Biochemistry, Molecular Biology
New York University
Dr. Nudler is also Julie Wilson Anderson Professor, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine.
Cellular Stress Responses
Evgeny Nudler vividly remembers the Moscow lab where his microbiologist father raised bacterial strains for pharmaceutical research. "I was very impressed by his petri dishes," Nudler says. The bacterial cultures "were all sorts of colors." Nudler decided to follow in father's footsteps. "If he's interested in this, I thought, I should go in the same direction."
When Nudler began his university studies, historic events were unfolding in the Soviet Union. With the fall of communism, Nudler seized an opportunity to travel to the United States to work with Alex Goldfarb, a Soviet émigré and dissident who had relocated to Columbia University in New York. Nudler made his first significant discoveries in Goldfarb's lab while studying transcription, a step in protein synthesis during which the enzyme RNA polymerase fashions an RNA copy of a gene, known as messenger RNA. Researchers had thought that RNA polymerase moved along the DNA by inchworming—contracting and expanding—as it advanced. But Nudler and colleagues demonstrated that the enzyme repeatedly slides forward a certain distance and then slips back, a maneuver he calls backtracking.
"That finding was the foundation for many of the projects in my career," says Nudler, who began building on the result when he started his own lab in 1997 at the New York University School of Medicine. Backtracking isn't a mere hitch in RNA polymerase's progress, his team has found. The enzyme's herky-jerky movement influences how much RNA a cell can synthesize as well as its ability to repair and copy its DNA. For example, studying bacteria, his lab revealed in 2010 that ribosomes, the cell's protein-manufacturing organelles, prevent RNA polymerase from backtracking, thus speeding the completion of messenger RNA molecules and precisely coordinating protein synthesis with that of corresponding RNA.
Nudler's fascination with transcription also allowed him to discover a hidden talent of RNA. Bacteria make the molecules thiamin and riboflavin, which are crucial for many metabolic reactions. The mystery was how bacteria control their production. "Cells don't want to synthesize riboflavin if they already have lots of it," Nudler says.
Researchers suspected that a protein sensed the amounts of these molecules and then shut off their synthesis at the appropriate level, but Nudler's team searched in vain for a protein that could do the job. To their surprise, they found specific messenger RNA molecules that monitor thiamin and riboflavin quantities in bacterial cells. A group led by Yale University's Ronald Breaker, also an HHMI investigator, independently identified these so-called riboswitches at the same time.
Ready to branch out from transcription, Nudler and his colleagues began probing how cells add nitrogen-containing compounds to their proteins, a modification that can alter a protein's activity. After a few twists and turns, the researchers learned that bacteria use the gases nitric oxide and hydrogen sulfide for protection. The compounds enable bacteria to withstand antibiotics, shield them from the ill effects of oxidative stress, and foil their host's immune system. Researchers knew that these gases are important in our bodies, but their role in bacteria came as a surprise, Nudler says. "That means bacteria invented these things." It also means that drugs that block nitric oxide or hydrogen sulfide may add punch to antibiotics—a possibility his lab is now exploring.
His team is also exploring the link between bacterial metabolism and aging. Nudler and colleagues recently showed that nematode worms cannot make nitric oxide, but they can absorb it from certain bacteria that live in their bodies. They found that worms inhabited by bacteria that can produce the gas outlive worms colonized by microbes that cannot synthesize it. Plus, they found, the gas activates major anti-aging biochemical pathways in the worm. Our intestines teem with bacteria that affect our health; perhaps, Nudler says, some of them influence our life spans.
From the mechanics of transcription to antibiotic resistance to aging, diversity is the hallmark of Nudler's career. Talented lab members and good fortune partly explain his success, Nudler says. "We've been lucky in that when we started on something and spent time on it, we were rewarded." Another key, he adds, is being willing to follow up on results that may never pan out. "If you find something unexpected that does not fit your theory, you can discard it or you can explore it."