The painful blood disorder, which mostly affects Black people, is just one of thousands of rare diseases that could be cured by Beam Therapeutics’ revolutionary gene editing technology.
Beam Therapeutics CEO John Evans loves rocket launches—and not just the ones that succeed. He makes his team watch all the SpaceX failures, too, when the unmanned rockets explode. “For the first many years, all the rockets crash and there’s a lot of failure along the way, and then suddenly, they start working,” he says.
Gene editing, Evans believes, is on a similar trajectory, poised for a series of successful launches in the years ahead. “The stuff we can do now in genome editing would have seemed like magic five or ten years ago,” he says, as technological advancements suddenly have biotechs competing to cure rare genetic diseases long out of reach.
The first generation of gene editing was Crispr, a technology developed in 2012 that can target and cut sections of DNA like a pair of scissors. Now Cambridge, Massachusetts-based Beam is pioneering Crispr 2.0. Its advancement, known as base editing, works more like a pencil, which can target a single misspelling in the DNA code allowing for much greater precision, says Evans, who is 43. Beam’s technology, which has yet to be tested in humans, could theoretically cure thousands of the genetic diseases caused by single letter misspellings, known as point mutations. Topping the company’s targets is sickle cell disease—a point mutation that predominantly affects Black people and has been neglected through more than a century of racist attitudes.
Beam, which was founded in 2017, went public in February and now has a market cap of $1.5 billion despite having no revenues and losing $95 million over the past year. What the company does have is 12 research programs for 10 different rare diseases, including beta thalassemia, another inherited blood disorder, and two types of blood cancer. None of the treatments have been cleared for clinical trials, but the company hopes to file a slew of applications in 2021.
Sickle cell disease is the most promising opportunity. It’s the most common inherited blood disorder in the United States, affecting about 100,000 people. The disease produces abnormal hemoglobin, the molecule that helps red blood cells carry oxygen throughout the body. While normal red blood cells are shaped like doughnuts, sickle cells look like pointy crescent moons (thus the name), which clog up blood vessels and cut off oxygen supply to the bones and organs, causing “excruciating pain,” explains Dr. Robert Liem, director of the comprehensive sickle cell program at the Lurie Children’s Hospital of Chicago.
With one out of every 365 Black babies born with sickle cell, the disease has an ugly racial history. By the mid-1900s, the presence of sickle-shaped cells in the blood viewed under a microscope were a “marker for race,” says Shawn Bediako, professor of psychology at the University of Maryland Baltimore County, who focuses on stigma in healthcare. “When people who were not Black had sickle cell disease then the societal assumption was that then that person wasn’t completely white,” even though the disease is found in people of many other ethnicities. In the 1960s, the Black Panther Party began to champion the right to health and implemented a national sickle cell screening program in the wake of government inaction.
But racist attitudes and a lack of federal funding still persist today. Sickle cell patients, who can end up in hospital emergency departments with serious pain, waited, on average, 25% longer than general patients and 50% longer than patients with bone fractures to be seen, according to a study in the American Journal of Emergency Medicine. Sickle cell received an average of $812 in federal research funding per person over the last decade, while cystic fibrosis, a lung disease that predominantly affects white people, received more than $2,800 per person, even though sickle affects three times as many people, according to a paper in JAMA Network Open. “If we really have to have this debate about whether or not Black life matters, I think we need look no further than sickle cell and how it’s been treated as a medical condition to indicate that it really doesn’t,” says Bediako.
Sickle cell was the first “molecular disease” discovered, revealing how a change in one single amino acid could disrupt blood and oxygen supply to the entire body. The first drug to treat sickle cell, hydroxyurea, wasn’t approved until 1998, even though the disease has been known in the medical literature since 1910, with three more drugs coming to market since 2017. The only cure is a bone marrow transplant, which is limited to a small percentage of patients who have a matching sibling donor. But Beam is hoping to change that with its potentially curative base editing technology. “We’re going to go in and land our editor right on the mutation that causes sickle cell and change it to something that’s normal,” Evans says.
Base editing was pioneered in 2016 in the lab of David Liu, a core faculty member at the Broad Institute and a professor at Harvard University, along with postdoctoral fellows Alexis Komor, now an assistant professor at the University of California San Diego, and Nicole Gaudelli, the head of gene editing technologies at Beam. Liu cofounded Beam in 2017 along with Feng Zhang, a professor at the McGovern Institute at the Massachusetts Institute of Technology and core faculty member at the Broad Institute, and Dr. J. Keith Joung, endowed chair in pathology at Massachusetts General Hospital and professor at Harvard Medical School. This is the second of three gene editing companies the scientific power trio has founded since 2013, along with Cambridge-based Editas Medicine, which is developing Crispr-based therapeutics, and Durham, North Carolina-based Pairwise Plants, which is using both Crispr and base editing to develop more nutritious crops. In 2019, Liu founded Prime Medicine, a third generation “search and replace” genome editing technology, which he likens to a word processor.
“I certainly, in my wildest dreams, never imagined this kind of precise capability to edit the genome,” says Dr. Francis Collins of the National Institutes of Health.
Liu calls the human genome the “most important gift your parents ever gave you.” It’s made up of 6 billion combinations of four letters known as bases: A, T, G, and C. A person with sickle cell disease has one base pair misspelling at a crucial location in their adult hemoglobin gene: a ‘T-A’ where there should be an ‘A-T’. That typo, which appears twice among the 6 billion letters, is the difference between normal hemoglobin and the abnormal hemoglobin that causes the rigid crescent-shaped cells.
Beam is the first company to try to directly fix the base pair misspelling, though they can’t yet switch a T to an A. Instead, Beam switches the T to a C and the A to a G. While it appears odd to swap one typo for another, the new typo mimics a natural phenomenon, known as the Makassar variant, which results in functional red blood cells instead of the sickle shape.
Beam is also trying another approach to curing the disease: Introducing a second mutation in a different location to override the production of sickle hemoglobin. It mimics a naturally occurring phenomenon in which a person has two sets of sickle hemoglobin genes, but doesn’t show signs of the disease. The reason? A different mutation in the fetal hemoglobin gene, which usually turns off in favor of adult hemoglobin as people age, but remains turned on and producing normal hemoglobin. “They won the genetic lottery after losing it twice,” says Liu. Both programs showed promising results in mice.
Liu, 47, prefers to focus on his academic and research pursuits, rather than commercialization of the technologies, as do his cofounders Zhang and Joung. The trio like to hire well-credentialed executives to run their companies, like Evans, who has a track record of successfully bringing precision medicines from the lab to the market.
In 2009, Evans, who earned an MBA from Wharton and a Masters in biotechnology from the University of Pennsylvania, was an early employee at Agios Pharmaceuticals, then a tiny biotech with a pre-clinical target related to cancer metabolism. The following year he helped broker a unique alliance between Cambridge-based Agios and big biopharma Celgene, ultimately leading to two FDA approvals for treatments for acute myeloid leukemia in the span of ten years, which sounds like a long time, but is much faster than the usual drug development timeline.
“Celgene, gave us $130 million dollars upfront to explore this area of biology and Agios was able to preserve commercial right, and many other important features, so it was a very creative deal,” says David Schenkein, the former CEO of Agios and a general partner at Mountain View, California-based venture firm GV (formerly known as Google Ventures), which invested in Beam.
After eight years at Agios, Evans left to become a venture partner at Arch Venture Partners, an early investor in Beam. In late 2016, he met Liu in his office in Cambridge to discuss the company, which was in stealth mode at the time. “I couldn’t sleep that night, I was so excited about it,” Evans recalls.
Since base editing is a platform, rather than a single drug, once the technology works in one disease, it will likely work in others. “That ease of retargeting is going to mean that as we get it up and running, we can very quickly go through and treat a whole bunch of diseases and create a kind of sustainable flow of new medicines,” says Evans. He started in an interim CEO role at Beam and officially took the top job in January 2018.
Beam can’t attack every disease so Evans has pursued strategic partnerships and licensing agreements with other gene editing companies, including Editas, Prime and another Cambridge-based biotech called Verve, which is using base editing to develop heart disease therapies. Joung is a Verve cofounder, and Evans serves on the boards of Prime and Verve. “It’s kind of a divide and conquer approach, where we’re reducing redundancy and now I think more diseases, more patients are potentially going to benefit from the technology than otherwise,” Evans says.
Of course, it’s impossible to predict whether Beam’s technological edge with base editing will ultimately prevail over earlier Crispr technologies that have the first-mover advantage, says David Nierengarten, a biotechnology analyst at Wedbush Securities. But what sets Beam apart so far based on their work in mice is “more efficient” gene editing, meaning that “higher numbers of modified cells” will get into patients, says Nierengarten.
Beam is researching a number of other rare diseases it hopes to treat, or even cure, with its precision gene editing technology. Here are the seven it has disclosed.
Sickle Cell Disease
Estimated U.S. Patients: 100,000
Inherited blood disorder causes severe pain.
Estimated U.S. Patients: 1,000-2,000
Inherited blood disorder causes severe anemia.
T-Cell Acute Lymphoblastic Leukemia
Estimated U.S. Patients: 500-1,000 per year
Fast-growing blood cancer.
Acute Myeloid Leukemia
Estimated U.S. Patients: 20,000 per year
Fast-growing blood cancer.
Alpha-1 Antitrypsin Deficiency
Estimated U.S. Patients: 60,000
Inherited disorder causes lung and liver disease.
Glycogen Storage Disoder 1a
Estimated U.S. Patients: 1,400
Inherited disorder where body can’t store sugar.
Estimated U.S. Patients: 5,500
Inherited eye disorder causes progressive vision loss.
Beam has one key advantage: with its technology, the DNA double helix doesn’t need to be cut, like with first generation Crispr technologies. This means greater precision with less risk of random insertions and deletions of code.
Beam’s true test will come next year, when the company plans to apply for authorization from the U.S. Food and Drug Administration to begin clinical trials in humans. Even in these early stages, Dr. Francis Collins, director of the National Institutes of Health, the $41.7 billion (2020 budget) federal research agency, says he’s “really excited” about the potential of base editing to take on the 7,000 rare diseases caused by DNA misspellings.
“By delivering this kind of base editor to the right tissue at the right time, you can imagine many of these [rare diseases] becoming treatable, maybe even curable,” says Collins, who is working with Liu on an NIH-funded research project using base editing (currently in mice) to correct the point mutation for progeria, a disease that causes children to rapidly age and die by the time they are teenagers. “I certainly, in my wildest dreams, never imagined this kind of precise capability to edit the genome, where you could go and find one letter out of 3 billion that needed to be fixed, and provide the apparatus to do that with relatively little risk of causing trouble elsewhere,” Collins says reflecting on his career and the rapid progress in gene editing over the past few years.
But one of the big technical challenges ahead for many diseases will be refining the delivery methods of successfully getting base editors into the patient’s body. While the sickle cell therapy can be done outside the body and inserted, for other diseases, like progeria, the base editor will have to be directly inserted into the patient, and there are several methods being developed. “You have to come up with a delivery system that is going to take that base editing apparatus and efficiently and safely get it to the cells where it needs to do its magic,” says Collins. “And that’s a big challenge.”
The other hurdle on the horizon will be affordability. Existing gene therapies tend to be outrageously expensive. Novartis, for instance, made headlines in 2019 for charging $2.1 million for Zolgensma, a breakthrough cure for spinal muscular atrophy. The majority of adult sickle cell patients don’t even have access to hydroxyurea, which is the cheapest generic treatment on the market. “We just have a long way to go before we can realistically say that a substantial number of patients might benefit from these therapies,” says Dr. Liem, who chaired the American Society of Hematology clinical practice guidelines on sickle cell disease. While gene therapies are exciting, “the vast majority of patients out there still need basic care,” says Liem.
But Evans hopes Beam can fundamentally change the rules of engagement. “We’re going to have profound impacts for patients’ lives in the very near future,” he says, since patients who participate in phase one could potentially leave the trial cured of sickle cell. “That’s the amazing thing about these one-time therapies.”
This post was updated at 11:30 am ET July 10 to incorporate two additional co-inventors of base editing.