world's first sonics graduate courses provided cutting-edge instruction in the burgeoning area of clinical ultrasonography. This was followed by the first national medical meeting to be held in Winston-Salem--the Association of Ultrasound in Medicine, whose president (1974-1976) was Dr. McKinney. On the clinical front, the establishment of the Neurobehavioral Unit in 1974, resulting ultimately in the Section of Neuropsychology, united the expertise of psychiatrists, psychologists, and neurologists in the area of stroke patients. This clinical innovation was recognized in 1975, when Mainliner magazine named the North Carolina Baptist Hospital as one of the nation's 7 best medical centers for treatment of neurologic disorders.

Clinical-trial research in cerebrovascular disease burgeoned at BGSM during the next decade. In 1985, the Asymptomatic Carotid Atherosclerosis Study (ACAS) began, with the operations center at BGSM and Dr. Toole as the principal investigator of this multisite, 9-year trial funded by the National Institute for Neurological Diseases and Stroke. Subjects were asymptomatic individuals who had suffered transient ischemic attacks and had 60% or more stenosis of the carotid artery. The results of ACAS were that carotid endarterectomy, combined with aspirin therapy and risk-factor reduction, proved superior to aspirin therapy and risk-factor reduction alone in preventing ipsilateral stroke. (4) The combined perioperative and arteriographic-surgery-related mortality rate was only 2.3%, a reflection of the carefully selected surgical teams participating in ACAS. This was also the first randomized clinical trial at BGSM with a dedicated epidemiologist and biostatistician, a model now commonly adopted at this institutio n and elsewhere.

Also in 1985, BGSM became a participating site in the Atherosclerosis Risk in Communities (ARIC) cohort study, funded by the NHLBI. Dr. Toole was one of the principal investigators of this 5-site observational study. The ARIC study has resulted in numerous publications, adding greatly to our understanding of the natural history and pathogenesis of cardiovascular and cerebrovascular disease in a free-living population of men and women. (5) In 1988, BGSM was named a participating site in another cohort study funded by the NHLBI, the Cardiovascular Health Study, a longitudinal study of cardiovascular risk factors in 5,201 older subjects recruited from four sites. Like the ARIC study, the Cardiovascular Health Study has also been a rich source of important public-health information up to the present, (6) and similarly has benefited from collaborators in the fields of cardiology, neurology, internal medicine, epidemiology, and others.

The most recent clinical trial focused on stroke at Wake Forest University School of Medicine (as it was renamed in 1997) is also the most ambitious. With over 50 sites, the Vitamin Intervention for Stroke Prevention (VISP) clinical trial is the biggest trial ever done with a nutritional focus. Funded by Neurological Diseases and Stroke (with Dr, Toole as the principal investigator and the operations center at WFUSM), VISP seeks to determine the effects of high-dose folic acid therapy and treatment with supplemental vitamins [B.sub.6] and [B.sub.12] on risk of recurrent stroke. The premise is that reducing elevated levels of plasma homocysteine will reduce risk of stroke. (7) A total of 3,680 subjects are now enrolled, and will be followed up through December 2003.

The expertise in cerebrovascular disease at WFUSM has led to interesting offshoots. In one intriguing development, the late Dr. Arthur Link (a historian and world-renowned expert on Woodrow Wilson), joined Dr. Toole to form the Working Group on Disability in US Presidents. They held several workshops in 1995 and 1996 at locations such as the Carter Center (with former president Jimmy Carter) at Emory University, Wake Forest University (with former president Gerald Ford), and the White House Conference Center (with President Bill Clinton). (8)

Predictions for the future for cerebrovascular disease research at WFUSM revolve around many of its past strengths. The increasing sophistication of computer-assisted imaging techniques used in clinical and research studies of the brain will be part of important contributions in the future, and serves as a focal point for WFUSM experts in neurology, radiology, cardiovascular disease, and epidemiology, among others. Future plans for the VISP cohort may include genetic investigations and examinations of dementia, areas of research strength at WFUSM, with its Center for Human Genomics and the Sticht Center on Aging and Rehabilitation.

CANCER RESEARCH: GROWTH AND DEVELOPMENT

Even before the NIH began to fight the war on cancer, researchers at BGSM were active in the field. Efforts began when Dr. Charles Spurr, who pioneered the use of nitrogen mustard as chemotherapy for lymphoma, joined BGSM in 1957. His interest in training medical oncologists in the growing number of cancer therapeutic options led to the development and funding of a clinical cancer training grant in 1966, directed by Dr. Spurr. Growing interest from Dr. Manson Mead, then dean of BGSM, and others stimulated a successful application to the National Cancer Institute (NCI) for a planning grant. Then, in 1972, one year after the National Cancer Act mandated the institution of nationwide cancer centers through the NIH, BGSM was named as a specialized clinical cancer research center, with Dr. Spurr as its leader.

The designation as a cancer center helped to solidify the growing regional referral network that practitioners at BGSM had built in North Carolina and throughout the contiguous states. In 1976, this network was formally designated the Piedmont Oncology Association (POA). The POA's goals were to maintain a regional outreach and referral program, and, in addition, to provide a vehicle to organize regional clinical trials in oncology research among community physicians. (9)

In part because of the training program BGSM had begun, the POA grew to a remarkable 106 members in a referral area of 90,000 square miles containing more than 9 million residents. It is a measure of its success that in 1981 the POA was named a regional cooperative group by the NCI. This designation continued until the NCI instead shifted support to community-based clinical oncology trial programs. Fortunately, the POA's long-standing focus on community oncology programs served it in good stead, and in 1987, the NCI awarded funds to the Southeast Cancer Control Consortium, originally consisting of 11 communities from the POA (later expanded to 14). The focus of the consortium, as in other areas of the country, changed to emphasizing cancer prevention rather than improving cancer treatments. (10)

New leadership came to BGSM's cancer initiatives in 1982, when Dr. Spurr retired and Dr. Robert Capizzi became the leader of the Cancer Center. Dr. Capizzi continued the growth of oncology programs by establishing a leukemia service in 1986 and a bone marrow transplantation program in 1989. The following year, the NCI recognized the Cancer Center as a Comprehensive Cancer Center, 1 of only 37 in the country. The designation is awarded only to centers with a multifaceted approach that includes cancer prevention and control programs, clinical trials, and community outreach.

The current director of Wake Forest University's Comprehensive Cancer Center, Dr. Frank Torti, arrived in 1993 from Stanford Universky, and established the Department of Cancer Biology, an academic locus for Cancer Center members who now spanned the fields of hematology, immunology, pharmacology, transplantation, surgery, and the growing discipline of molecular biology. The Comprehensive Cancer Center designation was recently renewed by the NCI for another 5-year period.

Substantial growth marks the next phase of the Wake Forest University Comprehensive Cancer Center. A 4-floor, 175,000-square-foot outpatient Comprehensive Cancer Center is being built next to the 830-bed tertiary care Wake Forest University Baptist Medical Center complex, which will house Centers of Excellence in most oncologic specialties. The Cancer Center's most recent accomplishment was ranking 23rd in the nation among cancer centers in the US News and World Report annual survey.

The legacy of the POA and its community outreach has only grown over time. Wake Forest University cancer specialists now participate in more than 200 active protocols, and are affiliated with numerous national cooperative clinical-trial research groups, among them the Cancer and Leukemia Group B and the National Surgical Adjuvant Breast and Bowel Project. In 1999, Dr. Edward Levine was awarded a Research Base for Cancer Treatment and Control Grant, the only one awarded to a cancer center for both clinical trials and cancer control efforts. This expands the efforts of Wake Forest University into cities within the region, encompasses a substantial minority population, and serves a total population of more than 10 million residents.

The explosion of information in molecular biology and the addition of a Human Genomics Center at Wake Forest University in 2000 led to new research goals centered on ways to control and prevent DNA damage that results in cancer. An NIH training grant awarded in 2000 incorporates doctorate-level training in cancer biology into these research initiatives, and helps ensure that new scientists will continue the marked progress seen in studies of cancer at the molecular and cellular level.

By 2000, researchers of the Wake Forest University Comprehensive Cancer Center had doubled the NCI funding flowing to the institution. In cancer control alone, 32 funded projects are ongoing, encompassing breast, cervical, prostate, ovarian, colon, and skin cancer. New basic research led to increased wet-lab space that more than doubled the previous space available.

The physical setting of Wake Forest University's Comprehensive Cancer Center has certainly changed since Dr. Spurr's day, and many technical and treatment innovations have improved patients' lives since that time, as well. But despite the tremendous growth in the last 3 decades, the spirit of interdisciplinary activity in the service of better health--and the quest to conquer cancer in its many forms--are fundamental driving forces that he would recognize immediately.

Acknowledgments. I would like to thank Dr. Thomas B. Clarkson (arteriosclerosis section); Dr. James Toole, Ms. Elizabeth Sides (cerebrovascular section); Dr. Robert Cooper and Dr. Todd Thornburg (cancer section).

References

(1.) McCollum S: "Like a Star Sapphire": Reflections on basic science at Wake Forest University School of Medicine. South Med J 2002; 95:1243-1247

(2.) Clarkson TB, Prichard RW, Bullock BC, et al: Pathogenesis of atherosclerosis: some advances from using animal models. Exp Mol Pathol 1976; 24:264-286

(3.) Clarkson TB, Lofland HB, Bullock BC, et al: Atherosclerosis in some species of New World monkeys. Ann NY Acad Sci 1969; 162:103-109

(4.) Executive Committee for the Asymptomatic Carotid Atherosclerosis Study: Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273: 1421-1428

(5.) Liao D, Cooper L, Cai J, et al: Presence and severity of cerebral white matter lesions and hypertension, its treatment and its control: The ARIC study. Stroke 1996; 27:2262-2270

(6.) Kuller LH, Shemanski L, Psaty BM, et al: Subclinical disease as an independent risk factor for cardiovascular disease. Circulation 1995; 92:720-726

(7.) Spence JD, Howard VJ, Chambless LE, et al: Vitamin Intervention for Stroke Prevention (VISP) trial: rationale and design. Neuroepidemiology 2001; 20:16-25

(8.) Toole JF, Link AS, Smith JH: Disability in US Presidents report. Recommendations and commentaries by the Working Group. Arch Neurol 1997; 54:1256-1264

(9.) Muss HB, Richards F II, Cooper MR, et al: Chemotherapy versus chemoimmunotherapy with methanol extraction residue of Bacillus Calmette-Guerin (MER) in advanced breast cancer: a randomized trial by the Piedmont Oncology Association. Cancer 1981; 47:2295-2301

(10.) Paskett ED, Cooper MR, DeGraffinreid CR, et al: Community Clinical Oncology Program as a recruitment vehicle for cancer control research. The Southeast Cancer Control Consortium experience. NC Med J 1995; 56:283-286

From the Department of Internal Medicine/Cardiology and the Women's Health Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC.

Reprint requests to Karen Potvin Klein, MA, Department of Internal Medicine/Cardiology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157.