When Hurricane Sandy’s colossal storm surge slammed into NYU Langone Medical Center on October 29, 2012, it knocked out the power and forced the evacuation of 322 inpatients, including premature babies.
No human lives were lost, miraculously, but thousands of research rodents drowned when saltwater flooded labs.
The 900 mice living in the laboratory of Jane Skok, PhD, professor of pathology at NYU School of Medicine, survived, but at a cost. “We didn’t lose our mice, but they were traumatized, and they wouldn’t breed properly,” recalls Dr. Skok. What’s more, precious reagents stored in her freezers melted.
After the building that housed her lab shut down, her team moved to laboratory space at NYU. It took her more than a year to restore the status quo. “Losing everything is devastating,” Dr. Skok says. “But we took the long view that if we couldn’t test things easily, we should start over.”
Dr. Skok, who arrived at NYU Langone in 2006, is no stranger to dramatic do-overs. Born in Johannesburg, she has pursued a path that has taken her, by twists and turns, through the labyrinths of genetics and immunology.
That journey included a 12-year break from the lab, after she completed her PhD thesis in genetics while raising 2 young children, 1 of them frequently hospitalized with serious kidney problems. When Dr. Skok returned to science in 1997—by then a mother of four—she hadn’t read a single scientific paper in more than a decade. Despite this gap, “she not only came back to science but came back and became a leader of her field,” says cancer biologist Iannis Aifantis, PhD, the Hermann M. Biggs Professor and chair of the Department of Pathology at NYU Langone Health, who is a close collaborator.
Dr. Skok’s field, specifically, is nuclear organization, or the science of how cells store an impossibly large amount of genetic information inside an impossibly small amount of space.
In particular, she studies the enduring puzzle of how B and T cells—the linchpins of the adaptive immune system—can generate more than 100 billion different antibodies and T-cell receptors, drawing from the limited genetic material of a handful of genes inside the nucleus of each cell.
Cracking this puzzle has profound implications for the treatment of certain blood cancers and immune disorders, which can arise when the process goes awry.
Many people, when they picture DNA, might think of the famous model constructed by James Watson and Francis Crick in 1953: a double helix, with strands neatly wound around an axis like a spiral staircase. The reality is that in human cells, nuclear DNA looks more like a ball of knotted wool.
“Dr. Skok’s work showed that variable regions of DNA that are far from each other on a linear chromosome actually find partners as frequently as those close by. The system she has elucidated provides equal opportunities for all.”—Kees Murre, PhD, Professor of Molecular Biology at the University of California, San Diego
If untangled, the DNA from each cell would stretch 6.5 feet long, which is about 200,000 times as wide as the nucleus in which it resides. The DNA, scientists now understand, collapses into a tiny three-dimensional structure, spooling intelligently wound nucleosome proteins to form a complex called chromatin. But how does this deliberate, highly controlled packaging process regulate the genes? When Dr. Skok returned to science in 1997, she had little idea that she would build a career around this question, let alone advance a line of inquiry that would become “one of the most important questions in the study of biology,” says Dr. Aifantis. Even though Dr. Skok had managed to complete a doctorate in genetics before her 12-year career break, she reoriented after the gap, earning a master’s degree in immunology from Imperial College School of Medicine in London, “reading like crazy to make sense of it all.”
At the time, she confessed, she had “zero confidence” but persevered out of a fear that “if I didn’t get back into it, I’d be standing in the same place in another 10 years’ time.”
Today, Dr. Skok employs sophisticated imaging and molecular biology techniques to study how chromatin organization orchestrates a delicate ballet of cutting and pasting to mix, match, and join distant segments of DNA and ultimately generate wildly versatile B- and T-cell receptors that can recognize an almost infinite variety of foreign antigens.
Dr. Skok’s fascination with this elaborate process took off in 1999, when she was awarded a Wellcome Trust Career Re-entry Fellowship and began working as a postdoctoral research fellow with Amanda Fisher, PhD, at the Medical Research Center in Imperial College, studying the biology of B cells. It was in London that she and collaborators published a handful of widely cited papers, showing that during lymphocyte development, the genes encoding the B- and T-cell receptors migrate from the periphery of the cell’s nucleus toward its center, contracting like a paper napkin folded into rosettes. The insight was made with the aid of a visualization technique called three-dimensional fluorescence in situ hybridization, or three-dimensional FISH, which uses fluorescent probes to locate and bind to specific DNA sequences.
Although many other labs had studied this type of recombination, Dr. Skok’s major contribution was to solve the puzzle of how widely separated segments on a very long gene can be brought into contact to undergo recombination. Her FISH analyses revealed that contraction of each gene occurs through chromatin looping. “It was a very important finding,” says Kees Murre, PhD, professor of molecular biology at the University of California, San Diego. “Dr. Skok’s work showed that variable regions of DNA that are far from each other on a linear chromosome actually find partners as frequently as those close by,” Dr. Murre says. “The system she has elucidated provides equal opportunities for all.”
At NYU School of Medicine, Dr. Skok has broadened her focus on basic molecular mechanisms by tackling particular immune diseases and pioneering new techniques, often in a highly collaborative way. She and Dr. Aifantis, for example, have coauthored at least six papers on DNA looping and nuclear organization.
The pair are now planning a major research program that would explore the molecular mechanisms by which nuclear organization can affect the progression of leukemia and lymphoma, cancers that involve white blood cells. In her lab, Dr. Skok has studied the underlying causes of these cancers using the B and T cells of mice.
She has investigated the tightly controlled process by which a pair of enzymes, called RAG1 and RAG2, precisely cuts and pastes the gene segments that code for antibodies.
When the process goes astray—occurring too frequently, for instance—errant DNA breaks can cause “the wrong chromosome bits to be joined together,” explains Dr. Skok. “It actually happens a lot.” Leukemia and lymphoma can follow.
Working with NYU Langone’s Perlmutter Cancer Center, Dr. Skok and Dr. Aifantis plan to submit a proposal to the National Cancer Institute this fall for their project, with an estimated annual budget of around $1.3 million. It aims to study precisely how such mutations and other missteps in cell development can lead to these cancers. Dr. Aifantis, who has made major strides toward understanding and developing new treatments for T-cell acute lymphocytic leukemia, a common form of leukemia in children, brings his lab’s extensive expertise in this form of cancer, as well as animal models it has developed for different types of the disease. Collaboration has been key in advancing their science. “Jane is very open to sharing tools, sharing techniques, sharing reagents, and sharing ideas,” he says.
If every cloud has a silver lining, not everyone can see it. Jane Skok is different. When she relocated her laboratory downtown after Hurricane Sandy, she met researchers with whom she now collaborates on numerous projects. In one such collaboration, published last May in Nature Communications, Dr. Skok employed the genome-editing technique CRISPR-Cas9 to label repeat regions of DNA within live cells, with “guide RNAs” tagged with fluorescent proteins. This new imaging approach is a step up from FISH, which looks at fixed cells. “FISH is only a snapshot in time, like taking a photograph of a crowd of people,” Dr. Skok explains. “If you took a photograph five minutes later, they’d be in a completely different conformation.”
Like video, the technique enables her to track mouse cells over time. “Our aim,” she says, “is to label up a whole locus and follow recombination as it’s going on—so you can see the bit that’s being deleted as it’s being deleted.”
Former collaborator Edith Heard, PhD, professor of epigenetics and cellular memory at the Collège de France in Paris, marvels at Dr. Skok’s technical ingenuity. “There aren’t many people who are able to look at the processes of immune gene regulation at the single cell-level using both imaging and molecular techniques,” says Dr. Heard. “She is one of the rare people who combine all of these approaches. She ends up getting things done efficiently.”
Tracking this intricate DNA dance, with its potential missteps and careful repairs, is another apt analogue to Dr. Skok’s career trajectory. “I didn’t plan anything in my life. Everything that I planned never happened,” she says. “So I stopped planning.” Dr. Skok’s mantra of going where life takes her is a clue to her resilience and optimism. Her 12-year gap from science and the early experience of motherhood—trekking to and from hospitals with a sick child whose illness was undiagnosed for years—was a “complete nightmare,” she says, and yet an important part of her journey that put life’s hardships in perspective.
“If your child’s health is threatened, that is the worst thing that can happen to you. Everything that comes after it, you think, ‘Okay, this is bad. But it isn’t as bad as that,’” Dr. Skok says calmly. “With stressful situations like Hurricane Sandy, you want to sit down and cry, but you’d better not, because you have a lab to run, and you need to motivate all the people in it. Nothing terrible happened to anybody. So you think, ‘I better pick myself up and carry on.’”