New opportunities for microbiome researchers
At Dana-Farber and the nearby Broad Institute in Cambridge, Bullman had built a reputation as a rising star for her postdoctoral research on a bacterial species, Fusobacterium nucleatum, known to be linked to colorectal cancer. Her research published in the journal Science showed this bug was concentrated in colon tumors, and was even found in tumors that had spread to the liver.
Early in her East Coast stay, Bullman became acquainted with the Seattle cancer center. At a microbiology conference in Boston, she listened to an address by Hutch’s Dr. Denise Galloway on the role of microbes in cancer. “I was furiously writing down everything she was talking about,” Bullman recalled. "I thought she was amazing.”
Now holder of the Paul Stephanus Endowed Chair at the Hutch, Galloway heads a multidisciplinary, collaborative research program, the Pathogen-Associated Malignancies Integrated Research Center, or PAM-IRC, which focuses Hutch research on cancers caused by bacteria and viruses. So, when the Hutch expressed interest in Bullman’s work, she was eager to join.
Meanwhile, back in 2016, Johnston had set up his own laboratory at the Forsyth Institute, an independent research center in Cambridge affiliated with the Harvard School of Dental Medicine. When the Hutch began recruiting his wife last year, his own lab’s work was well underway. He had already hired staff, set up shop and had won a coveted NIH Directors Transformative Research Award. He specialized in bacteria that inhabit the mouth, and he was gaining notice for an ingenious new way to make bacteria of all kinds easier to modify with genetic engineering tools.
Scientists have been swapping genes in an out of lab mice for decades, a technique that is useful for finding the purpose of a gene by observing what happens when it is changed or missing. But it is still surprisingly more difficult to engineer the genes of simple bacteria. That is because these bugs have evolved, over billions of years, sophisticated barriers against viruses that try to insert their foreign DNA into their bacterial genomes. When a scientist inserts a snippet of new DNA into a bacterium’s genome, it appears just like a virus to the bug and runs directly into these defenses. Such bacteria are known as “genetically intractable.”
There are many strategies around intractability, but Johnston has developed a method that can be likened to Harry Potter’s invisibility cloak. In effect, it blinds the bacterium to the new DNA’s foreign identity, so researchers can more easily slip in a new gene. This lab tool, dubbed SyngenicDNA, is allowing swift and efficient genetic manipulation in previously intractable species.
Johnston was anxious about his wife’s wish to move to Seattle, but he was struck by how positive she was about her prospects. Then came the call from Seattle. This time, it was for him: “Would you mind interviewing for a new opening at the Hutch?”
Johnston admits he was taken with the researchers he met, and with the Seattle environment.
“After one visit, he became just as enthusiastic about the possibility as I was,” Bullman said.
In her new post, Bullman continues to study the role of Fusobacterium nucleatum in colon cancer. “What is important to me is to grow these fastidious bacteria from patient tumors, to tease apart their role in colorectal cancer,” she said. Key to that is her tissue bank of colorectal tumors from which she has isolated more than 120 different Fusobacterium strains, whose genomes she also has sequenced.
One of her research goals is to determine for certain whether the bacterium is causing colorectal cancer or merely turning up in tumors after they form. She wants to learn fully the gene functions and inner workings of this problematic bug — to figure out exactly how it might be causing colorectal tumors, and if possible, how to interfere with that.
To do so, she must overcome a trait that makes it difficult to study: Fusobacterium is one of those genetically intractable bugs.
Not to worry. Just across the street from her new lab, her husband Chris has an app for that.