SeattleHub In Vivo Team: Back row (lest to right) James Acosta-Clark and Kyle O'Connor; Front Row (left to right) Lauren Kuo, Jordan Knuth, and Elena Gamo. According to Acosta-Clark: 'Some may believe our work is science fiction, but we are really only a few steps away from reality.'
During his undergraduate studies in genetics at West Chester University of Pennsylvania, James Acosta-Clark was determined to create a pet dragon.
“I was convinced I could combine the genes of a cat, a lizard, and a fire-breathing Bombardier Beetle,” he said. “I explored the weight-to-lift ratio of wings to understand how to get the dragon airborne. I got ideas from the hollow bones of birds. But, in the end, I realized it was not possible with our current understanding of genetics.”
Now, 15 years later and nearly 2,800 miles away in Seattle, Acosta-Clark is helping lead the efforts to create another animal that is possible: a recorder mouse. He and members of the In Vivo team at the Seattle Hub for Synthetic Biology (SeattleHub) do not need the mouse to fly or breathe fire. But they do need it to record the lineage of its own cells by implanting DNA-based “smart watches” to chronicle the health, actions, and experiences of individual cells.
That cellular lineage may include internal events and decisions, external signals or stressors, and phenotypic changes. Importantly, this information is recorded sequentially, thereby creating a timeline of each event as it happens, that later would report back on the health, actions, and experiences of each individual cell. The result? Invaluable insights that could inform and influence the future of biotechnology and medical professions.
No one is following the work of the In Vivo Team more closely than Jesse Gray, Ph.D., SeattleHub’s Executive Director of Strategy and Platform.
“The In Vivo Team, as well as all of us at SeattleHub, are focused on turning science fiction into reality,” said Gray. “Day by day, we are creating a revolution in recording and programming biology. That revolution has the potential to transform the biotech ecosystem and to address many of our society’s unmet medical needs.”
The In Vivo team is one of four groups whose members are working daily to fulfill this unprecedented objective. The other three are:
- Sense Team led by Hina Iftikhar – Creating sensors that convert cellular events into barcodes that can then be written into DNA.
- Write team led by Molly Gasperini – Engineering and testing genetic sequences and constructs to create permanent records that are stored in sequential order in the DNA tape in a cell’s DNA.
- Read Team led by Florence Abadie – Developing computational pipelines and methods to analyze sequencing data and to characterize lineage relationships and biological signaling between cells across various tissues.
So, how did a 37-year-old researcher from Allentown, Pennsylvania, who first worked with lab mice as a post-doctoral fellow, become an expert in mouse development? It’s quite simple: Acosta-Clark studied under a world-renowned mouse developmental biologist, Philippe M. Soriano, Ph.D. at the Icahn School of Medicine at Mt. Sinai in New York City.
Three months after completing a Ph.D. in Biology at the City University of New York, Acosta-Clark joined Soriano’s lab in September of 2018.
“Working with Phil was instrumental in bringing me to SeattleHub,” said Acosta-Clark. “He is widely known for identifying the ROSA26 locus, a ‘safe harbor’ in the mouse genome, which has become a key tool for genetic engineering.”
Under Soriano’s direction, Acosta-Clark started making genetically modified mice and, over five years, created upwards of seven of them. At SeattleHub, Acosta-Clark and his In Vivo colleagues are expecting to double, maybe triple, that to more than 20 transgenic mice by the end of this year.
The process is as delicate as it is complex.
The team incorporates technologies developed by the Sense and Write teams and injects synthetic DNA into the nucleus of one-cell mouse embryos shortly after fertilization using a sophisticated microscope. An In Vivo Team member then implants that embryo – too small to see with the naked eye – into the oviduct of the “mother mouse.”
Synthetic DNA being injected into mouse embryo (Photo courtesy James Acosta-Clark)
“It’s very hands-on,” Acosta-Clark said. “The chances of success are higher if you are able to control every step of the process, so we recently hired a Kyle O’Connor, a veteran microinjection specialist. With Kyle joining the team, our mouse production is accelerating rapidly, and its center of gravity is moving in-house. It’s going to be a year of mouse-making!”
What is the greatest challenge the team faces? It is “silencing,” when the embryo suppresses the synthetic DNA. In many cases, the innate immune system senses “foreign” DNA in the genome of the embryo and “shuts it down.”
“We have to play by the mouse’s rules,” Acosta-Clark said. “We’re trying to evade nature.”
Like his counterparts on the other three teams, Acosta-Cark praised the commitment and camaraderie of all the In Vivo Team members, as well as the entire SeattleHub enterprise.
“It was evident when I arrived in June of last year that this is a dedicated group of professionals,” he said. “Some may believe our work is science fiction, but we are really only a few steps away from reality.”
