Unlike folks who equate work with drudgery, Danny Reinberg can’t wait to start each day. “Every day in the lab is just fascinating. It gives you something new,” he says. “It’s as if someone touched you when you were born and made you do something that would give you happiness for the rest of your life.”
One thing that makes him happy is studying proteins that associate with DNA.
Reinberg’s father didn’t approve of this career. He expected Reinberg to join the family business—or at least become a doctor or lawyer. But Reinberg became captivated by biochemistry while attending a small college in Chile. “I love how enzymes work together to accomplish something,” he says.
A transfer to Catholic University in Santiago was initially disappointing, because the classes and labs were geared to histology instead of biochemistry. But a young professor changed Reinberg’s scientific life and helped him find his way to Jerry Hurwitz’s lab at the Albert Einstein College of Medicine in New York, where he struggled with English and obtained a Ph.D. Five months into a postdoc at the University of California, Berkeley, he fled back to New York. “I am a very intense person,” he explains, “and I love the intensity of New York. There is no city like it in the world.”
Reinberg explores the biochemistry of gene transcription, which transfers information from DNA to the RNA that directs protein synthesis. When he became an independent researcher, he wanted to identify the factors that load RNA polymerase II (the enzyme that transcribes genes) correctly onto DNA. Because the field was so competitive, Reinberg’s friends advised him to choose a different topic. “But I said, ‘This is what I like, and I will continue working on it,’” he recalls.
The validity of his work was questioned at one point, because one of the proteins he isolated differed from the one thought to play its role. But Reinberg proved to be correct, and he later purified many of the proteins involved in loading the polymerase, cloned some of the genes, re-created the process in a test tube, and deduced the mechanism. “When faced with challenges to the veracity of one’s contributions,” he says “one of the beauties of science is that time always tells.”
Unlike the DNA in those test tubes, DNA in the cell is not naked; it wraps around histones. In human cells, this coiling shrinks 1.8 meters of DNA to about 90 millimeters. But genes in that configuration can be made inaccessible to RNA polymerase. So Reinberg wanted to know how the polymerase can move along DNA when confronted with the obstacle course the histones present.
After two years, his group isolated a key helper they called FACT. Other workers in the field dubbed the protein “the Reinberg artiFACT.” But again, Reinberg was correct. “If your assay is valid, eventually the other scientists will come back and acknowledge that you’re right,” he says.
Histones are partly responsible for the differences between cell types, because these proteins can lock up different sets of genes. The genes needed to make muscle fibers aren’t accessible in the insulin-producing cells in the pancreas, for example. Therefore, Reinberg is looking for proteins that modify histones. “There are factors that work to allow transcription and factors that repress transcription,” Reinberg says. “So I said, ‘Let’s look for representatives of each.’”
His group has now purified a cadre of proteins that allows histones to imprison genes. Many of them modify the histones. “The question now is what controls when they do what they do and how they do it,” Reinberg says.
A question even more on his mind is whether modifications to histones are retained during cell division so that a particular cell type can produce daughter cells of the same type. “We still don’t understand it, but we think we’re on the right track,” Reinberg says.
His long-term goal is to study how histones and their modifications function in ants, which form a society of workers and a queen, all with identical genes. “If you remove the queen, one of the workers becomes a new queen,” he explains. “This change in the programmed status of this lucky ant arises from changes in gene expression that reflect alterations in the histone components that structure the DNA.” With funding from HHMI, he has formed a consortium with Jürgen Liebig from Arizona State University and Shelley Berger from the Wistar Institute. “We were provided with sufficient funds to explore the beauty of ants,” Reinberg says. “Once we have finished genome sequencing, we are going to tackle how and if changes in histones and chromatin structure occur when ants change from workers to queens.”
Reinberg has been on the New York University faculty since 2006. But he often leaves Manhattan for Boston, where he cofounded the company Constellation Pharmaceuticals, which focuses on histone-modifying enzymes. “We’re looking for good markers for some of those enzymes being misregulated in different kinds of cancer and, down the road, in other types of disease as well,” he explains.
With so much to learn about histones, Reinberg dreads the days when he can’t be in the lab. “I am a very competitive person,” he says, “so I think I have found my niche in life.”