This “Absolutely Tireless” Researcher Made an Important Breakthrough for Cancer Patients

Theo Roth.

(Photo credit: Noah Berger/UCSF)


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."

Emily Mullin
Emily Mullin is a freelance science journalist based in Maryland. She most often writes about the cutting edge of medicine and biotechnology. Previously, she was the associate editor for biomedicine at MIT Technology Review. Her stories have also appeared in The Washington Post, Scientific American, National Geographic, The Atlantic and elsewhere.
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The event on November 12th will explore what lies ahead for science and policy in the near-future.

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EVENT INFORMATION

________

Date

Thu Nov 12, 2020 12:00pm - 1:10pm EDT

                            


Contact

kira@goodinc.com

Location

Virtual

Hosts

LeapsMag, the Aspen Institute's Science and Society Program, and GOOD

"The Future of Science in America Summit" will dive into the high stakes ahead as we emerge from a hotly contested election, with the pandemic on the upswing.

Through rotating paired conversations with five experts from academia, industry, advocacy, and government, followed by a public Q&A, this event will explore (re)building public trust in science, the latest science and policy developments on the COVID vaccine front, and moonshots in science that deserve prioritization over the next four years.


________

Nancy Messonnier, M.D.
Director of the National Center for Immunization and Respiratory Diseases (NCIRD)

Saad Amer
Founder, Plus1Vote, a nonprofit organization dedicated to getting out the vote on issues such as climate change and equality

France Córdova, Ph.D.
Astrophysicist, past Director of the National Science Foundation, past President of Purdue University

Joseph DeRisi, Ph.D.
Professor of Biochemistry and Biophysics, University of California San Francisco and Co-President, Chan Zuckerberg Biohub

Seema Kumar
Global Head of the Office of Innovation, Global Health, and Policy Communication, Johnson & Johnson

Michelle McMurry-Heath, M.D., Ph.D.
President and CEO of the Biotechnology Innovation Organization (BIO)

This summit is co-hosted by LeapsMag, the Aspen Institute Science & Society Program, and the social impact company GOOD, with support from the Gordon and Betty Moore Foundation and the Rita Allen Foundation.

The event accompanies our recently published digital magazine, The Future of Science in America: The Election Issue.

Kira Peikoff
Kira Peikoff is a journalist whose work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and son.

Understanding the vulnerabilities of our own brains can help us guard against fake news.

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This article is part of the magazine, "The Future of Science In America: The Election Issue," co-published by LeapsMag, the Aspen Institute Science & Society Program, and GOOD.

Whenever you hear something repeated, it feels more true. In other words, repetition makes any statement seem more accurate. So anything you hear again will resonate more each time it's said.

Do you see what I did there? Each of the three sentences above conveyed the same message. Yet each time you read the next sentence, it felt more and more true. Cognitive neuroscientists and behavioral economists like myself call this the "illusory truth effect."

Go back and recall your experience reading the first sentence. It probably felt strange and disconcerting, perhaps with a note of resistance, as in "I don't believe things more if they're repeated!"

Reading the second sentence did not inspire such a strong reaction. Your reaction to the third sentence was tame by comparison.

Why? Because of a phenomenon called "cognitive fluency," meaning how easily we process information. Much of our vulnerability to deception in all areas of life—including to fake news and misinformation—revolves around cognitive fluency in one way or another. And unfortunately, such misinformation can swing major elections.

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Gleb Tsipursky
Dr. Gleb Tsipursky is an internationally recognized thought leader on a mission to protect leaders from dangerous judgment errors known as cognitive biases by developing the most effective decision-making strategies. A best-selling author, he wrote Resilience: Adapt and Plan for the New Abnormal of the COVID-19 Coronavirus Pandemic and Pro Truth: A Practical Plan for Putting Truth Back Into Politics. His expertise comes from over 20 years of consulting, coaching, and speaking and training as the CEO of Disaster Avoidance Experts, and over 15 years in academia as a behavioral economist and cognitive neuroscientist. He co-founded the Pro-Truth Pledge project.