“I was born a criminal.”
The words flow easily from Zhao Zhang’s mouth and hang in the air. It’s a confusing statement from a young, charismatic cancer biologist who is doing groundbreaking work on the genetics of aggressive, often fatal diseases.
How can this be?
Zhang was born in China in 1984, his family’s second child during the early years of the government’s one-child policy. His parents hid him in his grandmother’s home, afraid to visit him more than once or twice a year the first six years of his life. Even when they felt safe enough to bring him home, he recalls sometimes fearfully peeking out of a closet, still partly hidden from the world. It wasn’t long before a neighbor, motivated by a reward to turn in violators of the one-child policy, exposed him to the authorities.
The official who investigated the Zhang family eyed the terrified 6-year-old and shrugged. There was nothing that could be done at that point. The government slapped the family with a large fine and walked away.
Initially resentful of the way he had been treated, Zhang soon began crafting a positive narrative about his life. Perhaps, he thought, his illegal nascence gave him the ability to see things that others did not, and to survive despite inhospitable conditions. He was different – special.
This identity formation extended to his name. Zhao Zhang is a combination of two of the most common surnames in China, which he says labeled him as generic and indistinguishable. “ZZ” felt light, powerful and unique.
“You have to think a bit harder, think a bit differently, so you can define your own thing,” he says. “When you have that kind of humble background, you always want to prove yourself.”
ON THE MOVE
Recently, ZZ gave away all of his fruit flies.
Genetics research is often conducted using Drosophila melanogaster because of its simple genome, rapid reproduction, and genetic similarity to humans. Most of his career, Zhang’s research needed a supply of flies: His early work was on piRNA, a genetic pathway that can suppress and silence transposable elements. Also known as transposons, transposable elements are the so-called “jumping genes” responsible for DNA mutations – some of which cause cancers.
He continued this line of study after coming to Duke in 2019 from Johns Hopkins University’s Carnegie Institution for Science, but soon switched to investigating how transposons move around the genome. This is how he really made his reputation, becoming a Pew Scholar in the Biomedical Sciences and earning a Distinguished Scientist Award from the Sontag Foundation along with support from the National Institutes of Health, the U.S. Department of Defense, and numerous other organizations.
Ideas are not precious to ZZ – results are. He describes scientific research as coming in waves. After a groundbreaking discovery is made, there’s an exponential wave: A lot of researchers jump in to study the new topic, and advances come fast for a decade or so. Then comes the saturated wave, when tons of people are doing the research, but progress is slow because new, groundbreaking knowledge becomes difficult to find.
For Zhang, this is the time to switch focus to a more promising topic. That reflects his restless personality and his ambition to lead, rather than to follow.
“Life is short. Why don’t you do the things you are most excited about?” he asks. “I always like to chase the high-risk, high-reward stuff. And I never get satisfied if I do the same routine for a long time. I like to do things slightly different from what other people are doing, so we can bring some unique angles, unique perspectives. That’s our philosophy about doing research. Keep your mind open, and eventually, your curiosity will lead you to something new.”
ZZ’s years of work on piRNA and transposons led him to form an interest in extrachromosomal DNA (ecDNA) about the time he came to Duke. As the name indicates, ecDNA is found outside of the chromosome and inside the nuclei of aggressive cancer cells, making it a major factor in the fast growth of brain tumors, lung cancer, pancreatic cancer, and other rapid-moving deadly cancers. Over time, Zhang and his research associates learned that ecDNA and transposons form a symbiotic relationship, where the mobile nature of both elements allows for fast adaptation of cancer cells to treatment.
Over time, ZZ’s lab shifted away from the mature subject of transposons to the pre-exponential topic of ecDNA. So it was time for the flies to go.
CIRCULAR LOGIC
Here’s the thing about chromosomes and cancer: A regular set of chromosomes within a cell can carry only two copies of oncogenes, whose activation causes cancer. But extrachromosomal DNA allows cancer cells to carry hundreds of copies of those cancer-causing genes. The rocket fuel of oncogenes combined with the massive carrying capacity of ecDNA results in a highly “fit” cancer cell that expands faster than therapies can stop, or even slow, in some cases.
Zhang believes that cancer cells must pay a significant cost to maintain hundreds of copies of ecDNA, and this vulnerability could present a unique opportunity for targeted elimination. His lab discovered that the accumulation of these genomic rogue elements is a dangerous event, and for cancer cells to achieve it, they must disable their own built-in security systems. Through persistent efforts, Zhang’s team has now developed a way to reactivate that security system – enabling it to detect and destroy these cells, ultimately eliminating the cancer. So if studies and clinical trials are successful, their approach could be used to create therapies for killer cancers.“That’s why studying new topics brings us such excitement,” ZZ says. “We are really pushing the boundary of human knowledge on this. At this moment, we really don’t know much about the biology of ecDNA. Every piece of discovery can be translational for cancer treatment. It’s hard to find a topic that has such a huge potential to be translational, to bring therapeutic benefits for patients.”
Donald McDonnell, Glaxo-Wellcome Distinguished Professor of Molecular Cancer Biology in the School of Medicine, hired Zhang at Duke as the first Duke Science and Technology Scholar. His charge was to recruit someone with bold ideas who was passionate about his work and who loved to collaborate. McDonnell was stunned when Zhang told him he was moving his research focus from transposons to ecDNA, but says that willingness to take risks is part of what makes ZZ successful.
“When you stick your neck out, that’s when it gets tough, but that’s where the big discoveries are made,” McDonnell says. “He just loves discovery. I don’t know that he has any interest in incremental discoveries. He wants to work on big things.”
SLOWLY BUILDING MOMENTUM
It wasn’t always that way for ZZ. When he started grade school, he often found himself in trouble in a Chinese educational system that stressed uniformity. He attended a mid-tier Chinese university, where he majored in biology because he believed it offered him a way to see the world outside China. He was bored learning about biology in textbooks and lectures. It wasn’t until late in his college years that he began working in a lab and something clicked.
“It’s exciting to test your own idea, especially when you’re about to know your result,” he says. “That kind of feeling got me hooked for the first time in my life. That’s the moment that I felt biology may be a good choice for me.”
Zhang was admitted to the Ph.D. program at UMass Chan Medical School in Worcester, Massachusetts, where he found himself in a program with several other Chinese students from elite undergraduate institutions. He was ready to work hard to prove himself, and the competitive environment made him shine.
His adviser and mentor, Phillip Zamore, a molecular biologist and biochemist, soon realized he had a student who was not only bright, but crafty and highly motivated. ZZ started off rotating between Zamore’s lab and the lab of Bill Theurkauf, but soon requested to join Zamore’s group with Theurkauf as a co-adviser.
"He just loves discovery. I don’t know that he has any interest in incremental discoveries. He wants to work on big things.”
Donald McDonnell
“He’s just really, really smart and incredibly hardworking and very charismatic,” Zamore says. “He did this thing where he would be really sympathetic to me about my ideas, and then he would explain that Bill really was opposed to that line of reasoning. And I think he was doing the same thing to Bill. And then he just did whatever he wanted.
“That’s the most you can ever hope for in a student, is that they have good enough ideas that they can ignore you. The best students and postdocs are the ones who you point in a general direction, and when they need help, they come to you. They’re unafraid to test their ideas in addition to yours. It’s not common. You get a couple in your life like that.”
ZZ basically blew the doors off at UMass. When he finished his doctorate, he was immediately offered his own lab at the Carnegie Institution for Science. Zamore says Zhang is one of the few students he has had in almost three decades who was truly ready to run their own lab without needing to do a postdoc. Zamore also says that despite ZZ’s relative youth as a scientist, he passes Zamore’s ultimate determining factor for relevance – the deletion test.
“If we deleted you from the history of science, would anyone notice?” Zamore asks. “People would notice if we deleted ZZ.”
INFECTIOUS ENTHUSIASM
As the leader of his cancer biology lab at Duke, Zhang loves his lab members, and the feeling is mutual. He is not prone to brag unless you ask how many of his former students and postdocs have gone on to direct their own labs.
He ensures that his lab members have fun as they’re working hard. His lab web page has a special tab for “moments” – lab outings for paintball, go-karting and ceramics, celebrations for Ph.D. defenses and holidays, and group photos at conferences. Zhang’s office shelves are decorated with champagne bottles, awarded any time a lab member gets a research paper published.
“We celebrate every single milestone for every person in the lab,” he says. “You have a team to stand behind you to give you support. If you need help from this person, they will drop whatever they’re doing and help you first and then continue their own work.”
Lu Wang was a postdoc in the ZZ Lab before leaving to lead his own research group at the Center for Excellence in Molecular Cell Science in Shanghai. He still keeps three of ZZ’s lab rules in mind at all times: 1) Only do experiments that make you feel happy and confident; don’t waste your time and my money. 2) Three words to remember when you perform experiments: control, control and control. 3) Design your experiment carefully and thoughtfully – garbage in, garbage out.
“ZZ places great emphasis on training postdocs in scientific thinking and independent thought,” Wang says. “He consistently taught us how to approach science more deeply and from different perspectives. He also guided us in improving experiments, pondering problems, broadening our intellectual horizons, and fostering a collaborative spirit. As a person, it was his kindness and generosity that made his lab a warm and welcoming place.”
McDonnell agrees: “His group works very hard, but they work hard because he’s been able to recruit people to his lab who had the same infectious enthusiasm for science.”
GOING TO THE MOUNTAIN
Early in his tenure at Duke, Zhang asked Dr. Bob Lefkowitz, the physician who won the 2012 Nobel Prize in Chemistry, to mentor him. Lefkowitz shared his thoughts about one’s dedication to research: it’s either a job, a career, or a calling. This resonated with ZZ because it helped him understand that his passion for science was indeed a calling.
“I was influenced by him,” Zhang says. “I just need to stay dedicated to the stuff we’re most excited about and not worry too much. Just focus on it, keep studying it and, eventually, hopefully, we can achieve something people have never achieved before.”
Lefkowitz has spent much of his 50-plus-year Duke career mentoring many hundreds of physician-scientists, and he describes ZZ’s skills and potential as one of a handful he has worked with.
“The guy is amazingly courageous and iconoclastic,” Lefkowitz says. “He has characteristics that you see in all great researchers: You’re willing to question dogma. You’re willing to come up with bold new ideas. He has a certain intellectual chutzpah – a brazen gall to question things, and the confidence to go after it. And he understands that about himself.”
ZZ also understands the short-term path forward. He is working with Duke’s Office for Translation & Commercialization on a patent and a company to bring his lab’s discoveries about ecDNA into clinical trial and, if all goes well, cancer treatments. Zhang is collaborating with a company that has already developed a drug that suppresses the genes of aggressive cancers. The drug has not worked well because existing screening is not adequate to identify and target ecDNA. ZZ believes that his findings about the biology of ecDNA will enable precision screening that would ensure effective cancer treatment.
“This is the thing that makes me really excited every single day,” he says.
Zhang has already organized an international conference on ecDNA – a small one, because the field is not even in its exponential wave yet. He is hoping to host a workshop at Duke Cancer Institute to bring together everyone at the university who’s interested in ecDNA.
McDonnell is a likely attendee, joking that he is as excited about ZZ's research as he is his own. He is convinced that ZZ is still in the early stages of the many discoveries he will make that could have lasting impacts. And, of course, he has no idea which direction his colleague will go next – just that he will make a difference.
“His research is going to be incredibly impactful, and not just in cancer,” McDonnell says, “even in our understanding of human physiology and immunity.” Anything less might feel like a crime.