Research Overview
Major Research Programs
Introduction of Computers into Medicine
DNA Synthesis and Cell Cycle
Expanding Cancer Chemoprevention Studies
Dietary Calcium for Human Chemoprevention
The First Automated Correlation of Medical Information and Introduction of Computers Into Medicine.
When Dr. Lipkin began his research career as a postdoctoral fellow at the Comell University Medical College, he had the good fortune to develop and carry out a most unusual study. It evolved from extracurricular conversations he had with his mentor Dr. James Hardy in the Department of Physiology at Cornell. Those discussions led them to explore an area that was quite novel at that time, completely outside the scope of medical research and practice, and far removed from the subject of physiology. They asked the following question: Could information used in medical research and practice be analyzed by methods that were automated, in order to increase and improve its utilization by a wide variety of colleagues in disparate scientific disciplines.
In that era of medical research and practice as well as in other scientific fields, the volume of new and useful information that was beginning to emerge was increasing more rapidly than before, and the flow and storage of the information had to be managed by individuals without the assistance of any particular technology. By the 1950s the volume of new data emerging in many areas of science had begun to accelerate dramatically. They decided to explore this interesting new subject by attempting to automate information that was used regularly in medical research and practice.
They carried out a study demonstrating for the first time that information derived in laboratory and clinical medicine could be recorded, analyzed, and correlated by automatic mechanical methods (Science 125: 551, 1957).
On the basis of those findings, Dr. Lipkin then carried out the first study that used an actual electronic computer to process and analyze medical information. Although difficult to understand today, no computers were available at any medical institution, and he was fortunate in gaining access to the first computer then being developed at the RCA Corporation for financial and commercial applications. This became possible because Dr.Vladimir Zworykin became interested in this topic. Dr. Zworykin had previously developed the electron microscope and the television tube at the RCA Corporation where he had recently retired as Vice President for Research, and he had recently come to The Rockefeller Institute adjacent to the Cornell Medical School. Through his efforts, they carried out and published the first actual use of a computer to process and analyze medical information (Archives of Internal Medicine 108: 56, 1961).
Their studies published in Science, the Archives and several others that followed, originated the use of computers in the medical sciences, and facilitated the eventual application of computers to many scientific areas that are routinely used today. When their studies were first published they were completely novel and outside of scientific activities underway at the time. When first published, they believed it would take decades for these studies to develop into practical advances involving computers in medicine, and as anticipated advances slowly but significantly took place
The first of these was the automation of scientific literature and bibliography, accomplished about 10 years later at the U.S. National Library of Medicine, leading to Medline and other literature and bibliographic search applications. Soon after that came the automatic recording and compilation of laboratory and other clinical data obtained from patients, automation applied to medical instrumentation, and the further development of computer assisted applications to the wide variety of diverse topics in medical research, laboratory, hospital and outpatient services that we see today.
These early studies became well-known worldwide. Several historians wrote generously about the activities. The computer historian Josef Schmid described the article in Science as having originated the automation of information in the medical sciences, and the field of computer medicine (Schimd J, Health Communications and Informatics 6: 352, 1980).
Dr. Saul Jarcho, a well known and prolific medical historian during that period very kindly referred to this work as a landmark development, and compared the first automation of medical information to work that had been carried out by Giovanni Battista Morgagni, who published the earliest comprehensive recording of medical information and its relationship to human disease (Morgagni G, DeSedibus et Causis Morborum per Anatonem Indagatis, 1761). Dr. Jarcho wrote: I think we can trace a line of historical connection between the Morgagnian correlation exemplified in these indices and the recent use of calculating machines as adjuvants to medical diagnosis (Jarcho S., Bulletin of the History of Medicine 35: 489,1961).
The early studies cited above illustrate extracurricular activities of a young medical researcher who had the opportunity to work in an outstanding environment. Those efforts resulted in the introduction of computers medicineand were followed by the widespread application of computers to the processing of medical information, with computer applications to patient and laboratory services and medical instrumentation as seen today.
Identification of DNA Synthesis and Cell Cycle Phases in Humans
During that period in the Departments of Physiology and Medicine at Cornell, Dr.Lipkin had mainly focused attention on a newly emerging area in the biology of cell development: it had recently been demonstrated that epithelial cells lining several organs of the body did not have a quiescent life cycle, but were actively growing and reproducing and were being replaced more rapidly than previously had been suspected.& In particular, cells in the intestine appeared to renew quite rapidly compared to cells in other organs (Amer J. Anat 106: 247, 1960; Exp. Cell Res. 17: 420, 1959). Again, he had the good fortune to work with a superb scientist, Dr. Henry Quastler, at the Brookhaven National Laboratory just outside of New York City. They carried out the first study of cell proliferation kinetics in mouse colon, quantifying for the first time the flow of cells through the phases of the cell cycle together with the rapid and orderly differentiation, maturation and senescence of epithelial cells as they migrated from the crypt base to the mucosal surface (J. Clin Invest. 41: 141, 1962).
Because of those observations it was then possible to carry out further translational studies in humans, that provided the first measurements of DNA synthesis and cell proliferation kinetics in human subjects (Nature 195: 175, 1962). Those studies defined for the first time the spatial distributions of proliferating and differentiating cells in all regions of the human gastrointestinal tract, and the kinetics of rapid epithelial cell proliferation, differentiation, migration, extrusion and turnover in the colon and other gastrointestinal organs (Nature 195: 175, 1962; J Clin Invest 42: 767, 1963; Gastroenterology 45: 721, 1963). The studies identified in human subjects the progression of epithelial cells through proliferative, differentiation, and senescence phases of their life cycle.
Those interesting findings led Dr. Lipkin and his colleagues to carry out a further series of studies bringing together new findings they had identified in human subjects (J Clin Invest 42: 1922, 1963; J Natl Cancer Inst 36: 849, 1966; J Natl Cancer Inst 44: 175, 1970; Cancer 35: 413, 1975); and findings they observed in animal models (Cancer Res 33: 940, 1973). The results both in humans and in mice led them to propose the first multistep molecular model of colonic tumor development (Cancer 34: 878, 1974) based on a stepwise accumulation of errors of epithelial cell proliferation and differentiation; this provided a model for human colonic carcinogenesis that was later expanded by numerous investigators to include mutational and cell-cycle regulating events. During those early studies, they also found expanded distributions and increased size of proliferative compartments in the epithelial lining of stomach and esophagus, in diseases predisposing to gastric and esophagical cancer (J Natl Cancer Inst 38: 615, 1967; J Natl Cancer Inst 42: 9, 1969; J Natl Cancer Inst 48: 1567, 1972; J Natl Cancer Inst 79: 1241, 1987).
In addition to multistep colonic carcinogenesis and further cell cycle studies of cell growth and development, some of these early observations have also been of interest in other studies, eg, a top-down migration of colonic adenomatous cells carrying APC mutations (Cancer Res 42: 4280, 1982; Proc Natl Acad Sci 98: 2640, 2001) and precancerous hyperproliferative atrophy in prostate gland (Amer J of Path 155: 1985, 1999).
Expanding Human Cancer Chemoprevention Studies Worldwide
Following those studies it was quite interesting to see two different areas of research join together to create a new field of clinical investigation. The findings on cell growth and maturation noted above, had evolved separately from other new and exciting studies that were beginning to identify natural and pharmaceutical compounds capable of inhibiting tumor development.& Dr. Lipkin surveyed recent accomplishments in the latter field and published them in a first textbook summarizing chemoprevention studies: Inhibition of Tumor Induction and Development (1981).& Although preclinical animal model studies were then being carried out, no human studies had been carried out to evaluate new potential chemopreventive agents in human subjects, because it was very difficult to initiate human studies of this type. The reason was that large numbers of experimental subjects had to be studied for long durations using cancer as an endpoint, in order to measure the effect of a chemopreventive agent given to human subjects.
From his experience in studies of cell growth and maturation, Dr. Lipkin knew that many new findings on normal and abnormal cell growth and development were becoming available, and these could be standardized and studied more readily than the evolution of cancer itself in human subjects. He had also developed the first comprehensive registry of patients with multiple diseases increasing their risk for colon cancer, from which human subjects could be encouraged to enter clinical trials of chemopreventive agents (Prev Med 9: 335, 1980).
With these two new resources available he proposed (Perspectives in Cancer Research, Cancer Res 48: 235, 1988) that human chemoprevention studies not be carried out initially with cancer as the endpoint. Instead he proposed that biomarkers of abnormal cell growth and maturation that were associated with the development of tumors be introduced into clinical chemoprevention trials, initially studying these pretumor endpoints in smaller groups of human subjects for shorter durations, in order to begin to measure the effects of chemopreventive interventions in the subjects. Interventions demonstrating efficacy in normalizing early biomarkers relevant to tumor development could then become candidates for larger population studies of longer duration, using benign, and later malignant tumors as endpoints. This approach was carried out in a large number of NCI sponsored studies and worldwide by many investigators, facilitating a broad expansion of human chemoprevention clinical trials, and markedly increasing clinical investigators' ability to study large numbers of chemopreventive agents, thus enabling many nutritional and pharmacological agents to be rapidly studied in human populations (Adv. In Cancer Res. 78: 199, 2000).
Introducing Dietary Calcium for Human Cancer Chemoprevention
In beginning to test this new multistep approach to human chemoprevention clinical trials, the agent chosen has now successfully completed most of the testing steps noted above, ie, supplemental dietary calcium used as a potential chemopreventive agent to inhibit colon cancer. Dr. Lipkin and colleague carried out an initial study giving increased dietary calcium to human subjects: findings showed normalization of a colonic proliferative biomarker in the study subjects (New Engl J Med 22: 1381, 1985); this was later validated by other larger randomized clinical trials in which calcium had the same effect. (Ann of NY Acad of Sci 889: 120, 1999). Following earlier studies (J of Natl Cancer Inst 72: 1323, 1984; Calcium, Vitamin D and Prevention of Colon Cancer, 1991;) and the initial study of calcium supplementation in human subjects (New Engl J Med 22: 1381, 1985) other large clinical trials studied the inhibition of colonic adenoma recurrence, and demonstrated significant inhibition of adenoma recurrence after increasing dietary calcium intake (eg, Digestion 59: 148, 1998; N Engl J Med 340: 101, 1999; The Lancet 356: 1300, 2000).
Further studies in murine models showed utility of calcium in decreasing colonic tumors in the presence of strong genetic predisposition to this disease (Cancer Research 58: 5713, 1998; Frontiers in Cancer Res, 2004), as well as when tumors were induced by dietary factors (Carcinogenesis 22: 1871, 2001). Many studies in rodent models as well as human studies have thus shown increased dietary calcium's ability to reduce colonic tumor development, which now appears well established.
Various reviews have summarized mechanisms through which increased dietary calcium inhibits tumor development in the colon.& Earlier observations noted decreased hyperproliferation of colonic epithelial cells, increased differentiation and maturation of colonic epithelial cells, and reduced cytotoxicity of fecal water (Calcium, Vitamin D and Prevention of Colon Cancer 1991; J. of Cell. Biochem. 22: 65, 1995; Ann of NY Acad of Sci 889: 120, 1999). Mechanisms leading to antiproliferative, differentiation-inducing and apoptotic effects of calcium also have been described and reviewed (Nature Rev. Cancer 3: 1, 2003).
References Cited in the Order They Appear in the Text
Lipkin, M., Hardy, J.D. Differential Diagnosis of Hematologic Diseases Aided by Mechanical Correlation of Data. Science, 125: 551, 1957.
Lipkin, M., Engle, R.L, Davis, B.J., Zworykin, V.K., Ebald, R., Sendrow, M., Berkley, C. Digital Computer as Aid to Differential Diagnosis. Archives of Internal Medicine 108: 56, 1961.
Lipkin, M., Quastler, H.& Cell population kinetics in the colon of the mouse.& J Clin Invest 41: 141, 1962.
Lipkin, M., Sherlock, P., Bell, B.& Generation time of epithelial cells in the human colon.& Nature 195: 175, 1962.
Lipkin, M., Bell, B., Sherlock, P.& Cell proliferation kinetics in the gastrointestinal tract of man.& I. Cell renewal in colon and rectum.& J Clin Invest 42: 767, 1963.
Lipkin, M., Sherlock, P., Bell, B.& Cell proliferation kinetics in the Gastrointestinal tract of man.& II. Cell renewal in stomach, ileum, colon and rectum. Gastroenterology& 45: 721, 1963.
Deschner, E., Lewis, C., Lipkin, M.& In vitro study of human rectal epithelial cells. I. Atypical zone of 3H thymidine incorporation in mucosa of multiple polyposis.& J Clin Invest 42: 1922, 1963.
Deschner, E., Lipkin, M., Solomon, C.& Study of human rectal epithelial cells In vitro.& II.& 3H thymidine incorporation into polyps and adjacent mucosa.& J Natl Cancer Inst& 36: 849, 1966.
Deschner, E., Lipkin ,M.& Study of human rectal epithelial cells in vitro.& III. RNA, protein and DNA synthesis in polyps and adjacent mucosa. J Natl Cancer Inst 44: 175, 1970.
Deschner, E.E., Lipkin, M.& Proliferative patterns in colonic mucosa in familial polyposis.& Cancer 35: 413, 1975.
Thurnherr, H., Deschner, E.E., Stonehill, E.H., Lipkin, M.& Induction of adenocarcinomas of the colon in mice by weekly injection of 1,2 dimethylhydrazine. Cancer Res 33: 940, 1973.
Lipkin, M.& Phase 1 and Phase 2 Proliferative lesions of colonic epithelial cells in diseases leading to colon cancer.& Cancer 34: 878,1974.
Bell, B., Almy, T.P., Lipkin, M.& Cell proliferation kinetics in the Gastrointestinal tract of man.& III. Cell renewal in esophagus, stomach and jejunum of a patient treated with pernicious anemia.& J Natl Cancer Inst& 38: 615, 1967.
Winawer, S.J., Lipkin, M.& Cell proliferation kinetics in the gastrointestinal tract of man.& IV. Cell renewal in the intestinalized gastric mucosa.& J Natl Cancer Inst 42: 9, 1969.
Deschner, E.E., Winawer, SJ, Lipkin, M.& Patterns of nucleic acid and protein synthesis in normal human gastric mucosa and atrophic gastritis.& J Natl Cancer Inst 48: 1567, 1972.
Yang, G-C., Lipkin, M., Yang, K., Wang, G-Q., Li, J-Y., Yang, C.S.,Winawer, S., Newmark, H., Blot, W.J. and Fraumeni, J.F., Jr.& Proliferation of esophageal epithelial cells among residents of Linxian, People's Republic of China.& J Natl Cancer Inst 79: 1241, 1987.
Lightdale, C., Lipkin, M., Deschner, E.& In vivo measurements in familial polyposis:& Kinetics and location of proliferating cells in colonic adenomas. Cancer Res 42: 4280, 1982.
Zedeck, M., Lipkin, M., eds.& Inhibition of Tumor Induction and Development. New York:& Plenum Publishing Corp, 233 pp, 1981.
Lipkin, M., Scherf, S., Schecter, L., Braun, D., Jr.& Memorial Hospital Registry of population groups at high risk for cancer of the large intestine: Age of onset of neoplasms. Prev Med 9: 335, 1980.
Lipkin, M.& Biomarkers of increased susceptibility to gastrointestinal cancer. New application to studies of cancer prevention in human subjects. Perspectives in Cancer Research.& Cancer Res 48: 235, 1988.
Lipkin, M., Newmark, H.& Effect of added dietary calcium on colonic epithelial cell proliferation in subjects at high-risk for familial colon cancer.& New Engl J Med 313: 1381, 1985.
Lipkin M.& Preclinical and Early Human Studies of Calcium and Colon Cancer Prevention.& Annals of the New York Academy of Sciences 889: 120, 1999.
Calcium, Vitamin D, and Prevention of Colon Cancer, ed: Lipkin, M., Newmark, H.L., Kelloff, G. CRC Press, 435 pp, 1991.
Yang, K., Edelmann, W., Fan, K.H., Lau, K., Leung, D., Newmark, H., Kucherlapati, R. and Lipkin, M.& Dietary modulation of carcinoma development in a mouse model for human familiar adematous polyposis. Cancer Research 58: 5713, 1998.
Lipkin, M., Yang, K., et al. AACR Frontiers in Cancer Prevention. Research, p202, 2004.
Newmark, H., Yang, K., Lipkin, M., Kopelovich, L., Liu, Y., Fan, K., Shinozaki, H. A Western-style diet induces benign and malignant neoplasms in the colon of normal C57Bl/6 mice.& Carcinogenesis 22: 1871, 2001.
Lipkin, M., Newmark, H. Calcium and the prevention of colon cancer.& J. of Cell. Biochem 22: 65, 1995
Lipkin M.& Preclinical and Early Human Studies of Calcium and Colon Cancer Prevention.& Annals of the New York Academy of Sciences 889: 120, 1999.
Lamprecht, S., Lipkin, M. Chemoprevention of colon cancer by calcium, Vitamin D, and folate: molecular mechanisms. Nature Reviews Cancer 3: 601-614, 2003.
