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The combination of chemistry and genetics is one that other scientists have joined forces to explore. HHMI investigator Gerald Crabtree, a developmental biologist at the Stanford University School of Medicine, frequently collaborates with Stuart Schreiber, a chemist and HHMI investigator at Harvard University and the Broad Institute. Crabtree studies how signals from other cells or the surrounding environment are transmitted into a cell, eventually leading to changes in gene expression. Schreiber, with his organic chemistry training, can build molecules that block these signals at any step along the way.
Their first collaboration, in the 1990s, showed how an immunosuppressant drug blocks immune cell functioning. Schreiber altered different parts of the immunosuppressant at a time. After each chemical alteration, Crabtree tested whether the drug still blocked immune function.
“That collaboration allowed us to say which regions of the molecule were essential and to accurately order each of the steps of the pathway,” says Crabtree.
Despite being on opposite coasts of the country, the two continue to use small molecules designed by Schreiber to block chemical reactions within the cell. “Sometimes I’ll have a question about how a biological process works, and I’ll ask him how we can study this chemically,” says Crabtree. “Other times he’ll be interested in a particular molecule he’s made and approach me about studying what it does in the cell. Such molecules allow biologists to order and test biological pathways and circuits. They also provide verification for mathematical models of how things work, an essential aspect of modern biology.”
“The marriage of biology and chemistry has never been more important than today.”
Stuart Schreiber
Schreiber is seeing more scientists embarking on this kind of collaboration. He says that now is a defining time in the intersection of chemistry and biology. He compares it, in fact, with the aftermath of Sputnik and the challenge by President Kennedy to send a spaceship to the moon.
“Kennedy didn’t propose that a group of very smart physicists come together to calculate the thrust required of a rocket to escape our atmosphere. He brought many types of scientists—physicists, engineers, mathematicians, even biologists—together. And he didn’t just have them calculate what would be needed to build a rocket. He had them actually do it. Fly a rocket to the moon.”
Biology without chemistry, Schreiber says, is like “hypothesizing without testing things.” Together, biologists and chemists might not be able to fly a rocket to the moon, but they can test biological hypotheses—and do things—using compounds created by chemists.
“The marriage of biology and chemistry has never been more important than today,” he says. “We are in a position to use small molecules to test emerging concepts in human disease in physiologically relevant settings.”
Learning from Biology
There are biological mysteries that chemistry can help solve, and there are also chemical phenomena that the biological world can help explain. The ultimate goal of the field of chemistry historically has been to be able to synthesize any molecule in the most efficient way possible. And Nature often is the best teacher when it comes to efficiency. The ways that cells produce chemicals—whether they’re hormones, defensive molecules, or signals between cells—have been culled by billions of years of evolution.
“Natural enzymes are generally really efficient and good at their jobs,” says Wilfred van der Donk, an HHMI investigator at the University of Illinois at Urbana–Champaign. Van der Donk, a chemist by training, takes apart reactions that occur in the natural world to learn how chemists can carry out the same reactions more efficiently in the lab.
Microbial cells naturally produce all sorts of antibiotics and antifungal chemicals, for example. His lab hopes to distinguish how cells do it and figure out which of these products have potential as human drugs. In a paper published July 19, 2011, in Journal of the American Chemical Society, van der Donk pieced apart how cells make one antibiotic that’s currently in clinical development against cystic fibrosis. Understanding how the cell makes the chemical could help him design related molecules that also fight cystic fibrosis.
And then there’s cellular chemistry that’s like nothing chemists can do in the lab. He wants to understand that too.
“There are enzymes that do reactions where, as a chemist, you look at it and scratch your head and say ‘How can we do that?’”
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