GROBSTEIN, CLIFFORD

(b. New York, New York, 20 July 1916; d. La Jolla, California, 6 September 1998),

ethics, developmental biology, stem cell biology, public policy.

Grobstein was one of the preeminent scientists of the twentieth century, influencing the now blossoming field of developmental biology, pioneering in the area of biological and medical education, and contributing materially to the controversies and ethical underpinnings surrounding fetal research and manipulation. The studies he initiated on tissue interactions in development influenced a whole generation of researches in developmental biology and oncology. In his later years, as he assumed advisory positions on committees of the National Institutes of Health, the National Science Foundation, and the National Academy of Sciences, he demonstrated a unique ability to communicate difficult concepts in simple but eloquent language, thereby influencing the establishment of bioethical guidelines for fetal research, guidelines that are still contemporary in the current context of human embryonic research and stem cell biology.

Education . Clifford Grobstein was the son of Aaron and Birdie Grobstein. His siblings included a brother, Richard, and a sister, Fern. Grobstein received his early training in New York City at what became the Bronx High School of Science, one of the exciting new educational ventures of Fiorello H. LaGuardia that predated the magnet schools of later decades. The Bronx High School of Science selected students from the greater New York area and provided the springboard for numerous scientific careers. After high school, Grobstein attended City College in New York. Just as the Bronx High School of Science gave a start to many young prospective scientists, City College was almost unique in providing a free or near-free opportunity to further the careers of promising students regardless of income, sex, or religious orientation. Grobstein continued his scientific training by pursuing a doctorate in zoology at the University of California at Los Angeles (UCLA), receiving a PhD in 1940. The doctoral research focused on endocrine influences on anal fin regeneration in fish, work that greatly influenced many of the subsequent studies in developmental biology carried out first on fish and then on mice.

Professional Appointments . Following completion of his formal scientific training, Grobstein assumed an academic appointment at Oregon State University where he continued to study tissue interactions and regulation of appendage differentiation in fish (1940–1942). However, World War II interrupted his scientific career: He served in the U.S. Army Air Force for three years (1943–1946). On returning from military service, he accepted a research appointment in the Biology Division of the National Cancer Institute (NCI) in Bethesda, Maryland, and it was here that his seminal studies in developmental biology led to his preeminence in that field. In 1957 he left the NCI to accept a professorship at Stanford University. In the mid-1960s, however, he was recruited by the University of California System to head the Department of Biology at the newly formed University of California at San Diego (UCSD). Here he moved rapidly from chair of the biology department to a deanship of the medical school, the vice chancellor for health sciences and finally the position of vice chancellor for special programs, a position he held until his retirement as a result of progressive illness.

Contributions to the Field of Developmental Biology . The early work on fish embryos had introduced Grobstein to the field of embryology (which was renamed “developmental biology”). He resumed his own research program on his return from military service in 1946, at which time he received an appointment as a researcher in the Biology Division of the NCI in Bethesda, Maryland. Grobstein first established a fish colony to continue to study fish development, but, surrounded by mammalian biologists, he soon recognized both the advantages and the challenges provided by changing to the mouse. The Biology Division at NCI included the chair, Walter Heston, an expert on mouse genetics; Wilton Earle, a pioneer in the area of tissue culture; and Glenn Algire, a leader in the field of experimental oncology, who studied the interactions of tumor cells with their tissue environment in vivo through the use of diffusion chambers. The influence of these three scientists can readily be seen in the work carried out by Grobstein, which included in vivo transplantation studies of early mouse embryos, the study of cell and tissue interactions during morphogenesis of embryonic mouse organ rudiments in vitro, and the adaptation of diffusion chamber technology to permit analysis of tissue interactions across diffusible membranes in tissue culture.

The number of scientists with whom Grobstein collaborated in these research studies were relatively few, but each in turn became prominent over the subsequent years. Among the first was Edgar Zwilling, with whom Grobstein described the role of tissue mass in controlling the growth and differentiation of early chick and mouse rudiments. They initiated work on separating different tissues of early embryonic rudiments, work that led Zwilling to the seminal studies of tissue interactions during chick embryonic limb development. A second visitor to the NCI laboratory of Grobstein was Julius S. Youngner, whose work with Grobstein on kidney cell differentiation led to Youngner’s subsequent establishment in Pittsburgh of the kidney cell culture system that was of key importance in the development of the polio vaccine by Jonas Salk. Howard Holtzer, over a three-month visit to Bethesda, collaborated with Grobstein and his longtime assistant, George Parker, in establishing the in vitro system for studying somite development into cartilage, a system that Holtzer and his student Jay Lash later employed over a lifetime of research at the University of Pennsylvania. Robert Auerbach, the only junior fellow to work with Grobstein at the NCI (1955–1957), applied the cell dissociation and reaggregation systems introduced a decade earlier for amphibian systems by Johannes Holtfreter, and stimulated by Aaron Moscona’s description of trypsinization protocols, led to the recognition that self-organization of tissues and organs developed gradually during organ differentiation. Auerbach, in his subsequent studies on thymus differentiation and angiogenesis and along with his students, Veerappan Muthukkaruppan, Joseph Taderera, and Jane Barker, extended Grobstein’s influence into the areas of lens, lung, and yolk sac differentiation in mice.

Perhaps most important was Grobstein’s work describing the role of cell contact and extracellular matrix in the regulation of tissue interactions. The major ideas were described best in the symposium paper presented at the Growth Society (later named the Society for Developmental Biology) meeting in 1954 (published in 1955). In this paper Grobstein described the results obtained when ultrathin millipore filters were interposed between epithelium and mesenchyme from mouse embryonic organ rudiments. This first use of millipore filters led to an explosion of studies, first with millipore and then Nucle-pore filters (later called transwell assays) in the investigation of cell interactions and cell migration.

In a 2004 series of articles celebrating the centennial of the Journal of Experimental Zoology, Grobstein’s work at the NCI was placed in contemporary perspective:

Grobstein had made the transition from fish to mouse in 1951. Half a century later we are now making the transition back from mouse to fish (and beyond). Grobstein’s keen insight into the mechanisms governing differentiation is as contemporary now as it was at the time. The questions that Grobstein defined so long ago are still largely unanswered. Will genomics and proteomics, site-specific mutagenesis and gene knockouts, multi-proton microscopy and highspeed cell sorting, cloned growth factors and signaling cascades provide the answers Grobstein was eager to find? Are we entitled to be optimistic or will another half century be needed before we truly understand the nature of inductive interactions during development? (Auerbach, 2004, p. 116)

Grobstein continued the research studies initiated at the National Institutes of Health (NIH) on his move from the NIH to Stanford University in 1957. Stanford hoped to bring together three of the most prominent figures in biology—Arthur Kornberg, Joshua Lederberg, and Grobstein, who, together, were hoping to make major inroads into the key problem of developmental biology, the role of DNA and genetics as regulators of cell differentiation during embryogenesis. That, in fact, they did not fully succeed is a stark reminder that cell differentiation is a complex, elusive process requiring more than three brilliant minds to unravel.

At Stanford, Grobstein’s most notable professional collaborators included Norman Wessels and William Rutter, whose work on pancreas development have become classic examples of epithelial-mesenchymal interactions leading to functional differentiation. Their work has become important for the interpretation of the late-twentieth-, early-twenty-first-century work of Douglas Hanahan and Judah Folkman on the progression of angiogenesis during the development of pancreatic cancer. Frances Kallman was a major contributor to the work of Grobstein during this period, as were a number of undergraduate and graduate students. However, even at Stanford, Grobstein had begun to move from experimental studies into the area of bioethics, and this move was reflected in the transition of one of his undergraduate students, Michael Flower, from studies of embryonic induction begun at Stanford as an undergraduate, continued during Flower’s doctoral studies at Wisconsin, and by his subsequent long-term collaboration with Grobstein in the study of ethical considerations in the area of developmental biology.

Contributions in the Area of Bioethics and Public Policy . In 1976 Grobstein became identified with various ethical and safety questions relating to biological research. A meeting in Asilomar in 1975, following a prior Gordon Conference, was convened to discuss guidelines that might be proposed for the then emerging recombinant DNA technology. A 1976 publication by Grobstein in Science provided significant new insight into the problems associated with regulating DNA research—problems that, in a way, were still current even thirty years later. From this early beginning of his emergence as an intellectual leader in the area of research ethics and responsibilities, Grobstein could be viewed both as a proponent of and a restraining influence in the area of fetal research. In his 1976 paper, Grobstein’s vision is clear:

[We] should be dominated not by fears but by fundamental and positive objectives (i) to continue expansion of the understanding of genetic phenomena, (ii) to minimize foreseeable hazards, whether to health, essential human relations, or biotic environment; (iii) to consider the priorities to be assigned to realization of positive social benefits from growing genetic engineering capability; (iv) to give “due process” to deeply held values whose accommodation may require time and special

attention, and to provide opportunity for “informed consent” or other reaction from the several publics that may otherwise see themselves involuntarily placed at risk. (Grobstein, 1976, p. 1134)

These words are as apt at the beginning of the twenty-first century when applied to the areas of genetic engineering and stem cell research as they were when DNA manipulations were first begun.

Grobstein’s views on in vitro fertilization (the first child following in vitro fertilization was born in July 1978) became widely discussed in the popular press after the appearance of his Scientific American article, “External Human Fertilization,” in 1979. His discussions ranged from questions such as when does the human embryo become more than groups of cell, tissues, and organs, to ethical and legal questions such as storage of frozen human embryos. More importantly, perhaps, was a paper by Grobstein, Flower, and John Mendeloff, published in Science in 1983 after five years of this new in vitro technology; that paper became the foundation for much of the legislation and policy determinations up to the beginning of the twenty-first century, when stem cells became the focus of national ethical, legal, and political attention. A further expansion of Grobstein’s discussion of embryo storage was published in collaboration with Flower and Mendeloff, appearing in the New England Journal of Medicine in 1985. Grobstein’s From Chance to Purpose: An Appraisal of External Human Fertilization (1981) was chosen as the “Best Publication of the Year” by the Association of American Publishers.

The essence of Grobstein’s approach to ethics and public policy has been described by Michael Flower:

Cliff was especially convinced … that it was important to sketch out and direct to the appropriate audiences the specific public policy implications that were consistent with what developmental and molecular biologists could tell us about blastocysts, embryos, fetuses, genome structure, and gene expression mechanisms. He didn't hesitate to say what directions for policy-making the science was and was not consistent with. (Personal written communication to the author)

Contributions to Education in Biology and Medicine . Although not as visible as Grobstein’s forays into bioethics and public policy, Grobstein’s contributions to biology education were equally influential. His book The Strategy of Life (1965) showed his interest in the organization of biological systems, and presaged his proposal—outlined in two publications in 1966—of a major reorganization of biology curricula in secondary school and college programs. His ideas were incorporated into the revolution in high school biology teaching seen in the incorporation of the Biological Sciences Curriculum Study (BSCS) series of course outlines initially sponsored by the National Science Foundation.

Grobstein’s influence in medical education, already seen in the changes initiated at Stanford University during his tenure there, was exerted forcefully and convincingly in the development of the medical curriculum at UCSD. Grobstein had the opportunity to be at UCSD as the first class of medical students was enrolled and the medical curriculum was established. The curriculum evolved under his influence as he became increasingly influential during his transition from the chair of biology to dean of the medical school and to vice chancellorship. His role in medical education was well described by Norman Wessells:

Just as Grobstein in the early 1960s had helped formulate and advance the levels-of-organization debate in the life sciences, he used his decanal pulpit to stimulate thinking about medical education. Beginning in 1970, a series of five papers published in such places as The Journal of Medical Education and The British Journal of Medical Education focused on the two-cultures issue, and more specifically on research, teaching, and curriculum in clinical and basic science departments of medical schools. Those were days when new medical schools were being started in the United States and when both new and old ones were being impacted by the early stages of the revolution in biomedical knowledge that continues ever faster today. Cliff used the UCSD Medical School as example, but really tried to help medical school faculty to think about what kinds of training could best help graduate physicians remain current during their careers as biomedical knowledge expands at unprecedented rates. (Wessells, 2000, Internet page)

An “In Memoriam” article published by the University of California in 2001 captures the essence of Grobstein’s contribution to biology education:

As an academic and scientific leader, Cliff Grobstein helped to reshape the biological community through his strong advocacy of a multilevel research approach involving different disciplines and simultaneous studies at the molecular, cellular and supracellular levels. This was a timely role for him in the 1960s.… In the decades that followed, Cliff’s vision became a reality as cell biologists, biochemists, geneticists, molecular biologists, physical and organic chemists, physicists and scientists from other backgrounds all brought to bear their particular insight to the solution of a number of complex phenomena in cell and developmental biology. (University of California: In Memoriam, 2001, available from http://oac.cdlib.org/texts/)

Personal Life . Grobstein’s children, Paul and Joan, were born while Grobstein and his wife Rose Gruyer, a social worker, lived in Bethesda and subsequently at Stanford. Paul Grobstein has become a distinguished neurobiologist and chair of biology at Bryn Mawr. Joan Grobstein is a practicing physician in Philadelphia, specializing in neonatal and perinatal medicine. A second marriage coincided with Grobstein’s acceptance of the biology professorship at UCSD. His second wife, Ruth Hirsch Beloff, was a well-known radiologist who later became founder and interim director of the Ida M. and Cecil H. Green Cancer Center at the Scripps Clinic in La Jolla, California. For thirty-two years, Ruth Grobstein was a collaborator, critic, and supporter of Clifford Grobstein, and she and her children protected Grobstein as his manifestations of Alzheimer’s disease became increasingly debilitating. In 2005, Ruth Grobstein published the widely acclaimed

The Breast Cancer Book: What You Need to Know to Make Informed Decisions(Yale University Press).

During the course of his career, Grobstein held research appointments at the NCI, professorships at Stanford University and UCSD, as well as chairmanship of the biology department, deanship in the medical school, and vice chancellorship for university relations and special programs at UCSD. Recognition of his status and achievement was shown by his election to the National Academy of Sciences, the Institute of Medicine, and the American Academy of Arts and Sciences. He received many awards including a “best book” award from the Association of American Publishers and the Brachet Medal of the Belgium Royal Society. His public service included leadership positions in numerous governmental policy committees, panels convened by the National Science Foundation and the National Institutes of Health, and study groups sponsored by the National Academy of Sciences.

Grobstein was one of the preeminent scientists of the twentieth century. Aside from being a brilliant experimentalist, he was a superb teacher and a warm person who cherished his role as a mentor and friend to young students. It was through the combination of his breadth of knowledge, his ability to express himself clearly, and the strength of his personality that he was able to communicate not only with students and colleagues but with a wider audience, thereby influencing science education and public policy.

BIBLIOGRAPHY

WORKS BY GROBSTEIN

“Inductive Epithelio-Mesenchymal Interaction in Cultured Organ Rudiments of the Mouse.” Science 118 (1953): 52–55.

“Morphogenetic Interaction between Embryonic Mouse Tissues Separated by a Membrane Filter.” Nature 172 (1953): 869–871.

“Tissue Interaction in the Morphogenesis of Mouse Embryonic Rudiments In Vitro.” In Aspects of Synthesis and Order in Growth, edited by Dorothea Rudnick. Princeton, NJ: Princeton University Press, 1954.

With Robert Auerbach. “Inductive Interaction of Embryonic Tissues after Dissociation and Reaggregation.” Experimental Cell Research 15 (1958): 384–397.

“Levels and Ontogeny.” American Scientist 50 (1959): 46–58.

“Cytodifferentiation and Its Control.” Science 143 (1964): 643–650.

With William J. Rutter and Norman K. Wessells. “Control of Specific Synthesis in the Developing Pancreas.” National Cancer Institute Monograph 13 (1964): 51–65.

The Strategy of Life. San Francisco: W.H. Freeman, 1965.

“New Patterns in the Organization of Biology.” American Zoologist 6 (1966): 621–626.

“Recombinant DNA Research: Beyond the NIH Guidelines.” Science 194 (1976): 1133–1135.

A Double Image of the Double Helix: The Recombinant-DNA Debate. San Francisco: W.H. Freeman, 1979.

From Chance to Purpose: An Appraisal of External Human Fertilization. Reading, MA: Addison-Wesley, 1981.

With Michael Flower and John Mendeloff. “External Human Fertilization: An Evaluation of Policy.” Science 222 (1983): 127–133.

With Michael Flower and John Mendeloff. “Frozen Embryos: Policy Issues.” New England Journal of Medicine 312, no. 24 (1985): 1584–1588.

Science and the Unborn: Choosing Human Futures. New York: Basic Books, 1988.

OTHER SOURCES

Auerbach, Robert. “From Fish to Mouse: Clifford Grobstein’s Work at the National Cancer Institute, 1951–1957.” Journal of Experimental Zoology 301A, no. 2 (2004): 115–117.

Flower, Michael. Personal communication.

Helinski, Donald R., Daniel Steinberg, and Norman K. Wessells. “Clifford Grobstein, Biology: San Diego.” California Digital Library (2001): 1–3.

Nanney, David L. “Biology Texts.” In Tilting at Windmills: Educational Misadventures in the Big Ten. Available from http://www.life.uiuc.edu/nanney/autobiography/index.html.

Wessells, Norman K. “Clifford Grobstein, 1916–1998.” National Academy of Sciences Biographical Memoirs 78 (2000): 65–93. Available from http://books.nap.edu/html/biomems/cgrobstein.html.

Robert Auerbach