The history of the discovery of the nerve growth factor

The Nerve Growth Factor (NGF) is the progenitor of a family of growth factors which is still expanding. The history of its discovery is very colorful; it is a rare combination of scientific reasoning, intuition, fortuities, and good luck. In addition, I believe that the collaboration of three scientists with very different backgrounds contributed to the success: I had grown up in a laboratory of experimental embryology, Dr. Levi-Montalcini came from neurology, and Dr. Stanley Cohen was from biochemistry. The decision where to begin the history of a discovery is always arbitrary. I shall give my reasons why I begin this story with my wing bud extirpations on chick embryos and the analysis of the effects of the operation on the development of spinal nerve centers, published in 1934. Of course, I am aware of the fact that the analysis of neurogenesis had been pioneered by Dr. R. G. Harrison and his students at Yale University since the beginning of this century. It should be mentioned that their experiments had been done on amphibian embryos. My own interest in problems of neurogenesis dates back to my Ph.D. thesis in the Zoology Department of Professor H. Spemann at the University of Freiburg in (the Federal Republic of) Germany; it dealt with the influence of the nervous system on the development of limbs in frog embryos. After I had obtained some inconclusive results I did the crucial experiment of producing nerveless legs. I removed the lumbar part of the spinal cord and the spinal ganglia before the outgrowth of nerve fibers. The nerveless legs developed normally in every respect, but the muscles atrophied eventually.     

An interview with Dr. Frank Slack on his highly cited paper published in Cell Cycle

Frank Slack received his B.Sc from the University of Cape Town in South Africa, before completing his Ph.D in molecular biology at Tufts University School of Medicine. He started work on microRNAs as a postdoctoral fellow in Gary Ruvkun’s laboratory at Harvard Medical School, where he co-discovered the second known microRNA, let-7. He is currently an Associate Professor in the Department of Molecular, Cellular and Developmental Biology at Yale University. The Slack laboratory studies the roles of microRNAs and their targets in development, disease and aging.     

Are Research Schools Necessary? Contrasting Models of 20th Century Research at Yale Led by Ross Granville Harrison, Grace E. Pickford and G. Evelyn Hutchinson

This paper compares and contrasts three groups that conducted biological research at Yale University during overlapping periods between 1910 and 1970. Yale University proved important as a site for this research. The leaders of these groups were Ross Granville Harrison, Grace E. Pickford, and G. Evelyn Hutchinson, and their members included both graduate students and more experienced scientists. All produced innovative research, including the opening of new subfields in embryology, endocrinology and ecology respectively, over a long period of time. Harrison's is shown to have been a classic research school; Pickford's and Hutchinson's were not. Pickford's group was successful in spite of her lack of department or institutional position or power. Hutchinson and his graduate and post-graduate students were extremely productive but in diverse areas of ecology. His group did not have one focused area of research or use one set of research tools. The paper concludes that new models for research groups are needed, especially for those, like Hutchinson's, that included much field research.     

Reminiscences of a journeyman scientist: studies of thermoregulation in non-human primates and humans

After graduating from Mount Holyoke College in 1948 where I majored in experimental psychology I worked at the College for 2 years with the Johns Hopkins Thermophysiological Unit. My graduate work later at the University of Wisconsin, centering on sensory psychology, culminated in my 1955 PhD thesis on human dark adaptation. I continued work in sensory psychology later with Neal Miller at Yale and then moved to the John B. Pierce Foundation--a Yale affiliate--where I began the studies of thermoregulation that constitute the center of my scientific career. Those studies were largely--later wholly--conducted using microwave energy as a thermal load and were thus published in Bioelectromagnetics even as I played an active role in the Bioelectromagnetics Society. In the beginning this work was centered on the responses of Squirrel Monkeys to thermal loads. Later, serving as Senior Scientist at the Air Force Research Laboratory at San Antonio, I completed an extensive analysis of thermal regulation in humans. I consider this work of special note inasmuch as the extraordinary human thermoregulatory ability was surely among the attributes that were paramount in initially separating humans from the other anthropoid primates.     

Edmund Beecher Wilson, Class of '81

Edmund Beecher Wilson was born in Geneva, Illinois in 1856.He attended Antioch College, the University of Chicago, Yale,and Johns Hopkins (Ph.D. 1881). Most of his professional lifewas spent in the Zoology Department of Columbia University togetherwith his close friend, Thomas Hunt Morgan. They were dominantfigures in developing the Chromosome Theory of Heredity. Wilsonbegan his professional life as a conventional 19th century biologiststudying problems of systematics, morphology, and phylogeny.Soon he became a key figure in the newer experimental disciplinesof embryology, cytology, and heredity. He is remembered todaylargely for his superb synthesis of these three fields in TheCell in Development and Heredity. He died in 1939.     

Bayer revisited

Bayer accuses me of wrongly claiming that he holds a negative thesis about the role that the liberal emphasis on privacy rights has had on AIDS public health policy. In his reply to my review essay, he denies holding such a thesis and, moreover, makes the stronger claim that his position is sympathetic to liberalism, or at least to some versions of it. Although I appreciate Bayer's efforts to clarify his views about liberalism and a "culture of restraint and responsibility", it is clear to me that our differences are related not to a misunderstanding on my part, but to a fundamental disagreement concerning what liberalism as a political philosophy is, and what public policy implications it entails in the case of AIDS....     

Abraham Flexner and the development of the Yale School of Medicine. 1999

Abraham Flexner first toured the Yale University School of Medicine in preparation for his report of 1910, but it was just the beginning of his relationship with the school. While his review of Yale in his report was generally favorable, he mentioned several shortfalls that needed to be improved to make the school acceptable. Throughout the next twenty-five years, Flexner worked with Deans George Blumer and Milton C. Winternitz to improve the school's finances, infrastructure, and quality of education through his work with the Carnegie Foundation and General Education Board. Flexner has been given great accolades for his work on medical education for the country, but little mention is made of him at Yale, even though he was one of the most influential figures in the development of Yale in the last century.     

Abraham Flexner and the development of the Yale School of Medicine

Abraham Flexner first toured the Yale University School of Medicine in preparation for his report of 1910, but it was just the beginning of his relationship with the school. While his review of Yale in his report was generally favorable, he mentioned several shortfalls that needed to be improved to make the school acceptable. Throughout the next twenty-five years, Flexner worked with Deans George Blumer and Milton C. Winternitz to improve the school's finances, infrastructure, and quality of education through his work with the Carnegie Foundation and General Education Board Flexner has been given great accolades for his work on medical education for the country, but little mention is made of him at Yale, even though he was one of the most influential figures in the development of Yale in the last century.     

Direct physical formation of anatomical structures by cell traction forces. An interview with Albert Harris by Lev Beloussov

Albert Harris was educated at The Norfolk Academy, Norfolk, Virginia, USA (1961). He then earned a Batchelor of Arts Degree in Biology from Swarthmore College, in Pennsylvania, USA (1965), followed by a Ph.D. in Biology (1971) from Yale University, where his Dissertation Advisor was the great John Phillip Trinkaus. He held a Damon-Runyon Postdoctoral Fellowship in Cancer Research in 1970-72, under Michael Abercrombie, FRS, at the Strangeways Research Laboratory of Cambridge University, England. Then he accepted a position as Assistant Professor in the Zoology Department of the University of North Carolina at Chapel Hill, N.C. USA. In 1977, he was promoted to Associate Professor of Zoology, and in 1983 was promoted to Full Professor of Biology. In Oct.-Nov. 1991 he was honored to be Distinguished Visiting Professor of Zoology at the University of California at Davis.     

(M,R)-systems, (P,M,C)-nets, hierarchical decay, and biological aging: reminiscences of Robert Rosen

I have the pleasure to present a number of personal experiences that I had with Robert Rosen, both as his student and as a research colleague, and I will describe how this affected my academic career over the past decades. As a matter of fact, Rosen's work with (M,R)-systems as well as his continuing mentorship guided me into my own research in gerontology and geriatrics. Amazingly, this still continues to affect my work in complexity theory after 30 years.     

My early days in photobiology with Philip Hanawalt

Phil and I started our careers on somewhat similar scientific paths. I had an undergraduate degree in physics from Swarthmore College and a Ph.D. degree in physics from Yale for research in the field for ultraviolet spectroscopy. Phil received an undergraduate degree in Physics from Oberlin College, joined the Yale Physics Department in 1954, and transferred to the new Biophysics Department in 1955. We began our interactions then by virtue of the fact that Phil had to take a Laboratory Course in Experimental Physics, one part of which was spectroscopy in which I was the instructor. One of my principal interests was in the effects of different wavelengths of ultraviolet (UV) radiation on proteins, viruses and bacterial cells. So what was more natural than for Phil to dream up a Ph.D. research project to investigate the effects of different wavelengths of UV on macromolecular synthesis in Escherichia coli. I became his mentor with expertise in UV, whereas he did most of the microbiological/biochemical work. Thus began a collaboration and a communicating friendship, the latter going on for 50 years. That communication was essential in elucidating some of the important steps in nucleotide excision repair-a field in which Phil is a pre-eminent scholar and investigator.     

On the legacy of W.S. McCulloch

In this paper, we review McCulloch's legacy, from his early work in neurophysiology, and its relationship to his philosophical quest for an 'experimental epistemology' to his role in the cybernetics movement during the 1940s and 1950s and his contributions to the development of computer science and communication theory. There are three parts in chronological sequence. First, the period up to his work at Yale University with Dusser de Barenne, where he concentrated on the experimental study of the functional organization of sensory cortex. Second, the time of his Psychiatric Chair at the University of Chicago and the organization of the Macy Foundation Conferences. To this period corresponds the genesis and publication of the most influential and quoted work by McCulloch and Pitts: A Logical Calculus of the Ideas Immanent in Neurons Activity. Third, the period of his research activity at the Massachussetts Institute of Technology where he, Lettvin, Maturana and Pitts produced epochmaking papers on epistemological neurophysiology, the modelling of the reticular formation and other work with da Fonseca and Moreno-Díaz. We finally refer to the International Conference that took place in McCulloch's memory at the 25th anniversary of his death. Our main conclusion is that McCulloch's writings are still a source of inspiration from neurophysiology to artificial intelligence and robotics.     

Synthesis of a Double Transmembrane Domain Fragment of Ste2p by Native Chemical Ligation

Native chemical ligation (NCL) approaches have been applied extensively to soluble proteins. Fewer successes have been achieved with membrane peptides. In this report, the synthesis and semisynthesis by NCL of peptides corresponding to 1.7 transmembrane domains of the α-factor receptor from Saccharomyces cerevisiae is described. Synthesis was achieved when the ligation point was approximately in the middle of the loop joining the two transmembrane regions. In contrast, little to no ligation was observed when the ligation point was at the putative membrane interface of the sixth transmembrane domain (TM6) and the third extracellular loop (EL3). Ligations of a chemically synthesized 22-residue thioester with a synthetic 29-residue N-Cys peptide and a biosynthetic 73-residue N-Cys peptide were successfully achieved in both trifluoroethanol/guanidinium hydrochloride (TFE/GnHCl) and sodium dodecyl sulfate (SDS) media when mercaptoethanesulfonic acid (MESNA) was used as a catalyst. The resulting 51-residue and 95-residue ligation products were purified by reversed phase HPLC and recovered on a mg scale. Both peptides were >95% pure as determined by HPLC and had the expected molecular weight as judged by mass spectrometry. Segmental labeling of the 95-residue fragment, in which the N-Cys portion was [¹⁵N] labeled, resulted in a peptide that gave an NMR spectrum which was comparable to that of the unligated 73-residue peptide alone. R B Merrifield personified the finest qualities of a human being. He was an outstanding individual who influenced the way research is conducted by tens of thousands of scientists. At the same time he was a warm, humble, sincere man who was extremely kind and generous. I (FN) personally saw his generosity during a seminar he invited me to give at Rockefeller University. He was already a Nobel laureate but he treated me as a colleague and the encouragement he offered concerning my research program was very important for my future in academia. It is an honor to be among the participants in a volume honoring his contributions to peptide science.     

Of moths and men: Theo Lang and the persistence of Richard Goldschmidt's theory of homosexuality, 1916-1960

Using an analogy between moths and men, in 1916, Richard Goldschmidt proposed that homosexuality was a case of genetic intersexuality. As he strove to create a unified theory of sex determination that would encompass animals ranging from moths to men, Goldschmidt's doubts grew concerning the association of homosexuality with intersexuality until, in 1931, he dropped homosexuality from his theory of intersexuality. Despite Goldschmidt's explicit rejection of his theory of homosexuality, Theo Lang, a researcher in the Genealogical-Demographic Department of the Institute for Psychiatric Research in Munich, revived it, maintained Goldschmidt's association with it, and argued on its behalf in publications from 1936 to 1960. Lang's appropriation of Goldschmidt's theory did not depend on his resolution of the difficulties Goldschmidt had found with his own theory. Lang and Goldschmidt, I argue, had fundamentally different scientific and social commitments that allowed one to reject this theory of homosexuality and the other to accept it.     

History of the Department of Cell Biology at Yale School of Medicine, 1813-2010

The Department of Cell Biology at the Yale University School of Medicine was established in 1983. It was preceded by the Section of Cell Biology, which was formed in 1973 when George E. Palade and collaborators came to Yale from the Rockefeller University. Cell Biology at Yale had its origins in the Department of Anatomy that existed from the beginning of classes at the Medical Institution of Yale College in 1813. This article reviews the history of the Department of Anatomy at Yale and its evolution into Cell Biology that began with the introduction of histology into the curriculum in the 1860s. The formation and development of the Section and Department of Cell Biology in the second half of the 20th century to the present time are described. Biographies and research activities of the chairs and key faculty in anatomy and cell biology are provided.     

Q & A. Carl R. Woese. [interview

Carl R. Woese was born and raised in Syracuse, New York. His undergraduate training was at Amherst College (AB 1950) and graduate work at Yale University (PhD 1953). He is currently the Stanley O. Ikenberry University Professor and Center for Advanced Study Professor of Microbiology at the University of Illinois (Champaign-Urbana), where he has been for the past forty years. He was trained as a biophysicist and molecular biologist. He views himself as a molecular biologist in search of Biology. Consequently, his career has been devoted to using molecular methods to approach evolutionary problems. His most notable accomplishments have been determining the universal phylogenetic tree, through molecular sequence analysis, and the discovery of the Archaea, the so-called ‘third form’ of life. For these he has received numerous awards, including a John D. and Catherine T. MacArthur Award, the Leeuwenhoek Medal 1990 (Netherlands Royal Academy), the Waksman Award (National Academy of Science USA), and the Crafoord Prize (Swedish Royal Academy). At present he works on the evolution of cellular organization.     

Dr. Haifan Lin. Interviewed by Han Lee and Rachel Rosenstein

Dr. Haifan Lin is professor of Cell Biology at Yale University, where he studies the mechanism of stem cell self-renewal in fruit flies, mice, and human cancer cells. Recently named director of the Yale Stem Cell Center, Dr. Lin has made seminal contributions to the stem cell field, most notably his demonstration of the stem cell niche theory using the fruit fly model, his discovery of the PIWI/AGO gene family that is essential for stem cell division in diverse organisms, and his recent finding of a group of small RNAs called PIWI-interacting, or piRNAs, which may play a crucial role in stem cell proliferation and germline development. Dr. Lin’s work on piRNAs was recognized by Science Magazine as a top scientific breakthrough of 2006. Recently, the Lin lab has begun exploring the role of these molecules in stem cell division and oncogenesis.     

Elihu Yale and the medicine he promoted: the government general hospital and Madras Medical College, India

Much has been written about the philanthropist Elihu Yale and his life in the Americas and England, where he spent his beginnings and end. Less publicized is his life in India, where he spent the majority of his adult life and where he raised his family. A major contribution of Elihu Yale to medicine in India was his promotion of a local hospital in the major Indian trading port city of Madras. This essay briefly describes the history of that hospital and the medical college that grew out of it.     

Q & A. [interview

Joel Rosenbaum was born and grew up in Massena, New York state, on the St Lawrence River border with Ontario, Canada. He received his undergraduate and PhD degrees from Syracuse University, and a Masters Degree in high school biology teaching at St Lawrence University. His PhD work was done with the protozoologist, George Holz Jr, and his post doctoral research on cilia and flagella was at the University Of Chicago with Frank Child and Hewson Swift. He has been at Yale University for 37 years where he has taught Cell Biology. His research has been on the synthesis and assembly of the proteins of cilia and flagella, showing that the flagellar axoneme assembles at the distal tip and that detachment of the flagella upregulates the genes for flagellar proteins. More recently his group has shown that this tip assembly process is facilitated by a rapid kinesin and cytoplasmic dynein-mediated motility underneath the flagellar membrane called ‘intraflagellar transport’. He is a runner with more than 20 marathons under his belt.     

Estimation of diffusive resistance of bundle sheath cells to CO2 from modeling of C4 photosynthesis

This account is focused upon the early part of my career in order to illuminate the logistics and the culture of our science in the period 1936 to 1949. A roundabout path took me from a farm in Pennsylvania to a PhD under George Burr at Minnesota in 1939. In studying the photosynthetic competence of chlorophyll formed by the green alga Chlorella in darkness, I stumbled upon the phenomenon of photoinhibition. In a two-year postdoctorate at the Smithsonian Institution, I worked under E.D. McAlister. Our major accomplishment was in making simultaneous recordings of fluorescence and CO₂ uptake during the induction period. Variations in photosynthetic behavior of Chlorella led to a study of culture conditions and a recognition of the changing conditions which occur in batch cultures. A continuous culture apparatus (turbidostat) was developed as a means of attaining steady-state growth and production of uniform experimental material. I exploited the device in work at my first (and only) position at The University of Texas in 1941 and subsequent years. Study of the CO₂/O₂ gas exchange ratio led to the recognition of the important role of nitrate in the photosynthetic metabolism of algae. The account ends with the 1949 American Association for the Advancement of Science symposium.Invited and edited by Govindjee