This “Absolutely Tireless” Researcher Made an Important Breakthrough for Cancer Patients
Theo Roth.
After months of looking at dead cells under a microscope, Theo Roth finally glimpsed what he had been hoping to see—flickers of green. His method was working.
"If we can go into the cell and add in new code and instructions, now we can give it whatever new functions we want."
When Roth joined the laboratory of Alex Marson at the University of California, San Francisco in June 2016, he set to work trying to figure out a new way to engineer human T cells, a type of white blood cell that's an important part of the immune system. If he succeeded, the resulting approach could make it easier and faster for scientists to develop and test cell and gene therapies, new treatments that involve genetically reprogramming the body's own cells.
For decades, researchers have been using engineered viruses to bestow human cells with new genetic characteristics. These so-called viral vectors "infect" human cells, transferring whatever new genetic material scientists put into them. The idea is that this new DNA could give T cells a boost to better fight diseases like cancer and HIV.
Several successful clinical trials have used virally-modified human T cells, and in fact, the U.S. Food and Drug Administration last year approved two such groundbreaking cancer gene therapies, Kymriah and Yescarta. But the process of genetically manipulating cells with viruses is expensive and time-consuming. In addition, viruses tend to randomly insert DNA with little predictability.
"What Theo wanted to do was to paste in big sequences of DNA at a targeted site without viruses," says Marson, an associate professor of microbiology and immunology. "That would have the benefit of being able to rewrite a specific site in the genome and do it flexibly and quickly without having to make a new virus for every site you want to manipulate."
Scientists have for a while been interested in non-viral engineering methods, but T cells are fragile and notoriously difficult to work with.
Previously, Marson's lab had collaborated with CRISPR pioneer Jennifer Doudna and her team at the University of California, Berkeley to use an electrical pulse together with CRISPR components to knock out certain genes. They also found some success with inserting very small pieces of DNA into a targeted site.
But Roth, a 27-year-old graduate student at UCSF pursuing MD and PhD degrees, was determined to figure out how to paste in much bigger sequences of genetic information. Marson says it was an "ambitious" goal. Scientists had tried before, but found that stuffing large chunks of DNA into T cells would quickly kill them.
"If we can go into the cell and add in new code and instructions, now we can give it whatever new functions we want," Roth says. "If you can add in new DNA sequences at the site that you want, then you have a much greater capacity to generate a cell that's going to be therapeutic or curative for a disease."
"He has already made his mark on the field."
So Roth began experimenting with hundreds of different variables a week, trying to find the right conditions to allow him to engineer T cells without the need for viruses. To know if the technique was working, Roth and his colleagues used a green fluorescent protein that would be expressed in cells that had successfully been modified.
"We went from having a lot of dead cells that didn't have any green to having maybe 1 percent of them being green," Roth says. "At that stage we got really excited."
After nearly a year of testing, he and collaborators found a combination of T cell ratios and DNA quantity mixed with CRISPR and zaps of electricity that seemed to work. These electrical pulses, called electroporation, deliver a jolt to cells that makes their membranes temporarily more permeable, allowing the CRISPR system to slip through. Once inside cells, CRISPR seeks out a specific place in the genome and makes a programmed, precise edit.
Roth and his colleagues used the approach to repair a genetic defect in T cells taken from children with a rare autoimmune disease and also to supercharge T cells so that they'd seek out and selectively kill human cancer cells while leaving healthy cells intact. In mice transplanted with human melanoma tissue, the edited T cells went to straight to the cancerous cells and attacked them. The findings were published in Nature in July.
Marson and Roth think even a relatively small number of modified T cells could be effective at treating some cancers, infections, and autoimmune diseases.
Roth is now working with the Parker Institute for Cancer Immunotherapy in San Francisco to engineer cells to treat a variety of cancers and hopefully commercialize his technique. Fred Ramsdell, vice president at the Parker Institute, says he's impressed by Roth's work. "He has already made his mark on the field."
Right now, there's a huge manufacturing backlog for viruses. If researchers want to start a clinical trial to test a new gene or cell therapy, they often have to wait a year to get the viruses they need.
"I think the biggest immediate impact is that it will lower the cost of a starting an early phase clinical trial."
Ramsdell says what Roth's findings allow researchers to do is engineer T cells quickly and more efficiently, cutting the time it takes to make them from several months to just a few weeks. That will allow researchers to develop and test several potential therapies in the lab at once.
"I think the biggest immediate impact is that it will lower the cost of a starting an early phase clinical trial," Roth says.
This isn't the first time Roth's work has been in the spotlight. As an undergraduate at Stanford University, he made significant contributions to traumatic brain injury research by developing a mouse model for observing the brain's cellular response to a concussion. He started the research, which was also published in Nature, the summer before entering college while he was an intern in Dorian McGavern's lab at the National Institutes of Health.
When Roth entered UCSF as a graduate student, his scientific interests shifted.
"It's definitely a big leap" from concussion research, says McGavern, who still keeps in touch with Roth. But he says he's not surprised about Roth's path. "He's absolutely tireless when it comes to the pursuit of science."
Roth says he's optimistic about the potential for gene and cell therapies to cure patients. "I want to try to figure out what one of the next therapies we should put into patients should be."
Here's how one doctor overcame extraordinary odds to help create the birth control pill
Dr. Percy Julian had so many personal and professional obstacles throughout his life, it’s amazing he was able to accomplish anything at all. But this hidden figure not only overcame these incredible obstacles, he also laid the foundation for the creation of the birth control pill.
Julian’s first obstacle was growing up in the Jim Crow-era south in the early part of the twentieth century, where racial segregation kept many African-Americans out of schools, libraries, parks, restaurants, and more. Despite limited opportunities and education, Julian was accepted to DePauw University in Indiana, where he majored in chemistry. But in college, Julian encountered another obstacle: he wasn’t allowed to stay in DePauw’s student housing because of segregation. Julian found lodging in an off-campus boarding house that refused to serve him meals. To pay for his room, board, and food, Julian waited tables and fired furnaces while he studied chemistry full-time. Incredibly, he graduated in 1920 as valedictorian of his class.
After graduation, Julian landed a fellowship at Harvard University to study chemistry—but here, Julian ran into yet another obstacle. Harvard thought that white students would resent being taught by Julian, an African-American man, so they withdrew his teaching assistantship. Julian instead decided to complete his PhD at the University of Vienna in Austria. When he did, he became one of the first African Americans to ever receive a PhD in chemistry.
Julian received offers for professorships, fellowships, and jobs throughout the 1930s, due to his impressive qualifications—but these offers were almost always revoked when schools or potential employers found out Julian was black. In one instance, Julian was offered a job at the Institute of Paper Chemistory in Appleton, Wisconsin—but Appleton, like many cities in the United States at the time, was known as a “sundown town,” which meant that black people weren’t allowed to be there after dark. As a result, Julian lost the job.
During this time, Julian became an expert at synthesis, which is the process of turning one substance into another through a series of planned chemical reactions. Julian synthesized a plant compound called physostigmine, which would later become a treatment for an eye disease called glaucoma.
In 1936, Julian was finally able to land—and keep—a job at Glidden, and there he found a way to extract soybean protein. This was used to produce a fire-retardant foam used in fire extinguishers to smother oil and gasoline fires aboard ships and aircraft carriers, and it ended up saving the lives of thousands of soldiers during World War II.
At Glidden, Julian found a way to synthesize human sex hormones such as progesterone, estrogen, and testosterone, from plants. This was a hugely profitable discovery for his company—but it also meant that clinicians now had huge quantities of these hormones, making hormone therapy cheaper and easier to come by. His work also laid the foundation for the creation of hormonal birth control: Without the ability to synthesize these hormones, hormonal birth control would not exist.
Julian left Glidden in the 1950s and formed his own company, called Julian Laboratories, outside of Chicago, where he manufactured steroids and conducted his own research. The company turned profitable within a year, but even so Julian’s obstacles weren’t over. In 1950 and 1951, Julian’s home was firebombed and attacked with dynamite, with his family inside. Julian often had to sit out on the front porch of his home with a shotgun to protect his family from violence.
But despite years of racism and violence, Julian’s story has a happy ending. Julian’s family was eventually welcomed into the neighborhood and protected from future attacks (Julian’s daughter lives there to this day). Julian then became one of the country’s first black millionaires when he sold his company in the 1960s.
When Julian passed away at the age of 76, he had more than 130 chemical patents to his name and left behind a body of work that benefits people to this day.
Therapies for Healthy Aging with Dr. Alexandra Bause
My guest today is Dr. Alexandra Bause, a biologist who has dedicated her career to advancing health, medicine and healthier human lifespans. Dr. Bause co-founded a company called Apollo Health Ventures in 2017. Currently a venture partner at Apollo, she's immersed in the discoveries underway in Apollo’s Venture Lab while the company focuses on assembling a team of investors to support progress. Dr. Bause and Apollo Health Ventures say that biotech is at “an inflection point” and is set to become a driver of important change and economic value.
Previously, Dr. Bause worked at the Boston Consulting Group in its healthcare practice specializing in biopharma strategy, among other priorities
She did her PhD studies at Harvard Medical School focusing on molecular mechanisms that contribute to cellular aging, and she’s also a trained pharmacist
In the episode, we talk about the present and future of therapeutics that could increase people’s spans of health, the benefits of certain lifestyle practice, the best use of electronic wearables for these purposes, and much more.
Dr. Bause is at the forefront of developing interventions that target the aging process with the aim of ensuring that all of us can have healthier, more productive lifespans.
