The rockefeller university

As a child, Maria Jasin relished exploring on her own. She lost her mother to cancer when she was eight years old, and her father moved her and her sister from Detroit to Florida, leaving their extended family behind. While he put in grueling hours as a sheet metal worker, the siblings largely entertained themselves. Jasin taught herself piano and tennis, and when her father bought a set of encyclopedias—the first non-school books in the house—she dove in, constantly “running and looking up things that I didn’t know,” she says. Immersed in Sputnik-spurred science fervor, she was soon feeding her curiosity with Time-Life books about astronomy, physics, and biology. Together, the family watched space walks, moon landings, and splashdowns on TV, and she got to go to a couple of rocket launches at Cape Canaveral.

As Jasin grew up, she shifted her attention from events in the sky to those inside our cells’ nuclei. She became an influential investigator who overturned dogma about a fundamental aspect of DNA biology, set into motion the study of homology-directed DNA repair in mammalian cells, and enabled gene editing, which is transforming our understanding of myriad physiological processes across the panoply of life. Jasin has also illuminated how mutations in two genes—BRCA1 and BRCA2—predispose people to familial breast and ovarian cancer.

Her personal path toward these distinctions has been marked by victories, setbacks, and eventual triumphs. In high school, Jasin’s intelligence shone, and she graduated as valedictorian. The school’s academics, however, fell short. At a summer NSF program in math, the other kids left her behind. She gained admission to Cornell University, but needed a bigger scholarship than the institution offered. She wound up attending the more affordable Florida Atlantic University in Boca Raton. There, she won a top-student award that came with $1000. “That was great news,” she recalls, as her immigrant dad was out of work during the 1970s oil crisis and the prize paid for a new water heater.

At college, she felt drawn toward the burgeoning field of molecular biology. She applied to Ph.D. programs, and MIT accepted her. Upon arrival, she realized immediately that her background didn’t hold up to that of her peers from Harvard and UC Berkeley. “I was at the bottom of the class,” she says. Academic unpreparedness might have debilitated some people, but she seized the opportunities that the intellectually rich environment offered and pushed ahead. She couldn’t do anything about her past, she figured, but she could try to make up for it. “Being from a background where nothing was particularly expected of me, I wasn’t disappointing anyone,” she says.

Her performance was hardly disappointing. She caught up, flew through her Ph.D. qualifying exam, and gained confidence. By the time she earned her doctorate, she had published first-author Cell and Nature papers and dug into the topic that has absorbed her ever since.

At MIT, she worked with Paul Schimmel, using recombinant DNA technology to explore how different sections of an essential protein—the Escherichia coli alanine tRNA synthetase—contribute to its activity. As part of her project, she devised a new way to supplant a bacterial gene with a gutted version of it, which she published in 1984. Her method exploited the bacterium’s capacity to perform homologous recombination, a process in which two similar—or homologous—stretches of DNA line up, and one then replaces the other. To manipulate this ability, she supplied a linear piece of DNA whose sequences at its ends matched those of a chromosomal gene. The middle of that incoming piece of DNA, in contrast, held an unrelated gene that conferred resistance to an antibiotic. Her graduate work underscored for her the power of targeted mutagenesis to understand gene function, and she wanted to develop similar approaches for studying mammalian genes.

Conventional wisdom held that, in mammals, homologous recombination occurs frequently only in cells that are en route to becoming sperm or eggs. In that setting, the process supports the halving of a cell’s chromosome numbers while also enhancing genetic diversity. Scientists had found scant evidence for homologous recombination in non-reproductive mammalian cells. But Jasin saw an unexplored avenue to investigate.

In yeast cells, cleavage through both strands of a piece of DNA stimulates homologous recombination at that location. Maybe, Jasin reasoned, she could uncover a similar process in mammalian cells.

She pursued this goal at the University of Zürich as a postdoctoral fellow with Walter Schaffner. There, she designed an experimental system that generated active versions of the mammalian SV40 virus only if recombination occurred between two partial chunks of its genetic material—one on the cell’s chromosome and one on added DNA—each of which lacked different crucial sequences. Her strategy succeeded, and the largest viral yield came when the input DNA contained a double-strand break at a spot with homology to the chromosomal DNA: this feature had significantly enhanced repair from the chromosome. She reported this discovery in a lead-author Cell paper.

Jasin extended these studies during a postdoctoral fellowship at Stanford University with Paul Berg, a pioneer of the recombinant DNA revolution. Her work continued to flourish.

In 1990, she set up her own lab at Memorial Sloan Kettering Cancer Center. Given that she aimed to precisely modify the genome, and double-strand breaks stimulate recombination in the severed DNA, she needed a way to cut the chromosome rather than the input DNA, as she did as a postdoc. But standard enzymes used for recombinant DNA manipulations recognize short sequences that appear frequently by chance, and she didn’t want to chop the chromosome into bits. So when she heard about a newly reported enzyme, I-SceI, that cuts a specific 18-base pair sequence, she was intrigued. This recognition sequence is long enough—and thus, rare enough—that it would randomly occur less than once per mammalian genome.

To detect repair of a defective gene through homologous recombination, she conceived a multi-step scheme. First, she inserted the I-SceI target site into a gene that encodes resistance to an antibiotic. She then integrated this interrupted, non-functional gene into the chromosomal DNA of mouse cells grown in the lab. When these cells encountered the antibiotic, they died. Next, she produced I-SceI in the cells and also supplied an intact portion of the antibiotic-resistant gene on a DNA fragment. She hoped that the added DNA would serve as a template with which to mend the chromosomal gene. If so, cells that contained it would survive in the presence of the drug.

The strategy worked fabulously. Jasin had efficiently and precisely introduced a change into a mammalian genome for the first time. The DNA break stimulated homologous repair more than 100-fold. Her results would eventually animate the entire field of gene editing, but at the time, Jasin struggled to get the manuscript accepted for publication. It was rejected from multiple high-profile journals without even being reviewed.

“I was flabbergasted,” she says. People apparently “didn’t get the idea” that it might be possible to easily modify the genome if one made a break at the desired position. Furthermore, her finding was a big deal for basic biology. “The lore at the time was that homologous recombination was inefficient in [non-reproductive] mammalian cells.” In 1994, her paper made its way to publication in Molecular and Cellular Biology.

Since then, the DNA-editing enterprise has exploded. Scientists have harnessed tools such as CRISPR-Cas9 to alter any sequence of interest. All of the methods hinge on Jasin’s seminal observation that putting DNA damage in the chromosome—in this case a double-strand break—could target specific modifications to that spot. These advances hold enormous potential, especially in medicine and agriculture.

Having laid the foundation for this revolutionary technology, Jasin followed her results in a different direction. “The timing was perfect,” she says, because of recent progress in the cancer arena. She pivoted and took aim at the mechanism by which mammalian cells repair double-strand breaks through homologous recombination.

Other scientists had established that defects in two genes, BRCA1 and BRCA2, underlie hereditary predisposition to breast and ovarian cancer. By 1996, both genes had been isolated, which facilitated their study. Initially, researchers assumed that the intact versions of the BRCA1 and BRCA2 proteins fend off cancer in a conventional way—by holding inappropriate cellular growth in check. But clues began accumulating that they act indirectly—by preventing genetic glitches that foment unrestrained replication.

In 1999 and 2001, respectively, Jasin found that the BRCA1 and BRCA2 proteins repair double-strand breaks in chromosomes by promoting homologous recombination. This work linked homologous recombination to protection from cancer. Loss of either protein leads cells to accrue genomic changes that can foster tumor development.

Furthermore, the work dovetailed with hints that BRCA1 and BRCA2 deficiencies sensitize cells to treatments that cause double-strand DNA breaks. In addition to shedding light on a mechanism of tumor formation, this revelation has informed treatment approaches for individuals who carry mutations in the BRCA genes. In 2011, Jasin showed that, in addition to helping to repair DNA, BRCA1 and BRCA2 thwart DNA damage from materializing in the first place. The observation “opened up this new idea” that these medically important proteins guard genomic integrity and prevent cancer in multiple ways, she says, and it stimulated an enormous amount of research activity on the topic.

Jasin’s inclination to persevere in unfamiliar terrain has fueled groundbreaking discoveries in multiple realms. Her fortitude and imagination have propelled conceptual leaps in biology and genetic engineering whose impacts will continue to reverberate far into the future.

Author: Evelyn Strauss, Ph.D.