Age: 28 | Graduate student | Weizmann Institute of Science
Yaakov Benenson wants to shrink your doctor. Or more accurately, he wants to replace physicians with molecular machines that diagnose and treat diseases with phenomenal precision, each what he calls a “doctor in a cell.”
In just five years, Benenson has taken the concept from drawing board to test-tube prototype. Working at the Weizmann Institute of Science in Rehovot, Israel, he has built molecular devices – essentially DNA strands and enzymes – able to analyze genetic changes associated with lung and prostate cancers and to release a drug in response. These prototypes are “a beautiful work of molecular and conceptual integration, pointing the way toward truly integrating diagnostics with therapeutics,” says George Church, director of the Center for Computational Genetics at Harvard Medical School.
“Using these tiny diagnostic machines, we could selectively treat only the diseased cells,” Benenson says. For example, the prototype device for small-cell lung cancer assesses the activity of four genes. Cancerous cells produce extra RNA copies of each of these genes. Consecutive sections of the DNA strand in the prototype bind, in turn, to these RNA strands; when they do, an enzyme chops them off. If all of the cuts are made properly, the enzyme releases and activates an anticancer drug that has been tethered to the DNA in an inactive form.
Benenson’s molecular machines offer a unique combination of precision and flexibility. A single one of them can be designed to look for up to 10 different diagnostic markers before it releases its drug payload. The devices can also be tailored to several different diseases through simple-to-make changes in their DNA sequences.
These machines represent a quantum leap not only in medicine but also in DNA computing. Benenson’s molecular “doctors” – which are computers in the sense that they store information and analyze it following a yes/no logic – are “directed at a practical interface with biomedicine rather than losing an abstract race with existing computers on their own turf,” says Church.
It will be a while before molecular machines replace existing systems of diagnosis and treatment: Benenson estimates three or four years before even simple versions that work in a living cell are ready, and perhaps decades before they can be tried in people. If the DNA doctors prove as successful in the body as they have in the lab, though, they might spark a revolution in medicine.
Age: 32 | Cofounder and CEO | Gene Network Sciences
Four out of five drugs fail in human trials. But Colin Hill says that at his Ithaca, NY, startup, “We think we are the answer.” The physicist turned entrepreneur aims to more than double human trials’ success rate by virtually prescreening drugs in computer models of human cells. His company uses these “virtual cells” to uncover how the compounds work and predict which ones will fare best in human tests. Drugmakers share his enthusiasm: his company has deals with two of the top five drug firms.
Age: 30 | Postdoctoral fellow | University of California, San Francisco
Tuberculosis kills two million people every year, a tragedy of which Smruti Vidwans was all too aware growing up in India. Resistance to TB drugs is on the rise, and Vidwans thinks the solution may be new drugs that don’t kill the bacteria but block the proteins that allow them to reproduce in people. She’s launching a company to develop such drugs. It’s a huge challenge, but those who know her say she’s up to the task.
Age: 32 | Assistant professor | Harvard University
Xiaowei Zhuang makes movies of the invisible. Peering into a microscope, she has filmed a single influenza virus infecting a cell. Her studies mark the first time anyone has recorded the stages of this process.
Zhuang accomplished this feat by attaching fluorescent molecular tags to the virus; when excited with a laser, the tags emit specific colors of light. She has used the approach to track the behavior of not only individual viruses but even individual molecules, such as strands of RNA, at unprecedented levels of detail. Coming from a traditional physics PhD program, Zhuang very quickly began to lead experiments in single-molecule biophysics as a postdoc in Steven Chu’s lab at Stanford University. “With total ease, she immersed herself in biological physics and did an astounding amount of seminal work,” Chu says. Since establishing her own lab at Harvard, Zhuang has continued to do “landmark experiments at a blistering pace,” he adds.
Direct observations of individual molecules are essential to really understanding how life works, Zhuang believes. “In the biology world, there are a lot of very small things that are doing critical functions,” she says. “There is a lot of interesting dynamic information one can get out of this kind of single-particle approach.” In her work on the flu virus, for example, Zhuang discovered that viruses move through the cell in three stages – one of which is so short that it could only be directly observed with high-speed imaging. “This experiment revealed unprecedented details of virus infection pathways,” says Harvard chemist Sunney Xie.
Eventually, this in-depth understanding of how viruses work will help researchers find entirely new ways of blocking viral infection, Zhuang says. Indeed, virologists have begun asking to work with Zhuang, hoping to use her methods to study their own pet viruses.