SUSAN MANGO TRACKS ORGAN DEVELOPMENT IN THE WORM
September 17th, 2009
After developmental biologist Susan Mango received a surprise call announcing her MacArthur Foundation Fellowship (casually dubbed a “genius grant”), congratulatory emails streamed in from New York, London, and Washington DC - places she had lived as her father, who was from Turkey, followed his career as a Byzantine historian.
The MacArthur Foundation cited her discoveries of the genes that control the formation and physiology of the digestive track - and that are often mutated in cancer and birth defects - and the role of the digestive track in starvation.
But the foundation also noted Mango's “infectious enthusiasm for science” and “clarity in thinking” - attributes that she has cultivated since her introduction to high school biology. “My teacher taught science as an intriguing puzzle to tussle with, not a collection of facts,” Mango recalls. “I loved the interplay of imagination and logic in science. I liked to ask questions about things that seem simple and then dream up experiments to test them. Inevitably, the experiments will give you unexpected results that prod you to formulate a new model to explain them and to try new experiments. It's fun.”
The fun continued when, as a biochemistry major at Harvard, she encountered Professor Richard Losick perching on a stool in freshman biology and brimming with “a sense of wonder of at the marvel of life.”
From Science to Art and Back Again
“I loved science but I was also interested in the arts,” Mango says. “My dream was to combine them in a career in art conservation.” After graduating, she worked among Rembrandts and other masters at the National Gallery of Art and the Smithsonian, puzzling over questions like whether a white fuzz on the oil paint represented mold or a chemical precipitate and then what do about it.
But she missed the logic of science, so she entered Princeton University for a Ph.D. in molecular biology and then concentrated on organ development as a postdoc in Judith Kimball's lab at the University of Wisconsin-Madison. “Lots of people were working on how individual cells were programmed, but few people were studying organogenesis. I wanted to know how cells organized themselves into groups with the specialized shapes and functions of an entire organ.” She was one of the first researchers to apply forward genetics - identifying mutations that produce a certain phenotype - to organogenesis.
Mango focused this work on the pharynx, or foregut (analogous to our throat, stomach and liver) in the tiny roundworm, Caenorhabditis elegans. When hatched, C. elegans has just 550 cells, and fewer than 100 comprise the developing pharynx. “That's an advantage because you get to know the individual cells and you can track how they turn genes on and off, change shape, and take on the functions of the pharynx,” she notes.
She continued these studies at her own lab at University of Utah, where she became the H.A. and Edna Benning Professor of Oncological Sciences in the Huntsman Cancer Institute. Why oncology? “Many of the genes that govern pharynx development also get mutated in cancer, so we can gain insights into the major pathways that initiate cancer by studying their normal roles in worms.”
Now, she is back in the Molecular and Cellular Biology Department as a newly appointed professor (and Losick's lab neighbor), happy to be amid the MCB's collegial atmosphere along with seven of her lab members from Utah.
A Beautiful Phenotype
After 13 years of research, Mango measures one special milestone: the birth of her son, now 10 years old. But she recalls several “Aha!” moments of unexpected results.
The first eureka moment came as a postdoc in the early 1990s when observing a plate of mutant worms that lacked just one gene, Pha-4, named for its role in pharynx development. These mutants had no pharynx but otherwise looked fine - until they died from malnourishment. “It was a beautiful phenotype, and I was fascinated that one gene could affect a whole group of cells that make up an entire organ. I wanted to know what Pha-4 did!”
Then in her own lab at Utah she discovered that the Pha-4 protein is a transcription factor that directly regulates an unexpectedly long list of other genes - that helped explained how the worm might lose an entire organ just by losing Pha-4.
Timing the Developmental Sequence
But just as children must do one-year-old behaviors before they do two-year old ones, a developing organ must turn on one set of genes before another. How does Pha-4 regulate these sets in the proper temporal sequence?
Typically, transcription factors head a hierarchy: Gene A turns on Gene B, which turns on Gene C, in a linear cascade. But Mango discovered that the Pha-4 works more like an umbrella, covering many gene targets all at once - but with different degrees of affinity. Like burrs on different textures, Pha-4 clings to some target genes stronger and longer, while it falls off more loosely bound genes sooner.
To unravel how the Pha-4 burrs bounce on and off of different gene targets to promote different activity during different developmental stages, Mango helped devise a method combining microarray analyses and computer algorithms that is now used by many other researchers.
During this time, Mango realized that Pha-4 resembles an ancient gene called FoxA that is present in all animals - and that is highly over-expressed in breast and prostate cancers. “It's very exciting because FoxA is always involved in forming the gut, but its downstream target genes are just now becoming known,” Mango explains.
Metabolism and Development
Among the seemingly simple questions a researcher intrigued by logical puzzles might ask is how our digestive track deals with nutrition and mobilizes the machinery for keeping our metabolism going. “Many animals, including humans, use genes in their gut to sense the amount of available food and to adjust their growth and development, including sexual maturity and aging,” Mango says. “We know that starvation during development can delay sexual maturity, for example, but that caloric restriction can also prolong lifespan.”
Also, the growing evidence of links between nutrition and the prevalence of cancer in the developed world makes her wonder if “our comfy well-fed lifestyle may help fuel cancer cells.” So she is tussling with that question by studying how food feeds into the Pha-4/FoxA pathway that influences development, longevity, and cancer. In 2008 she found an important clue when she showed that a gene called TOR, which slows aging in the worm and other animals, works through Pha-4/FoxA. Increasing TOR activity decreased Pha-4/FoxA activity downstream, for example. This interaction may help explain why worms fed a high-calorie diet had decreased lifespan and, conversely, why restricting calories lengthened lifespan.
Mango continues to investigate how the pharynx develops as an organ. How, for instance, does its tubular structure of tightly connected epithelial cells form? Surprisingly, the worm requires none of the genes considered critical for forming epithelial cells in vertebrates.
“We and others knocked out all those genes but the worm still made a pharynx,” she recalls. “So we are looking for the responsible genes by screening mutants that can't form the epithelia to see what genes they are missing.” Then she will figure out how these cells organize themselves into tubes, something she can literally watch happen in these tiny transparent embryos.
Pluripotency After All
But exactly how does the worm assign a group of still undifferentiated cells to a certain fate, such as becoming the pharynx? Previously, C. elegans researchers had charted how each embryonic cell divides and differentiates into various cell types in perfectly predictable and reproducible ways. Researchers thought the embryonic cell's fate was predetermined and immutable rather than plastic and pluripotent as in higher organisms.
“But we now realize that each early cell has many possible fates and lots of flexibility,” she says. “It could become muscle or gut or nerve. Only after it starts going down a particular path does it cut off other options. This means that many of the discoveries related to pluripotency in stem cells also apply to the worm embryo. Now the question is how do the worm's cells make the predictable decision on what they will become? What guides them so that we always get the same outcome?”
Mango is convinced that Pha-4/FoxA is part of the answer, and she is formulating new models and new experiments to test them in her new lab at MCB in hopes of discovering the rest of the mechanisms controlling this amazing process.
Although she no longer works in the art world, Mango still spends time in art museums, and with pictures in her head. “There's a visual aspect to biology,” she explains, “and I often imagine how processes happen visually, like seeing a Japanese anime movie of blobs of proteins on wiggly lines of DNA.”