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Physiology Is Back in Fashion

We all know that in fashion--if you wait long enough--each trend will come around again. The same, it seems, is also true of science. "Everybody was an integrative physiologist in the '80s," says Tim Tully of Cold Spring Harbor Laboratoryin New York. "But," adds Tully, who was in London on 25 March to take part in a meeting organised by the Wellcome Trust to highlight emerging opportunities for linking genomics, molecular biology, and whole-organism physiology, "molecular biology displaced physiology by channelling the energies [of the next generation of scientists]."

Driven by the success of the Human Genome Project, smart scientists are shaking out their metaphorical stay-press trousers and ra-ra skirts and once again looking at the big picture. "Molecular biology has provided more experimental tools, but the physiological questions remain," explains Tully, who, now that the genome project is nearing completion, is looking for ways to apply "molecular tools to physiology." Although some 30,000 human genes have now been identified, "only a fraction of these genes have been experimentally tested for their function," pointed out Allan Bradley of the Sanger Institute in Hinxton, U.K., at the same Wellcome Trust meeting.

Nevertheless, the increasing availability of gene sequences from many species allows scientists to integrate multiple techniques, systems, and models to connect genomics to specific physiological questions. Many research groups around the world have started bringing disciplines back together. The study of the genetics of behaviour in an organism as simple as the nematode worm Caenorhabditis elegans is a case in point. "It is possible to trace the effects of a nucleotide change in an ion-channel gene through the likely change in channel structure, changes in kinetics and biophysics, changes in the electrophysiological properties of the cell, [and] changes in the muscle contractions driven by membrane potential, to the changes in muscle motions that we recognise as abnormal behaviour," said Leon Avery of the Department of Molecular Biology at the University of Texas Southwestern Medical Center in Dallas.

The most controversial aspect of postgenomic integrative physiology is the concept that it will be possible to transfer knowledge across species. "When you identify a gene and its biology in an animal, there is a chance it will have a similar role all the way up to humans," said Tully. "Even at a molecular level, there is a basic core theme of biology, and different species only have different variations. The gene is the common currency of biology."

Scientists interested in applying their skills in this reemerging field face many challenges. Above all, they will need to be multidisciplinary, able to work with complex systems, and able to handle research at levels ranging from intracellular signalling to intact organisms. "There is a cry for more integration and for people with very diverse training," said Peter Davies of the Institute for Medicine and Engineering at the University of Pennsylvania in Philadelphia. The success of integrative physiology will depend crucially on establishing global networks with free transfer of skills and information, as well as close collaboration with clinicians. "I have been told that the USA is leading the way in integrative physiology, but I do not think anyone is in the lead on how to use complex genetics to understand complex human diseases--it is wide open," said Ken Chien of the Institute of Molecular Medicine at the University of California, San Diego.

The Physiology and Pharmacology Panel of the Wellcome Trust, together with the Biotechnology and Biological Sciences Research Council's functional genomics initiative, has been at the forefront of identifying the need to stimulate development of integrative physiology in the United Kingdom. "The Wellcome Trust has put in place a one-off initiative to provide training funds for Ph.D. students, postdocs, or clinicians within institutions that bring a variety of skills together," explained Michael Wilkinson, manager of the trust's Physiology and Pharmacology Programme. Three groups--one in Oxford, one in Cambridge and Oxford, and one at Imperial College, University College London, and King's College London--have already been awarded £5 million each over 5 years, and Wilkinson would welcome applications from other groups. He hopes the initiative will encourage people to think in new ways.

Judging by their numbers at the Wellcome Trust-sponsored conference, a number of young scientists are doing just that. Although the majority of the scientists in attendance were already applying an integrative approach in their research, the few who were not needed little persuasion to acknowledge its tremendous potential. The more experienced scientists were confident that the coming generation as a whole would be open to adopting an integrative physiology approach to their research. "I am extremely optimistic for scientific diversity, because scientists have a peripheral vision for techniques that affect them," said Peter Currie of the Medical Research Council's Human Genetics Unit in Edinburgh. "If you never read any journal [from disciplines other than yours], you will be a dinosaur and die--but if you came to this meeting with an open mind, you will do something new and exciting."

Paradoxically, although the postgenomic integrative approach has its roots in the genome project, some project contributors do not yet see themselves as postgenomicists. "Life is the translation of the information in the genome into the organism," said Hans Lehrach of the Max Planck Institute for Molecular Genetics in Berlin. "Once we can compute the phenotype from genes, I will say that we are in a 'postgenomic era,' but we still need a few hundred years. Ultimately we want to predict what is going to happen, like meteorologists do, and systematic analyses of many aspects of genes will have an important role in the future."

Meanwhile, the genome project looks set to revolutionise research in ways that go far beyond simply prompting a return to the integrative approach. Whereas research has traditionally been driven by hypotheses, the genome project has introduced the concept of the systematic generation of data with an increased role for database searches and experimental automation. "Though currently the generation of systematic data is restricted to sequence analysis, it is obvious it will cover a larger and larger fraction of biological research," asserted Lehrach. "In the longer term, we expect that biological processes will ultimately be too complex to be more than superficially 'understood' in the classical sense. We will then increasingly have to develop simulation systems able to predict results, and in my view computer simulation will increasingly complement over the next decades, and ultimately maybe even dominate, the 'wet' lab approach to biological research."

So, although some past scientific fashions may be back on the scene, research will continue to move on. Given what Lehrach and others are saying, you might just want to accessorise your bench skills with some carefully chosen computational techniques if you want to keep pace with the changes.

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