Jump Start

When biochemist Samuel Sternberg ’07 returned to Columbia in 2018 to set up his own research lab, he wasn’t sure he was up for it. After finishing his Ph.D., he’d spent a year writing a book, then a year at a biotech startup, forgoing the more traditional route of a multi-year fellowship in academic research. “I came back here with a huge bag of insecurities and a case of impostor syndrome,” he says. “I felt like, gosh, I hope that I’m going to be able to pull this off.” After not pursuing his own research ideas for a while, he says, “We had to kind of start from zero.”

What’s more, his Ph.D. advisor and co-author, and a co-founder of the biotech startup, was Jennifer Doudna, the biochemist known for her revelatory work showing how a molecule called CRISPR-Cas9 could be used to edit an organism’s genetic material; the discovery earned her a share of the Nobel Prize in chemistry last year. “I wanted to make sure I put my head down and worked on our research program, and didn’t try to rest on the laurels of Jennifer’s accolades,” Sternberg says.

Insecurities aside, Sternberg had in fact established himself as one of the country’s leading experts in CRISPR-Cas9 — with patents and prominent papers to his name — and he had ideas for expanding on the promise of that technology. His focus paid off almost immediately. Within months, Sternberg’s Columbia lab had a major paper in Nature, about so-called “jumping genes,” which could prove even better than CRISPR for gene editing. “Now we’re doing all these things that three years ago would have seemed well beyond reach,” he says. The work could someday help researchers treat cancer, produce biofuels, or make crops hardier and tastier. Indeed, last year Sternberg won a $2.4 million grant from the NIH, awarded to “especially creative” scientists working on innovative, high-impact projects.

I mentioned Sternberg’s initial self-doubts to Sanne Klompe GSAS’22, a graduate student in his lab and the lead author of the Nature paper. “That’s funny you say that,” she says. “I don’t know if he realizes how good he is.” Reflecting on her decision to join his lab, she says, “I knew he was going to be great. And I wanted to be part of that.”

Sternberg grew up in Lancaster, Pa., playing piano, saxophone and baseball. (He almost went to Oberlin for musical performance.) His dad was a geology professor, and Sternberg did science fair projects, but he was never passionate about the subject until he took chemistry and biology courses at the College. In high school bio, he’d learned about leaves and frogs, but not molecules. “It was taking organic chemistry sophomore year that I remember as being pivotal in awakening my true scientific curiosity,” he says. “Learning how chemicals can transform in very predictable ways. And that there’s a kind of logic.”

Carrying coffee, a textbook and a stack of plain white paper, Sternberg would go to Butler Library and sit at a wooden table under the high ceiling and draw out chemical reactions, exploring all the ways basic building blocks could transform under various conditions.

The other pivotal point came junior year, when he joined the lab of Ruben Gonzalez, an enthusiastic researcher “at the top of his game” who served as a great mentor. Sternberg was inspired enough to take on his own project in the lab — studying how cells complete the production of proteins — an unusual opportunity for an undergrad. “He was fantastic at the lab bench, and quickly became a voice in research meetings,” Gonzalez says. “I always told him he operated like a graduate student.” Sometimes he operated like a sailor. “His notebooks were very colorful,” Gonzalez says. “Let’s just say that when experiments weren’t working, you could tell.”

Sternberg stayed a year and a half past graduation to finish the project, becoming the lead author of a paper in Nature Structural & Molecular Biology. “Having gone through my first experience of not just how you do research at the bench,” Sternberg says, “but also how you plan experiments, how you put together a series of data into one story. at was an invaluable experience.”

Sternberg joined Doudna’s lab at UC Berkeley as a grad student in 2009, shortly before she made the discovery that would earn her a Nobel Prize. The lab had just begun working on CRISPR, which was a bit risky professionally, because at the time it was just “this very niche, esoteric thing in bacteria,” Sternberg says, and not the tool for studying cells or the therapy for treating genetic diseases that it is today.

In five years at Berkeley, including a six-month stint back at Columbia working with biochemist Eric Greene, Sternberg co-authored several important papers focusing on the Cas9 enzyme — a feature of many CRISPR systems — and how it works. One showed how to engineer versions of Cas9 that snip DNA more accurately, work that several companies have since licensed.

“When he was in the lab, I thought of him as our Renaissance man,” Doudna says. “Wonderful scientist, incredible musician, loved to have a good time and share ideas, a deep intellect, loved to debate ideas in science.” When asked for possibly embarrassing material, she mentioned his Michael Jackson tribute band. “The lab finally talked me into going to one of his performances in San Francisco, and it was a ton of fun,” she says. “I just loved it. It was a side of Sam that I hadn’t had a chance to experience.”

Sternberg didn’t co-author Doudna’s breakthrough paper demonstrating how CRISPR-Cas9 could edit genes, but he was there at the time, and suggested to Doudna that they write a book for general audiences about the discovery. When an agent reached out, they went for it. “It seemed like a bit of a gamble, but I also knew that I would probably never have a better opportunity to write a book like this,” Sternberg says. “And I think it was important for me to put my scientific work and the field’s development in a broader context.” A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution (2017) covers not just the science but also the ethics of gene editing (think designer babies). The New York Times called it “required reading for every concerned citizen.”

Sternberg worked with Doudna again at Caribou, the company she co-founded to further develop gene-editing technology; he was an early employee, acting as both a scientist and a leader of the technology development group. He learned a couple of lessons there, he says. First, he picked up the managerial professionalism he would bring to his lab at Columbia a year later. Second, he learned that he preferred academia — having the opportunity to experiment and explore ideas without concern for a bottom line.

Do jumping genes hold the key to a safer, more reliable gene-editing tool?

“The first discovery we made in my new lab is the perfect example of a project that would have been too speculative for a private company to pursue,” he says, “but has been absolutely transformative in creating new versions of CRISPR.”

One downside of CRISPR-Cas9 as a gene-editing tool is that it slices through DNA, which a cell must then repair. Many things can go awry in this process. While working at Caribou, Sternberg came across a paper on transposons, or jumping genes, which could offer an alternative. A jumping gene is actually a cluster of genes that reproduces by taking over bacterial machinery. It inserts itself into a bacterial genome and essentially forces the cell to reproduce it. Its clones then hop over to new bacterial cells and repeat the process.

Critically, a jumping gene inserts itself into a genome without creating the kind of DNA damage that CRISPR-Cas9 does. What’s more, the paper’s authors noted that some jumping genes contain the genetic code for a CRISPR system called Cascade, raising the possibility that jumping genes use it to target specific sites in bacterial genomes. Sternberg hoped to test this hypothesis in his Columbia lab (he had applied for faculty positions and been welcomed back in 2018). If jumping genes insert DNA into genomes without harming them, and do so in precise ways, they could perhaps be harnessed as a new gene-editing tool — one that would be safer and more reliable than any other at scientists’ disposal.

Sternberg recently gave me a tour of his eponymous lab, a series of rooms at P&S with his office in the center. He and Sanne Klompe, whom he’d known as a Caribou intern, started the lab from scratch, ordering pipettes and scrounging for equipment. (Sternberg actually used his jumping genes theory as his pitch to persuade Klompe to stay in the United States rather than return to the Netherlands for a Ph.D.) The pair were soon joined by two more graduate students, Tyler Halpin-Healy ’11, GSAS’21 and Leo Vo GSAS’21.

On our tour, Sternberg pointed out various machines that duplicate DNA or purify proteins. I watched as Klompe used a device to “heat shock” cells so that the DNA designed by the lab would enter them. “To be quite truthful, we don’t have much distinctive equipment,” Sternberg told me. “Our distinction is discovering new CRISPR systems.”

Much of that discovery happens on computers. “In the first few months in the lab, Sanne was spending most of her time at the computer sifting through genomes, deciding which candidate genes to prioritize to go after this hypothesis,” Sternberg says. On a computer in his office, he showed me the sequence of DNA letters for Cascade, alongside its 3D rendering. The cluster of proteins vaguely resembled a seahorse, with a spine made of guide RNA. Guide RNA is the genetic sequence a CRISPR system uses to target specific locations in a host genome. Wherever this bit of guide RNA matches a stretch of DNA, CRISPR does its gene-editing work.

In those early months, deciding on the exact Cascade design to test required “a zillion decisions,” Sternberg says. Once he and his team were ready, they made the DNA for their jumping gene and inserted it into bacteria. The genes dutifully targeted the bacterial genome in the right spot, and inserted their DNA payload. To see the results, they ran the bacterial DNA through a gel and looked for a telltale band of color, indicating that the bacteria now had the desired genetic code. “And my God, Sanne saw a little smudge of a band,” Sternberg says. They reran the experiment. “And now,” Sternberg says, “that smudge on the gel was a big fat band. And then within days of that, Sanne had sequenced that band and we knew, boom, it’s happening.”

They ran more experiments and published the Nature paper, which, Sternberg says, “landed the lab on the map, landed Sanne’s career on the map and in a ridiculous way played out the exact way that I had hoped and dreamed when I first proposed: Hey, what about we go after this project in my new lab at Columbia?”

Sternberg’s lab — and others, too — are now expanding on that research. For example, his lab is applying the tool to human cells and is working with the Cystic Fibrosis Foundation to replace the defective gene that causes the respiratory disease. They’re working with Harris Wang, a synthetic biologist at Columbia, to engineer jumping genes that can operate in the complex environment of the gut microbiome. And they’re looking for even better versions of Cascade in the diversity of living organisms. “We can barely compete with what nature has already invented,” Klompe says.

Sternberg’s lab now stands at about 15 people. “What I really appreciate in him as a mentor is that everything is a conversation,” Klompe says. “Instead of telling me what to do, it’s almost like, OK, what shall we do next?” When the lab was small and people stayed late to work on that first paper, Sternberg would order dinner. “It was like a little scientific family having dinner in the break room,” she says. The lab’s walls feature fliers celebrating members’ achievements; one advertises a lab outing to the sci-fi movie Rampage, in which a CRISPR-modified pathogen leads to the creation of a giant gorilla, wolf and crocodile. According to Sternberg, “We built an environment that’s not just about the science, but also a place where people will grow as individuals and develop their career aspirations.”

Colleagues have not been surprised to see Sternberg’s success. “His scientific instinct is amazing,” Ruben Gonzalez says. “It’s been a lot of fun to watch.” (The two still get beers and are collaborating on a project.) According to Doudna, “He’s doing some of the most creative work in the discovery of CRISPR systems right now and figuring out how they work.” Walter Isaacson, who wrote the best-selling biography The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race, met with Sternberg regularly to pick his brain. “There’s a boyish enthusiasm,” Isaacson says. “He’s excited about the smallest details of how nature works.”

Sternberg still sometimes questions why he’s the one with an office. He notes that some members of his lab have expertise surpassing his own. “My biggest learning experience here has been realizing that that’s actually OK,” he says. “Being a good scientist doesn’t mean you know how to do everything. One of the best skills I learned from Ruben and from Jennifer is to be resourceful, and to engage with your colleagues. It’s all about putting all the different skills in the pot.”

Matthew Hutson is a freelance science reporter in New York City and a contributing writer at The New Yorker.