After giving a talk in Seattle about chromosome pairing, Chao-ting (Ting) Wu boarded the redeye flight back to Boston and settled in to read a new research paper on an odd new discovery in the human genome. “It was so exciting, I had to get up and walk around on the plane,” she says. “I could not stay in my seat.”
The paper that had Wu pacing the aisle that day was the first report describing DNA sequences called ultraconserved elements (UCEs), from Gill Bejerano in David Haussler’s group at UC Santa Cruz. UCEs are nucleotide sequences more than 200 nucleotides long that are identical in the human, rat, and mouse genomes. It’s incredibly unlikely that a sequence that long could remain unchanged over hundreds of millions of years of evolution, and yet Bejerano reported finding 481 of them.
“I remember reading it and thinking, how can that be?” Wu says. “How could we have missed this? How can something be so important and so hidden?”
Intrigued, Wu began studying UCEs in her own lab. “They are considered by some to be the longest-standing mystery of the genome era,” she says. “We don’t have an explanation for why any genome would retain even one sequence that long. The reason my lab studies it is this: pairing could be a very simple explanation.”
Wu has spent decades studying how homologous chromosomes pair up. Once considered a quirk of Drosophila’s genome, the idea that chromosomes communicate by coming into contact with each other is now being studied in mammals, fungi, and even plants. “It’s moved from being an ‘artifact’ to possibly being a universal way in which homologous chromosomes can communicate,” Wu says. “That’s been extremely exciting to see.”
Wu’s studies began when she was a graduate student with William Gelbart, who was a professor at Harvard University and a previous awardee of the George W. Beadle Award, and continued in her own laboratory with Jim Morris, a graduate student and now a professor at Brandeis University, and Pam Geyer, a professor at the University of Iowa. These studies focused on transvection, in which gene expression can be regulated by interactions between homologous alleles on different chromosomes. If the basis of UCEs is pairing, she speculates, that could explain why the sequences cannot tolerate changes.
This model aligns two otherwise incongruous observations. First, she and Adnan Derti, a graduate student and now at Auron Therapeutics, discovered that copy number variation of a UCE – a deletion or duplication – is rarely found in healthy individuals. On the other hand, other groups found that some UCEs can be deleted from both chromosomes without causing lethality in mice. The pairing model, however, predicts exactly such outcomes for UCEs whose function is to pair.
Perhaps these perfectly conserved regions act as “guardians of the genome,” she speculates, helping preserve the integrity of the full set of chromosomes. Understanding them could ultimately provide protection from disease.
“She’s always thinking about the weird and the wonderful, and what are the things we have no idea about,” says Jack Bateman, a former postdoc who studied transvection and now heads his own lab at Bowdoin College. “She’s so fun to talk to because she just has these ideas that are different.”
In addition to her work as professor of genetics at Harvard Medical School, she directs the Consortium for Space Genetics and the Personal Genetics Education Project (pgEd), a public engagement program intended to empower citizens to educate themselves about the genomic technologies that pervade our modern society. This team of scientists, social scientists, educators, and community organizers work with schools, teachers, policymakers, filmmakers, communities of faith, and other groups to prompt conversations about the benefits and ethical and social implications of genetics.
For all of these diverse contributions, Ting Wu has been awarded the 2021 George W. Beadle Award from the Genetics Society of America, which recognizes individuals who have made outstanding contributions to the community of genetics researchers beyond an exemplary research career.
“She’s so passionate about things,” says Pamela Geyer, professor of biochemistry at the University of Iowa, one of the scientists who nominated Wu for the award. “She pushes you to think about things in a different way.”
At some point thinking becomes experimenting, and, eventually, time came to get a good look at the chromosomes, themselves. Thanks to work done in Wu’s lab, geneticists have powerful tools to visualize the 3D shapes of chromosomes and trace the dynamic system as they interact.
This story begins with Ben Williams, a graduate student and now with Helmsley Charitable Trust, whose idea for Oligopaints was demonstrated and then advanced by Brian Beliveau, a graduate student and now an assistant professor at the University of Washington, and Eric Joyce, a postdoctoral fellow and now an assistant professor at the University of Pennsylvania. Oligopaints are low-cost fluorescent probes that hybridize to specific locations along the chromosomes and, led by Beliveau, the Wu group and her collaborators, Peng Yin and Xiaowei Zhuang, professors at Harvard Medcial School and Harvard University, respectively, enabled Oligopaints to image chromosomes in super-resolution. “It’s been very exciting,” says Wu. “The super-resolution structures are giving us true measurements of distance, volume, and shape, and we are now looking at greater and greater expanses of the genome. We’re seeing how completely dynamic the genome can be.”
The infectious enthusiasm that has propelled her lab into uncharted scientific waters has also spilled over into the realm of education. The advent of home genetic testing and personal genomics sparked lots of probing conversations among her lab members about communicating with the public about the social and ethical considerations around advances in genetics.
“Have we communicated enough with everybody, non-scientists, about genetics?” Wu muses. “So that when these technologies come out, they are informed enough to make decisions for themselves about whether they want to use those technologies?”
To learn what questions were percolating through the community, she and her husband, geneticist George Church, and their daughter, Marie, took a road trip across the country to talk to people who had volunteered their DNA for the Personal Genome Project. “These were people from all walks of life,” Wu says. “We came back so much more enriched by their conversations and so much more knowledgeable about the challenges that we had to address.”
That trip sparked her to co-found the Personal Genetics Education Project, or pgEd, with Bateman and Dana Waring, who is the Education Director. The program started by visiting local high schools and making presentations in biology classrooms. Realizing that they wouldn’t get too far just visiting individual schools, the team began publishing curriculum and teacher training materials to spread genetics education into more classrooms, particularly those where students might not have a strong background in genetics or biology. But Wu emphasizes that the goal isn’t to teach the nuts and bolts of DNA, or recruit students into STEM careers. Rather, she says, pgEd seeks to spark curiosity and debate, such that when students encounter genetic technology in their lives, they feel qualified to ask questions.
“We’re not talking about what DNA bases are,” she says. “We’re talking about interesting things people might want to know to help them navigate their lives. When people are interested, they start asking questions. We’re hoping that when a physician comes along and says, ‘we’re going to do this DNA test,’ they aren’t silent, thinking, ‘oh, this person knows a lot more than I do.’ Instead, they will feel confident enough to ask questions, and I think that is the greatest protection you can give somebody. Laws are helpful, but one-on-one in a doctor’s office, you need the confidence that you can hold your own in a conversation about genetics. That’s what we’re going for.”
pgEd, whose activities are coordinated by Marnie Gelbart, Director of Programs, has spread well beyond schools into TV and film, congressional briefings, and faith communities. Recently, Gelbart, Robin Bowman (Professional Development Associate), and Nadine Vincentin (Research Fellow) worked on the public engagement programming and educational resources that accompanied the Ken Burns PBS documentary “The Gene: An Intimate History.” They have also been working closely with The Learning Center for the Deaf on lessons and curricula in American Sign Language, with Mohammed Hannan (Community Liaison) extending their engagement within communities. “It’s been amazing to see it grow,” says Bateman. “They’ve done so many things. They’ve done congressional briefings. How do these things happen? They happen because it’s Ting.”
The George W. Beadle Award honors individuals who have made outstanding contributions to the community of genetics researchers. Wu will accept the award at the 62nd Annual Drosophila Research Conference (#Dros21) and will present an Award Seminar online on April 29th from 1-2 pm EDT.
Interested in learning about public engagement from pgEd? GSA has partnered with pgEd for a program on inclusive public engagement for geneticists. Sign up now for the “Discussing Genetics” webinar series and join us for additional training workshops coming soon.