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Monroe E. Wall 1916-2002
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64

In Memoriam

Monroe E. Wall 1916-2002

Monroe E. Wall, Ph.D., a renowned natural products chemist whose discoveries defined the utility of botanical sources for cancer therapeutics, died of heart and kidney failure on July 6, 2002 in Chapel Hill, North Carolina. Dr. Wall was just three weeks shy of his 86th birthday at the time of his death. A dedicated and passionate investigator -- who for more than 40 years was a commanding presence in the Research Triangle Park, NC, scientific community -- Dr. Wall had worked continuously with his laboratory group at Research Triangle Institute (RTI) until just two weeks before his death.

Dr. Wall and Mansukh C. Wani, Ph.D., his colleague for more than 35 years, are credited as co-discoverers of the anticancer drugs paclitaxel, from the Pacific yew tree (Taxus brevifolia Nutt., Taxaceae), and camptothecin, from xi shu or "happy tree" (Camptotheca acuminata Decne., Cornaceae), a native Chinese tree that had been introduced to the United States. These discoveries were among hundreds of natural compounds identified by Dr. Wall and Dr. Wani.

Paclitaxel and camptothecin particularly stand out because each agent reveals previously unknown ways of killing cancer cells, and emphasizes the utility of plants as a source of drugs. In this post-genomic period of biology, where scientists are faced with thousands of potential drug targets that seek small molecule ligands, the contribution of paclitaxel and camptothecin to identify novel anticancer strategies cannot be understated. In the last century, only two other pairs of discoveries are of the same magnitude: the discovery of histamine H2 antagonists and b1-adrenoceptor antagonists, which earned Sir James W. Black, the 1988 Nobel Prize in Medicine, and the discovery of adrenergic and cholinergic agonists, which earned the 1936 Nobel Prize in Medicine for Sir Henry Hallett Dale and Otto Loewi.

Paclitaxel and camptothecin share interesting, yet distinct, stories. Originally isolated and characterized in 1971, the anticancer mechanism of action of paclitaxel was not evident until 1979 when a young New York scientist, Susan Band Horwitz, Ph.D., asked for a sample of the new drug. Now president of a leading cancer research society, the American Association for Cancer Research, the then-junior Dr. Horwitz demonstrated that paclitaxel uniquely promoted the overpolymerization of microtubules within cancer cells, effectively inhibiting cell division. Paclitaxel is now known as Taxol¨, the original generic name coined by Wall and Wani, which was selected by Bristol-Myers Squibb as the trade name of this anticancer drug.

J. Paul Eder, M.D., clinical director of the experimental therapeutics program at the Dana-Farber Cancer Institute, calls the discovery of paclitaxel, "One of the most significant clinical advances in cancer therapy in the last decade. Paclitaxel has increased the cure rate of metastatic ovarian cancer, breast cancer, and has important activity in lung cancer. It is essential to note that it took nearly 25 years from the time of Dr. Wall's initial discovery until the first clinical trials of paclitaxel began, underscoring the difficulties in bringing new agents to the clinic."

In contrast, camptothecin was initially unsuccessful as an anticancer drug due to severe toxic reactions during human trials sponsored by the National Cancer Institute (NCI) in the early 1970s. However, camptothecin has led to two semisynthetic derivatives, topotecan (Hycamtin®, manufactured by GlaxoSmithKline, Philadelphia) and irinotecan (CPT-11; Camptosar®, by Pharmacia & Upjohn Company, Peapack, New Jersey) as well as a number of other camptothecins currently in clinical development.

The development of camptothecins is an outstanding example of the partnership between folk medicine and modern synthetic chemistry because the naturally occurring molecule would have failed as a drug if not for the intervention of medicinal chemistry. In fact, the discovery of camptothecin (1966) preceded that of paclitaxel (1971). A. Robert Jeffcoat, Ph.D., RTI director of bioorganic chemistry research, credits Dr. Wall's perseverance in the realization of camptothecins as therapeutic agents.

"Without Dr. Wall's persistence," Dr. Jeffcoat said, "camptothecin would likely have been discarded by NCI, and the discovery of the mode of action by which it prevents cancer growth would have been significantly delayed."

It was not until 1985 that the laboratory of Leroy F. Liu, Ph.D., who was then at Johns Hopkins University, demonstrated conclusively that camptothecin acted to create an unusual type of DNA damage in cancer cells by trapping the enzyme topoisomerase I during its normal action in regulating DNA structure.

Monroe Wall was born on July 25, 1916 and grew up in Newark, New Jersey, earning his bachelor's, master's, and doctoral degrees from Rutgers University. His early work focused on the nutritional requirements of the tomato plant, the crop most responsible for New Jersey's designation as The Garden State. In 1941, Dr. Wall married his wife, Marian, and joined the U.S. Department of Agriculture (USDA) in Philadelphia where he researched agricultural sources for products essential to the war effort, such as alternatives to rubber. During the 1950s most of his research focused on the search for phytosteroids that could serve as precursors for cortisone. In doing so, he collected thousands of plant extracts. A serendipitous 1957 visit to USDA by NCI pioneer, Jonathan Hartwell, M.D., changed Wall's focus in a way that would chart the next 40 years of his efforts.

Hartwell had been a student of folk medicine and recognized that nature might also provide treatments for cancer. Dr. Hartwell seized upon the late 19th century folk use of the mayapple (Podophyllum peltatum L., Berberidaceae) by the Penobscot Indians of Maine for cancer. The same plant was also used by physicians in Louisiana and Mississippi for venereal warts. One of its components, podophyllotoxin, was later demonstrated to have anticancer activity in mice. In his role at the Cancer Chemotherapy National Service Center, Hartwell convinced Wall to send him 1,000 ethanolic plant extracts for antitumor activity testing. More than a year later, word came back that one possessed particularly potent activity: an extract from Camptotheca acuminata.

Since anticancer drug discovery was not a focus of the USDA, Wall's drive to identify this plant's anticancer component was tempered until July 1960, when he was recruited to establish a chemistry program and natural products group at the newly created Research Triangle Institute. From this beginning, RTI has become an internationally recognized research park, employing more than 40,000 in government, pharmaceutical, chemical, and computing research organizations. Wall recruited to RTI a number of young scientists, including Wani, many of whom went on to their own distinguished scientific careers. C. Edgar Cook, Ph.D., who worked with Wall and Wani on camptothecin and later directed the RTI Chemistry and Life Sciences unit that Dr. Wall founded, fondly describes the "Monroe Doctrine" as the basis of Wall's success: "Get good people, support them with good facilities, do good science, work hard, and keep doing it."

Another Wall recruit who also headed the same unit, F. Ivy Carroll, Ph.D., remarked, "Dr. Wall was much more than a scientist who conducted natural products research. His colleagues here at RTI and scientists all over the world have been inspired by his keen managerial ability combined with his people skills and warm concern for others."

Certainly, Dr. Wall's scientific accolades and hard-nosed, no-nonsense exterior belied the warm heart within. Jane Righter, his administrative assistant for the last 12 years of his career, recalled, "He gave regularly to charities and I have seen him offer loans to postdoctoral fellows when they first arrived at RTI, helping them before they received their first paycheck."

Susan Mayton, another close administrative colleague, remarked, "To the world, Dr. Wall was a brilliant scientist, but to those of us who were privileged to see him on a personal level, he was a warm and caring gentleman. That a man of his stature would have time to express sympathy over the loss of my mother or concern over my grandson's leukemia touched my heart deeply."

In fact, as Drs. Wall and Wani received the 2000 Charles F. Kettering Prize for Cancer Research, the highest honor in the field of cancer research, Wall remarked that the knowledge that his discoveries saved or improved the quality of life of, literally, millions of people was far more satisfying than any award or prize.

This past summer, Dr. Wall's contributions continued to be recognized. Over a year in development, RTI announced plans in July to carry on his legacy by creating the Wall and Wani Fellowships in Natural Products Research. These fellowships will to enable young scientists from around the world to train with Dr. Wall's group, now led by Dr. Wani and Nicholas H. Oberlies, Ph.D. (see http://www.rti.org/wallwani).

In August, with Wani and Oberlies in attendance, representatives from the U.S. Forest Service, the USDA, and the American Society of Pharmacognosy (ASP) held a plaque dedication ceremony in Washington state near the site of the original 1962 collection of Taxus brevifolia for the NCI screening program. ASP also held the 3rd annual Monroe E. Wall Symposium as part of its 2002 annual research meeting, which was conducted, appropriately, at Wall's alma mater, Rutgers University.

John M. Pezzuto, Ph.D., dean of Purdue University Schools of Pharmacy, Nursing, and Health Sciences reflected many shared sentiments in stating, "Having been affiliated with Monroe over the last 15 years has been one of the greatest honors of my life. Everyone recognizes him as a major icon of natural product drug discovery, but relatively few have had the privilege of knowing his incredible wit, sense of humor, and single-minded devotion toward beating the cancer problem. His passing is a great loss to society and the scientific community; I miss him greatly."

--David J. Kroll, Ph.D.

Senior Research Pharmacologist

Natural Products Laboratory

Center for Organic and Medicinal Chemistry

Research Triangle Institute

with contributions from Dr. Oberlies and Dr. Wani

Other tributes to Dr. Wall may be found online at <www.rti.org> and the July 11, 2002 issue of The New York Times. The website of the American Society of Pharmacognosy <www.phcog.org> includes links to both.