LeRoy Walters's Legacy of Bioethics in Genetics and Biotechnology Policy.

LeRoy Walters was at the center of public debate about emerging biological technologies, even as "biotechnology" began to take root. He chaired advisory panels on human gene therapy, the human genome project, and patenting DNA for the congressional Office of Technology Assessment. He chaired the subcommittee on Human Gene Therapy for NIH's Recombinant DNA Advisory Committee. He was also a regular advisor to Congress, the executive branch, and academics concerned about policy governing emerging biotechnologies. In large part due to Prof. Walters, the Kennedy Institute of Ethics was one of the primary sources of talent in bioethics, including staff who populated policy and science agencies dealing with reproductive and genetic technologies, such as NIH and OTA. His legacy lies not only in his writings, but in those people, documents, and discussions that guided biotechnology policy in the United States for three decades.

That 70s show: regulation, evolution and development beyond molecular genetics.

This paper argues that the "long 1970s" (1969-1983) is an important though often overlooked period in the development of a rich landscape in the research of metabolism, development, and evolution. The period is marked by: shrinking public funding of basic science, shifting research agendas in molecular biology, the incorporation of new phenomena and experimental tools from previous biological research at the molecular level, and the development of recombinant DNA techniques. Research was reoriented towards eukaryotic cells and development, and in particular towards "giant" RNA processing and transcription. We will here focus on three different models of developmental regulation published in that period: the two models of eukaryotic genetic regulation at the transcriptional level that were developed by Georgii P. Georgiev on the one hand, and by Roy Britten and Eric Davidson on the other; and the model of genetic sufficiency and evolution of regulatory genes proposed by Emile Zuckerkandl. These three bases illustrate the range of exploratory hypotheses that characterised the challenging landscape of gene regulation in the 1970s, a period that in hindsight can be labelled as transitional, between the biology at the laboratory bench of the preceding period, and the biology of genetic engineering and intensive data-driven research that followed.

Who owns what? Private ownership and the public interest in recombinant DNA technology in the 1970s.

This essay analyzes how academic institutions, government agencies, and the nascent biotech industry contested the legal ownership of recombinant DNA technology in the name of the public interest. It reconstructs the way a small but influential group of government officials and university research administrators introduced a new framework for the commercialization of academic research in the context of a national debate over scientific research's contributions to American economic prosperity and public health. They claimed that private ownership of inventions arising from public support would provide a powerful means to liberate biomedical discoveries for public benefit. This articulation of the causal link between private ownership and the public interest, it is argued, justified a new set of expectations about the use of research results arising from government or public support, in which commercialization became a new public obligation for academic researchers. By highlighting the broader economic and legal shifts that prompted the reconfiguration of the ownership of public knowledge in late twentieth-century American capitalism, the essay examines the threads of policy-informed legal ideas that came together to affirm private ownership of biomedical knowledge as germane to the public interest in the coming of age of biotechnology and genetic medicine.

Academic and molecular matrices: a study of the transformations of connective tissue research at the University of Manchester (1947-1996).

This paper explores the different identities adopted by connective tissue research at the University of Manchester during the second half of the 20th century. By looking at the long-term redefinition of a research programme, it sheds new light on the interactions between different and conflicting levels in the study of biomedicine, such as the local and the global, or the medical and the biological. It also addresses the gap in the literature between the first biomedical complexes after World War II and the emergence of biotechnology. Connective tissue research in Manchester emerged as a field focused on new treatments for rheumatic diseases. During the 1950s and 60s, it absorbed a number of laboratory techniques from biology, namely cell culture and electron microscopy. The transformations in scientific policy during the late 70s and the migration of Manchester researchers to the US led them to adopt recombinant DNA methods, which were borrowed from human genetics. This resulted in the emergence of cell matrix biology, a new field which had one of its reference centres in Manchester. The Manchester story shows the potential of detailed and chronologically wide local studies of patterns of work to understand the mechanisms by which new biomedical tools and institutions interact with long-standing problems and existing affiliations.

[A short history of anti-rheumatic therapy--VII. Biological agents]. / Piccola storia della terapia antireumatica--VII. I farmaci "biologici".

The introduction of biological agents has been a major turning-point in the treatment of rheumatic diseases, particularly in rheumatoid arthritis. This review describes the principle milestones that have led, through the knowledge of the structure and functions of nucleic acids, to the development of production techniques of the three major families of biological agents: proteins, monoclonal antibodies and fusion proteins. A brief history has also been traced of the cytokines most involved in the pathogenesis of inflammatory rheumatic diseases (IL-1 and TNF) and the steps which have led to the use of the main biological drugs in rheumatology: anakinra, infliximab, adalimumab, etanercept and rituximab.

Self-regulation of recombinant DNA technology in Japan in the 1970s.

Recombinant DNA technology was developed in the United States in the early 1970s. Leading scientists held an international Asilomar Conference in 1975 to examine the self regulation of recombinant DNA technology, followed by the U.S. National Institutes of Health drafting the Recombinant DNA Research Guidelines in 1976. The result of this conference significantly affected many nations, including Japan. However, there have been few historical studies on the self-regulation of recombinant technologies conducted by scientists and government officials in Japan. The purpose of this paper is to analyze how the Science Council of Japan, the Ministry of Education, Science adn Culture, and the Science and Technology Agency developed self-regulation policies for recombinant DNA technology in Japan in the 1970s. Groups of molecular biologist and geneticists played a key role in establishing guidelines in cooperation with government officials. Our findings suggest that self-regulation policies on recombinant DNA technology have influenced safety management for the life sciences and establishment of institutions for review in Japan.

Learning from the past and looking to the future.

BACKGROUND/AIMS: Leaders in the fields of nutrigenomics/genetics can benefit from studying the ethical and social issues raised by comparable biomedical developments in the recent past and their consequences for science and society. METHODS: Experience with recombinant DNA research, beginning in the early 1970s, and its commercial application, and with pharamacogenetics/genomics, beginning two decades later, is analyzed. RESULTS: Particular lessons are drawn from both experiences. As to the first, the conclusions are to encourage open discussion among scientists of the possible negative or risky consequences of their research; not to conduct such discussions behind closed doors, so as to involve rather than to surprise the public; and to keep in mind the international characteristics of science but the domestic nature of the manner in which it is regulated. As to the second, the lessons are to beware of hype, avoid genetic determinism, take account of the problems raised by similarities to traditional genetic screening/testing, overcome the medical system's lack of preparation to use the new information, and recognize that differences in access may exacerbate inequities in health and health care. CONCLUSION: Awareness of these problems, which are likely to recur, can at least prepare those working in the field.

Gene therapy oversight: lessons for nanobiotechnology.

Oversight of human gene transfer research ("gene therapy") presents an important model with potential application to oversight of nanobiology research on human participants. Gene therapy oversight adds centralized federal review at the National Institutes of Health's Office of Biotechnology Activities and its Recombinant DNA Advisory Committee to standard oversight of human subjects research at the researcher's institution (by the Institutional Review Board and, for some research, the Institutional Biosafety Committee) and at the federal level by the Office for Human Research Protections. The Food and Drug Administration's Center for Biologics Evaluation and Research oversees human gene transfer research in parallel, including approval of protocols and regulation of products. This article traces the evolution of this dual oversight system; describes how the system is already addressing nanobiotechnology in gene transfer: evaluates gene therapy oversight based on public opinion, the literature, and preliminary expert elicitation; and offers lessons of the gene therapy oversight experience for oversight of nanobiotechnology.

Cancer, viruses, and mass migration: Paul Berg's venture into eukaryotic biology and the advent of recombinant DNA research and technology, 1967-1980.

The existing literature on the development of recombinant DNA technology and genetic engineering tends to focus on Stanley Cohen and Herbert Boyer's recombinant DNA cloning technology and its commercialization starting in the mid-1970s. Historians of science, however, have pointedly noted that experimental procedures for making recombinant DNA molecules were initially developed by Stanford biochemist Paul Berg and his colleagues, Peter Lobban and A. Dale Kaiser in the early 1970s. This paper, recognizing the uneasy disjuncture between scientific authorship and legal invention in the history of recombinant DNA technology, investigates the development of recombinant DNA technology in its full scientific context. I do so by focusing on Stanford biochemist Berg's research on the genetic regulation of higher organisms. As I hope to demonstrate, Berg's new venture reflected a mass migration of biomedical researchers as they shifted from studying prokaryotic organisms like bacteria to studying eukaryotic organisms like mammalian and human cells. It was out of this boundary crossing from prokaryotic to eukaryotic systems through virus model systems that recombinant DNA technology and other significant new research techniques and agendas emerged. Indeed, in their attempt to reconstitute 'life' as a research technology, Stanford biochemists' recombinant DNA research recast genes as a sequence that could be rewritten thorough biochemical operations. The last part of this paper shifts focus from recombinant DNA technology's academic origins to its transformation into a genetic engineering technology by examining the wide range of experimental hybridizations which occurred as techniques and knowledge circulated between Stanford biochemists and the Bay Area's experimentalists. Situating their interchange in a dense research network based at Stanford's biochemistry department, this paper helps to revise the canonized history of genetic engineering's origins that emerged during the patenting of Cohen-Boyer's recombinant DNA cloning procedures.

Hybridizing bacteria, crossing methods, cross-checking arguments: the transition from episomes to plasmids (1961-1969).

Plasmids are non-chromosomal hereditary determinants, mostly found in prokaryotes. Whereas Joshua Lederberg coined the term "plasmid" as early as 1952, today's concept was not established until the early 1970s. In this eclipse period, the plasmid's place was taken by the episome, following the 1958 publication of Elie Wollman and François Jacob. This paper analyzes the transition from the episome to a renewed plasmid concept both on the experimental and the conceptual level. It will become clear that intergeneric transfer experiments were central to this development. These studies rely on conjugational transfer of extrachromosomal hereditary determinants between different bacterial genera. First, experimental systems employing intergeneric transfer shaped the new plasmid by enabling its representation as a species of circular DNA. Moreover, they had a destabilizing effect on the episome, leading to a crisis in the concepts of microbial genetics towards the end of the 1960s. The new plasmid then became one of the cornerstones of recombinant DNA technologies. In an historic perspective, intergeneric transfer experiments indicate a gradual transition of molecular biology from its early "analytic" to the "synthetic" phase of genetic engineering. Hence, the construction of genetic hybrids in vivo as epitomized in the studies shown here marks an intermediate state that one could designate as "recombinant DNA avant la lettre".

Treatment for chronic myelogenous leukemia: the long road to imatinib.

The scientists of today have become accustomed to the extremely rapid pace of progress in the biomedical sciences spurred on by the discovery of recombinant DNA and the advent of automated DNA sequencing and PCR, with progress usually being measured in months or years at most. What is often forgotten, however, are the many prior advances that were needed to reach our present state of knowledge. Here I illustrate this by discussing the scientific discoveries made over the course of the past century and a half that ultimately led to the recent successful development of drugs, particularly imatinib mesylate, to treat chronic myelogenous leukemia.

Allergen immunotherapy in ENT: historical perspective.

The origins of immunology and allergy are founded upon the early 19th century microbiological studies of Jenner and Pasteur. It was discovered that the immune system could cause harm. The subspecialty of allergy began with the coining of the term by Von Pirquet in 1906 to describe disorders resulting from hyper-reaction to normally innocuous environmental agents. Understanding the scientific basis of the immune system and allergy allowed Noon and Freeman, and later Cooke, to develop allergen immunotherapy. Initially the technique was crude, but with the subsequent key discovery of IgE, more accurate methods of diagnosis (such as the radioallergosorbent test (RAST)) and treatment ensued. The efficacy of specific immunotherapy has been demonstrated by many double-blind trials culminating in the WHO position paper. DNA recombinant technology has provided detailed molecular understanding of allergic disorders, which has resulted in several novel methods of immunotherapy that are potentially safer and more effective. Use of recombinant allergens, T-cell peptides, DNA vaccination with CpG motifs or plasmid vectors and anti-IgE strategies with monoclonal antibodies are showing promise.