More on physiology without borders.

Two previous editorials have referred to the international nature of physiology, the first from Presidents of the American Physiological Society (1) and the second from the Executive Committee of IUPS (10). The larger societies within the IUPS family hold meetings that are attended by scientists from many countries. This is not restricted to the US and UK societies. I recently lectured to the annual meeting of the Scandinavian Physiological Society in Helsinki and saw for myself how strongly international the meetings of that society have now become. The second editorial on “physiology without borders” acknowledged and welcomed these developments on behalf of IUPS and outlined the ways in which IUPS and those societies could cooperate in protecting the universality of science as enshrined in statute 8 of the International Council of Science (ICSU). Physiological societies around the world connect with ICSU through membership of IUPS. The full extent of this absence of borders will be evident at the IUPS World Congress in Birmingham in July, 2013. Over 50 nations will be represented, and some of them will be sending delegates for the first time, hopefully including Myanmar (Burma) and North Korea, where we have secured funding for travel fellowships. The Congress will be hosted by a society, that of the UK and Ireland, that has encouraged international cooperation ever since its foundation in 1876. The first minute books show how the young society welcomed guests from around the world even in the 19th century when travel was so much more difficult (8). No borders indeed. There is, however, another border that needs to be eliminated: that of the discipline itself. Physiology needs to reconnect with the mainstreams of biological thought and practice. Such reconnection would return us to our roots. Charles Darwin and Thomas Henry Huxley were both members of The Physiological Society. So were polymaths like George Henry Lewes. It was another 19th century physiologist, George Romanes, who coined the term neodarwinism. Yet, the 20th century witnessed a great fragmentation, as more specialist societies peeled off from physiology. Some of this specialization was benign. It recognized the need for biochemists, pharmacologists, pathologists, evolutionary biologists, neuroscientists, and many others to develop their own forums. But there was also a major development that was far from benign. A pincer movement, spearheaded by molecular biology on the one hand and evolutionary biology on the other, effectively squeezed physiology out from the mainstream. Of course, this is only a broad-brush description of what happened. There were always notable exceptions, including Jared Diamond and Knut Schmidt-Nielsen, both of whom spanned brilliantly between physiology and mainstream biology. It is worth recalling that Schmidt-Nielsen was President of IUPS and a founding editor of Physiology when it was called News in Physiological Sciences. IUPS has always reached out toward the other biological sciences and is now collaborating with other biological scientific unions within ICSU in organizing an inter-union satellite at the 2013 Congress. Both aspects of the pincer movement were, of course, unintended. But they were problematic nonetheless. Molecular biology created the undoubtedly exciting prospect of being able to work out all the molecular structures and mechanisms in physiological systems. To those with a mechanical frame of mind, this held out the prospect of completely understanding organisms from a bottom-up perspective. That view was reinforced by two developments in molecular biology: the coining of the term “genetic program” (by Ref. 6), later to be described as the “book of life” when the human genome project was launched, and the statement of the “central dogma of molecular biology” by Francis Crick (3). Both of these ideas and metaphors strongly reinforced the trend within evolutionary biology to relegate the phenotype to the role of a transient carrier of the “real” holders of the “secret of life,” the genes. The version of neo-darwinism that became the modern synthesis (4) went further. Genes became the real object of natural selection. Moreover, the source of variation was attributed to chance events, random mutations. But, if the source of change was entirely random, physiology would have no role whatever in understanding the process. It would become important only at the stage of selection among the random variations. Any influence of the environment on the genome, other than retrospectively through the selection process, was also excluded. No wonder that a central focus of biology became genes and their evolution. Within physiology itself, molecular biology and molecular genetics became dominant. In many cases, whole departments became devoted to these areas at the expense of more integrative approaches, whereas any contribution physiology might have to evolutionary biology was ignored. The wheels of evolution grind slowly, on time scales that are way beyond those of the great majority of physiological research. But two problems were waiting in the wings to upset this consensus. The first was subtle. It is more a philosophical problem than a scientific one. What precisely is meant when we talk about a gene (2)? When the term was introduced by Johanssen (7), it referred to a discrete inheritable phenotype: the gene for eye color, wrinkly peas, and all the other characteristics that could be identified as following Mendelian rules of inheritance. Notice that, although the assumption was that something inside the organism and transmitted through the gametes was the cause of this inheritance, they were defined in terms of function at the level of the phenotype. They were, therefore, hypothetical entities: the postulated causes of the observed phenotype. The modern molecular biological definition of a gene is very different. It is no longer hypothetical since it refers to a specific sequence or sequences of DNA. It has to be shown that it is the cause of particular phenotypes. This is problematic because organisms are robust and can buffer themselves against many forms of DNA variation, such as knockouts and mutations. Defining genes in terms of phenotypes so as to be equivalent to the original definition is difficult