The photos in John York's album suggest he was destined for a career in science. He's making hydrogen in the basement at age 9, banding a sparrow at age 11, showing off a radio-controlled plane he built at age 14, and assembling a canoe in a friend's garage at age 19. He majored in biochemistry, rather than any other branch of science, because he found chemistry "naked without application to biology" and because his father discouraged him from becoming a physicist, prophesying a lack of funding.
Another interest—computer science—made him wonder about the codes cells use when they talk to themselves, especially those involving inositol, a talented signaling molecule. He has since discovered more inositol codes than ever imagined and is exploring their roles in cell survival. "One of the things that attracted me to the field was that, by studying things no one knows much about, you can make quite an impact," he says.
As a graduate student with Philip Majerus at Washington University in St. Louis, York cloned the human gene for an inositol-signaling enzyme. This phosphate-removing enzyme, INPP, is inhibited by lithium, which is used to treat bipolar disorder. Through x-ray crystallography, York discovered that INPP shares a structural feature with six other phosphate-removing enzymes that lithium inhibits. By eliminating each enzyme in turn from mice, researchers are trying to explain lithium's actions. "If we could find one of the phosphatases that is a therapeutic or toxic target, we could try to design a drug that is specific to that one member of the family and not to all seven members," York says. "That should result in fewer side effects."
York finished his graduate studies in just three years, thanks to skills he acquired at Merck Research Labs. With encouragement and space from Majerus, he became an independent researcher instead of a postdoc. "That was risky, but I wanted to learn how to do yeast genetics so I could study inositol signaling in a simple system," he says.
He is trying to understand how cells use inositol codes to sense and adapt to their environments. The circular molecule has six arms that can be decorated—or not—with a phosphate group. Given the numerous permutations, inositol can present many codes to cells. But when York entered the field in the early 1990s, scientists thought its sole job was to release stored calcium. "It didn't make sense to me that if you were going to use something that can be phosphorylated in six places, you would use it for just one thing," he recalls.
He got more than he bargained for when he looked for the other things, because he discovered that IP3 (inositol with a phosphate group on three arms) is just the beginning of a signaling cascade that involves IP4, IP5, and IP6. More than 20 IPs are now known to be part of the fray, though most of their functions are unclear.
Using yeast, York's group systematically eliminated the enzymes that add phosphate groups to inositol and observed the biological consequences. To their surprise, they matched one of those enzymes to ARG82, a protein discovered 30 years earlier. ARG82 was known to be a transcription factor—a protein that binds to DNA to regulate the expression of specific genes. York discovered that ARG82, after cozying up to another protein on DNA, adds a phosphate group to IP3 if the latter becomes available. The product, IP4 then passes the signal on, triggering gene expression. "Our work solidifies the notion of nuclear IP messengers and provides a direct mechanism connecting IP signaling to transcriptional control," York says.
Several of the genes York has cloned were being studied by scientists who were interested in other processes while unaware of the genes' roles in inositol signaling. "So we feel as if we have gotten into a lot of different areas—gene transcription, RNA export from the nucleus, membrane trafficking, cell signaling, and nutrient responses," York says.
An encounter with another HHMI investigator in 2005 gave his work another twist. He had cloned the gene for the enzyme that converts IP6 into IP7 (which has two phosphate groups on one arm) but didn't know its function. Erin O'Shea, at Harvard, reported at a meeting that IP7 levels rise when yeast cells run short of phosphate, triggering a series of events that bring more phosphate into the cell. "We'd been looking for a function for the enzyme for many years," York says. "Sometimes a serendipitous observation allows you to act very quickly once you get all the right pieces."
The group is now exploring the functions of other IPs by searching for their receptors. "We would like to understand how these codes are interpreted," York explains.
The inositol field took another surprising turn when several labs discovered that IP6 is an integral part of certain proteins. "So as well as thinking about these molecules as being able to turn switches on and off, we think they might also control the landscape of the cell by affecting protein stability," York says. "We're very excited to see a whole new way in which cells use IP codes for regulation."
The group is also excited by their recent discovery that certain enzymes that add phosphate groups to inositol cause developmental mistakes in plants, flies, and mice. "So we are keen to find out how organisms alter patterns of IP molecules to give the different ensembles of messengers that enhance signaling specificity," York says.
