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Elite Scientific Endeavor
MODELS AVIAN LIMB DEVELOPMENT USING SYSTEMS BIOLOGY

The research collaboration of Stuart A. Newman, Ph.D., with a mathematician, computer scientist and three physicists is funded by a $3 million grant from the National Science Foundation.

Marjorie Roberts

ABOVE: The intellectual curiosity that abounds in Stuart A. Newman, Ph.D., has led him to collaborate with five other scientists in a project funded by the National Science Foundation. Using a systems biology approach, the group will advance his avian vertebrate limb research that he began 25 years ago. A developmental biologist, Dr. Newman has a reputation for taking a critical stance on human applications of research in this field. But in his department, the soft-spoken scientist is best known as a dedicated adviser for the doctoral candidates who work in his laboratory.
What sort of individual would choose to spend much of his life studying how wings of chicken and quail take form? To figure out the answer, it helps to be intimately familiar with the extraordinary discipline of basic science. A confirmed member of this subculture, Stuart A. Newman, Ph.D., is blunt about what has motivated his avian concentration-"intellectual curiosity," with little concession to practical medical rationale such as finding the cause of birth defects in the limbs of newborns. "Those are worthy goals," says the professor of cell biology and anatomy and of medicine, "just not my main motivation for doing scientific work." Even now, after having committed the last 25 years to the study of the avian vertebrate limb, the developmental biologist continues the investigation by channeling his research to fit in with the goals of a remarkable association with five colleagues from other universities who are collaborating through a National Science Foundation grant of $3 million over five years. Its title, "Biocomplexity: Multi-Scale Modeling of Avian Limb Development," reflects Dr. Newman's importance to the project, especially since he's the only biologist among them.

If this scientific pursuit brings fame to the group it will be nothing new for Dr. Newman, who already has a reputation for shaking up his profession. Several years ago Dr. Newman and Jeremy Rifkin, a writer and social critic who made his name by bringing legal action to stop certain kinds of genetic experimentation, applied for a U.S. patent to protect their method of creating new part-human life forms by gene manipulation. Their stated goals did not include actually making such creatures, but rather to promote public discussion on the new reproductive technologies emerging from developmental biology and to prevent other scientists from manipulating human biology with potentially dire consequences such as unprecedented birth defects. Their application was denied, but they have continued to contest the rejection and the controversy remains at a simmer in Congress. Dr. Newman stands by his convictions that certain kinds of gene therapy are a disaster waiting to happen, and although he doesn't justify his research by any direct benefits to society, he continues to write and speak in related policy areas to ensure that the fruits of developmental biology don't get misused. He avows that he is not bothered in the least by applications of this work to tissue and organ repair that don't attempt to redesign the human species.

Progressive changes in the cartilage skeleton of the chicken wing bud between 4 and 7 days of development are represented in these cross sectional drawings. The stippling represents precartilage cell aggregates known as condensations; the solid white represents definitive cartilage. Corresponding changes take place in the human embryo between days 30 and 50 of development. The cartilage skeleton is replaced by bone during later fetal development in both species.
Successful laboratory

At New York Medical College Dr. Newman's celebrity is less contentious. He was an early winner of the Dean's Distinguished Research Award in 1994, and has been lauded at the annual Author Recognition Celebration at the Health Sciences Library every year since its inception in 1993. From his laboratory have come discoveries of "matrix-driven translocation," a physically-based mode of tissue morphogenesis, as well as the roles of transforming growth factor beta (TGF beta) and the type 2 receptor for fibroblast growth factors (FGFs) in the development of the limb skeletal pattern. For example, if "alternative splicing" of the FGF receptor goes wrong and limb cells produce aberrant versions of that protein, properly spaced bones fail to form and anomalies are generated in the skeleton. A quarter century ago Dr. Newman and a physicist colleague, H.L. Frisch, laid out a mathematical theory of limb pattern formation in an article in the journal Science, but most of these growth factors and signaling mechanisms were unknown at the time. "All we knew then was that some adhesive molecules caused cells to enter into patterned structures-for example, fibronectin holding cells together," says Dr. Newman. "Its concentration was one of the variables in our original model of limb development."

It was not the busy Stuart Newman who had the impetus to form the eclectic sextet, but James A. Glazier, Ph.D., a physicist and professor at the University of Notre Dame with whom Dr. Newman had previously collaborated. Dr. Glazier has since moved on to Indiana University, but still at Notre Dame are Mark Alber, Ph.D., professor of mathematics, and Jesus Izaguirre, Ph.D., professor of computer science and engineering. Rounding out the team are Gabor Forgacs, Ph.D., professor of physics and biology at the University of Missouri, and George Hentschel, Ph.D., professor of physics at Emory University.

Systems biology

The study is designed to develop genetic, cellular and supercellular understanding of complex organ formation by focusing on avian limb development at multiple scales-molecular, cellular, tissue and organ levels-as a general model for organogenesis. Using chicken and sometimes quail, the research comprises experimental, computational and theoretical components to develop an integrated simulation of limb development that ultimately can be customized to fit the genesis of other organs. If the need for experts in physics and mathematics seems puzzling, it helps to recognize that it takes physicists to explain the phenomenon of patterning, such as waves on water, stripes on a zebra or fingers on the hand, and mathematicians to express many of the group's findings in the form of equations, which appear throughout their papers. Computer-generated renditions provide a way to bring the equations "alive" by simulating limb development.

ABOVE: Dr. Newman is assisted in his laboratory by graduate student Nadya Mezentseva, left, and by Jaliya Kumaratilake, M.D., Ph.D. The Russian Ph.D., candidate is investigating molecular control of differentiation in limb bud stem cells. Dr. Kumaratilake, a visiting scientist from the University of Adelaide in Australia, is an electron microscopist who is collaborating with Dr. Newman on several other aspects of development, including a project on the developing visual system with cell biology colleague Alan D. Springer, Ph.D.
"We need math and physics to explain how the interactions of the proteins and other biomolecules all cooperate together to make a skeletal pattern like that of the chicken limb," Dr. Newman asserts. "This is systems biology-the linking of mathematical equations and biochemistry and genetics as a way of dealing with complexity-seeking an explanation for forms and patterns that appear during embryonic development rather than simply crediting the genes exclusively." He made his case last summer in an article he wrote for the bulletin GeneWatch. The title alone, "The Fall and Rise of Systems Biology-Recovering from a Half-Century Gene Binge," said it all.

Gene bashing

Dr. Newman continues to refine his philosophy in step with his research on limb development. Dr. Newman explains the rationale for his campaign against "genetic reductionism," the notion that all biological phenomena are simply a reflection of their genes.

"Knowledge of genes alone cannot provide a complete understanding of an organism's significant traits, its shape and form, its behaviors, and so forth, because these traits are generated during the organism's embryonic development or later in life by systems of interactions across many levels," he stated. "Genes and their RNA and protein products are only a subset of the components of developing systems.

Swimming against the gene tide is not something the soft-spoken Dr. Newman ever anticipated. After the native New Yorker received his undergraduate degree (cum laude) at Columbia, he chose the University of Chicago for a Ph.D. in chemical physics. "Many people who entered physical science for purely intellectual reasons found their work applied to atomic and chemical weaponry," he recalls. "I did not want to participate in work that was going to be used for destructive purposes, so I went into a field that was intellectually highly challenging, but was seen as something of a backwater of science because of its small likelihood to ever yield practical applications. I had no idea developmental biology would turn into Big Science. How ironic it is that it is arguably the biggest one ever."

Great productivity

The biocomplexity consortium has produced half a dozen papers and is likely to turn out at least as many more, he states. "We can't renew this grant but we are applying for other funding to keep the work going." Despite his own non-practical motivations, he cannot resist pointing out the potential applications of such basic research. "The biological sciences produce spin-offs into other areas," he asserts, "because if you know how something develops, you get insight into repair. For example, the salamander can regenerate limbs, reactivating many of the same processes occurring during embryonic limb development. Our ultimate goal is to understand a developmental process from many levels-from genetic to biochemical and cellular to physical interactions among the components."

A schematic of the model proposed by Dr. Newman and colleagues shows formation of discrete cartilage skeletal elements by a "self-organizing" biochemical network. (Top) The signal protein TGF-beta (red arrows) stimulates formation of precartilage cell aggregates, as well as its own production. Unchecked it would cause the entire developing limb tissue to condense and to eventually form an amorphous mass of cartilage. (Bottom) If the sites of condensation also release an inhibitor of TGF-beta that diffuses away from its source, expansion of the condensations is restricted and a pattern of well-spaced cartilage elements is produced. - Courtesy of S. A. Newman.
One look at Dr. Newman's CV evinces a prolific writer of articles, chapters and books; a wanderlust that is satisfied by traveling to exotic sites to give invited talks, and a history of mentoring Ph.D. candidates. His pride in their achievements is reflected in a display of champagne bottles that he keeps within arm's length of his computer, where he spends the greater part of each day. His newest triumph is a book that was published last year by the MIT press entitled, Origination of Organismal Form: Beyond the Gene in Developmental and Evolutionary Biology, a 15-chapter multi-authored tome. Besides acting as editors, he and Dr. Gerd Muller wrote the introductory chapter and Dr. Newman wrote a separate chapter on physical mechanisms of morphogenesis. Co-author Muller, a professor at the University of Vienna, and he have received "enthusiastic reactions from philosophers of science as well as other biologists," Dr. Newman relates. "This book deals not only with how structures develop in embryos, but how they originated in the history of the species." He is also well along on a textbook, The Biological Physics of Embryonic Development, scheduled for publication in 2005 by the Cambridge University Press. Dr. Newman is writing it with Dr. Gabor Forgacs, the University of Missouri physicist in his systems biology group.

"We are pitching it to advanced undergraduates and graduate students in biological physics," he says. "It covers the major processes of early development, including formation of embryos with their distinct layers of tissue and differentiated cell types, and various organs, limbs, the circulatory system and the central nervous system. We show how these phenomena are as much physical processes as they are molecular and genetic."