More often than not, those who achieve success in their professional endeavors are motivated by an interest sparked early in life. MCB Professor Andy McMahon, with his studies of how embryos are formed, is no exception. “I’ve been interested in this since I was a kid,” McMahon says, snacking on sushi in his office on a gray, winter afternoon. “I used to read old biology textbooks for fun. Eventually, it all came together in trying to figure out how the early mammalian organism puts itself together. All of us are alive because of these functioning organ systems; I want to know how they get to that functional state.”
His curiosity has brought him to the leading edge of embryology. McMahon, who has just finished a three-year stint as Department head, is perhaps best known for his work describing cell-to-cell signaling in embryonic development. In November, 2004, this research garnered him the prestigious Senator Jacob Javits Award in the Neurosciences. This top prize provides for up to seven years of funding from the National Institute of Neurological Disorders and Stroke (NINDS). McMahon also leads investigations into the functional genetic organization of the kidney. His work reflects the diversity of the field: ranging from the early events that define embryonic body plans, to the molecular systems that govern formation of a complex organ.
McMahon attributes his work’s trajectory to “a lot of happy, chance situations.” “There hasn’t been a carefully reasoned plan of attack developed over 25 years,” he explains, speaking with the accent of his native England. “It’s really been a set of fortuitous, intuitive decisions made without really knowing what they would produce.”
The academic journey that brought McMahon to Harvard began at Oxford University. There, he completed his undergraduate degree in zoology, before moving onto a PhD in mammalian development at University College, in London. He came to the United States in 1981 for a postdoc at the California Institute of Technology, and then returned to England for several years to work as a staff scientist at the National Institute for Medical Research. In 1988 he came back to the United States, where he joined the now-defunct Roche Institute of Molecular Biology, in New Jersey. During this time, McMahon was also an adjunct professor in the Department of Genetics and Molecular Biology at Columbia University.
The call from Harvard came out of the blue, he recalls. Efforts to lure him to MCB were led in part by Doug Melton, who has remained a close friend and colleague ever since McMahon accepted the Department’s offer in 1992. “I guess it was one of those throw the balls up in the air kinds of decisions,” McMahon says with a smile. “But that’s what life is about: Trying out new experiences. This would be something new—working in a large teaching institute with a spectacular array of impressive colleagues. And as it turned out, the Roche Institute closed down several months after I left.”
McMahon traces his research on molecular signaling to a project in which he tried to identify the genes that regulate polarity along the embryonic axis in mice. At first, he and a postdoc with whom he was working in London divided embryos and looked for genes that might be present in one section of the organism and not another. But this approach ultimately failed, McMahon says, in part because the molecular screens that were available at the time weren’t sufficiently sensitive to detect the relatively low levels of expression of these regulatory factors.
Not to be deterred, McMahon looked at the problem in new way: He narrowed his search to oncogenes, assuming they might have regulatory properties because when they miss-regulate, they produce a important cellular consequences, such as cancer. As a further refinement, McMahon focused on oncogenes that encode signaling factors involved in cell-to-cell communication, which is required for interactions among developing tissues. Lastly, he limited the search to oncogenes that aren’t normally expressed in adult tissues, the inference being that their normal role is specific to the embryo.
(click for full size & legend)
Of the genes that emerged from that survey, one—Wnt1—has now also become a major focal point of McMahon’s research. With in-situ hybridization, McMahon was able to determine that Wnt1 is expressed exclusively in a subset of the developing nervous system, where it regulates development of the vertebrate mid-brain. Wnt1 pointed McMahon to another embryonic signaling molecule that has also played an important role in his career: Sonic hedgehog. Studies with mice in McMahon’s laboratory—and with fruitflies, chicks, and fish elsewhere—have shown that sonic hedgehog triggers undifferentiated embryonic cells to form complex structures, such as the pattern of nerves in the spinal cord, or fingers on the hand.
“A major focus of our work is trying to understand how this very important regulatory pathway operates,” he says. “And there are major questions to be answered at every stage of this process. For instance, we’d like to understand how sonic hedgehog moves through its target field and we’d like to know more about how it does that in real time.” To address these questions, McMahon uses GFP-tagged alleles for sonic hedgehog that he visualizes with a variety of sophisticated imaging techniques. Assisting him in this endeavor is MCB Professor Jeff Lichtman, whom McMahon describes as “one of the world’s experts in live imaging.”
McMahon relates that sonic hedgehog induces at least six classes of cells in the embryonic neural tube (the embryonic structure that gives rise to the brain and spinal cord). A remarkable feature of this process is its sensitivity: Slight signaling variations can induce one type of neural progenitor to switch its fate to that of another. How does the system accommodate these fluctuations, which vary as a part of normal physiology? The answer, McMahon suggests, is found in the feedback mechanisms that regulate the system. With these mechanisms, high levels of sonic hedgehog induce a set of genes that cause its levels to drop. Low levels of sonic hedgehog, on the other hand, fail to activate this mechanism, thus allowing more prolonged signaling to occur.
McMahon says he’s “very keen” to understand these control systems; not just because they are developmentally important, but because they may also play a role in cancer. Medulloblastoma, for instance, is a childhood brain tumor that forms when granule cells in the cerebellum proliferate in response to sonic hedgehog levels that are abnormally high. “If you could find a way to silence sonic hedgehog in those cells, you might be able to treat the tumor,” McMahon says. “And there are encouraging experiments showing that some small molecules can do that.”
Mapping Kidney Transcription Factors
The other major aspect of McMahon’s work concerns kidney development—and more specifically—the processes that govern formation of the kidney’s functional unit, which is the nephron. Each kidney contains roughly one million of these units, which perform the organ’s physiological roles, such as removal of waste biproducts. McMahon’s chief goal is to understand the genetic signals and pathways that dictate nephron development. With funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), he has launched a project to map all the transcription factors found in the developing mouse kidney.
The justification for this approach is two-fold, McMahon says. First, transcription factors are genetic markers for specific cell populations. And second, transcription factors control genetic activity. Therefore, they provide a useful framework for analysis—scientists can interrogate a factor’s activity in part by assessing its location. By mapping these factors in high detail, scientists in McMahon’s laboratory will study how and why specific sets of genes in the nephron are activated and how their arrangement modulates kidney physiology. An underlying theme expressed throughout much of this research involves the development of sophisticated genetic approaches for unraveling complex cellular mechanisms.
Reflecting on his career philosophy, McMahon says he’s reluctant to spend time analyzing the past. “I tend not to dwell on things that have already happened,” he says. “And I don’t tend to look for significance in our work to produce a justification for it. We try to do things that are worth doing and that are more broadly applicable beyond the question that we’re trying to answer. And if people think it’s interesting, then that’s great.”
Gray P.A., Fu H., Luo P., Zhao Q., Yu J., Ferrari A., Tenzen T., Yuk D.I., Tsung E.F., Cai Z., Alberta J.A., Cheng L.P., Liu Y., Stenman J.M., Valerius M.T., Billings N., Kim H.A., Greenberg M.E., McMahon A.P., Rowitch D.H., Stiles C.D., Ma Q. (2004). Mouse brain organization revealed through direct genome-scale TF expression analysis. Science. 306: 2255-7. [Pubmed]
Tian H., Jeong J., Harfe B.D., Tabin C.J., McMahon A.P. (2005). Mouse Disp1 is required in sonic hedgehog-expressing cells for paracrine activity of the cholesterol-modified ligand. Development. 132: 133-42. [Pubmed]
Jeong J., McMahon A.P. (2005). Growth and pattern of the mammalian neural tube are governed by partially overlapping feedback activities of the hedgehog antagonists patched 1 and Hhip1. Development. 132: 143-54. [Pubmed]
Harfe B.D., Scherz P.J., Nissim S., Tian H., McMahon A.P., Tabin C.J. (2004). Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell. 118: 517-28. [Pubmed]
Scherz P.J., Harfe B.D., McMahon A.P., Tabin C.J. (2004) The limb bud Shh-Fgf feedback loop is terminated by expansion of former ZPA cells. Science. 305: 396-9. [Pubmed]
Jeong, J., Mao, J., Tenzen, T., Kottmann, A.H. and McMahon, A.P. (2004) Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia. Genes & Development. 18: 937-951. [Pubmed]
Carroll, T.J. and McMahon, A.P. (2003) Overview: The Molecular Basis of Kidney Development. In: “The Kidney: From Normal Development to Congenital Disease.” Vize, P.D., Woolf, A.S., and Bard, J.B.L., eds. Academic Press, Inc., London, p. 343-376.