John Evans, CEO of Beam Therapeutics, is fond of rocket launches — and not only the good ones. He always lets his staff watch all of the SpaceX failures as the autonomous rockets explode. “All the rockets have exploded for the first five years and there is a lot of disappointment in the way, and then somehow they managed to succeed,” he states. Gene editing, claims Evans, is on a similar track, positioned in the years ahead for a string of positive releases. “The things we can do today in genome editing must have seemed like sorcery 5 or 10 years ago,” he says, when scientific advancements unexpectedly push genetics to fight far out of control for curing unusual genetic diseases like sickle cell disease.
Crispr was the very first generation of genetic modification, a technique introduced in 2012 which can target and break DNA parts like a pair of scissors. Today Beam located in Cambridge, Massachusetts, is the creator of Crispr 2.0. According to Evans, who is 43, his development, known as base editing, functions much like a pencil and can hit a single spelling mistake in the DNA code for greater precision. Beam’s invention, which has yet to be studied on humans, could potentially reverse thousands of genetic defects caused by misspellings of a single letter, recognized as point mutations. Topping the company’s goals is sickle cell disease — a point disorder that affects Black people mostly which has been ignored over a century of racial attitudes.
Beam, which was established in 2017, decided to go public in February and currently has a $1.5 billion market value, with no sales and losing $95 million in the last year. What the corporation does have is 12 clinical projects with 10 different genetic disorders, namely beta thalassemia, another genetic blood condition and two forms of blood cancer. Few of the therapies for clinical trials have been approved but the firm plans to file plenty of approvals in 2021.
The main issue is sickle cell disorder. This is the most prevalent blood disease in the United States and affects around 100,000 individuals. The disorder creates excessive hemoglobin, the agent that makes the red blood cells transport oxygen all over the body. Although regular red blood cells are structured like doughnuts, sickle cells appear like tipped crescents, which block blood arteries and cut off the bones and organs from providing oxygen, creating “impressive pain,” says Dr. Robert Liem, manager of the extensive sickle cell system at Chicago’s Lurie Children’s Hospital.
The disorder has a disturbing cultural past of one out of every 365 Black children diagnosed of sickle cell. Until the mid-1900s, a “marker for ethnicity” was the appearance of sickle-shaped cells in the blood seen under a microscope, says Shawn Bediako, professor of psychiatry at the University of Maryland Baltimore County, who works on stigma in healthcare. “If people who weren’t Black got sickle cell disease then the cultural presumption was that that individual wasn’t white,” while the disorder is present in people of many other ethnic groups. In the 1960s the Black Panther Party began lauding the right to health and in the wake of government inaction enforced a nationwide sickle cell screening programme.
But racial prejudice and a shortage of government funding continue to persist today. As per a study in the American Journal of Emergency Medicine, sickle cell cases, who might end up in hospital emergency departments with extreme discomfort, stayed, on average, 25% longer than regular patients and 50% longer than patients with broken bones to be treated. According to a report in the JAMA Network Open, sickle cell earned an average of $812 in federal grant funds per person during the past decade, although cystic fibrosis, a lung disease that primarily affects white men, received more than $2,800 per person, while sickle affects three times more people. “If we somehow have to have this discussion on how Black life counts or not, I believe we need to go no further than sickle cell and how it was handled as a medical disorder to show that it really doesn’t,” Bediako adds.
The first “molecular disorder” found was sickle cell, showing how a difference in a particular amino acid might interrupt the flow of blood and oxygen to the whole body. The first medication to cure sickle cell, hydroxyurea, was not approved until 1998, although this disease has been widely acknowledged since 1910 in the medical literature, with 3 more drugs coming onto the market since 2017. The only treatment is a bone marrow transplant, restricted to a select number of people who have a matched donor to their sibling. Yet Beam aims to improve this with its potentially curative platform for editing bases. “We ‘re going to go in and land our editor straight on the mutation that is triggering the sickle cell and transforming it into something natural,” says Evans.
Base editing was invented in 2016 by David Liu, a key faculty member at the Broad Institute and a lecturer at Harvard University, alongside postdoctoral fellows Alexis Komor, who is now an associate professor at San Diego University of California, and Nicole Gaudelli, Beam’s director of gene editing technology. In 2017, Liu co-founded Beam with Feng Zhang, a researcher at the McGovern Institute at the Massachusetts Institute of Technology and key faculty member at the Large Institute, and Dr. J. Keith Joung, a pathology chair at Massachusetts General Hospital and a researcher at Harvard Medical School. This is the second of three genome editing companies founded by the scientific power trio after 2013, together with Cambridge-based Editas Medicine, which is producing Crispr-based therapies, and Durham, Pairwise Plants located in North Carolina, which uses both Crispr and base editing to produce more nutritious crops. In 2019, Liu created the “search and replace” genetic manipulation technology of the third generation, Prime Medicine, which he compares like a word processor.
Liu considers the human genome “the most important present your parents have ever given you.” It consists of 6 billion four letter combinations labeled as bases: A, T, G, and C. An individual with sickle cell disorder has one base pair of misspelling in their adult hemoglobin gene at a critical location: a ‘T-A’ in which a ‘A-T’ should be present. The typo, which occurs twice amongst these 6 billion letters, is the distinction between normal hemoglobin and the abnormal hemoglobin which induces the cells in the form of a rigid crescent.
“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.
Beam is the first corporation to try to correct the base pair incorrect spelling explicitly, even though they can’t turn a T to an A yet. Beam rather moves the T to a C, and the A to a G. The new mistake imitates a natural anomaly, known as the Makassar type, which results in functioning red blood cells rather than the sickle shape.
Beam also seeks another method to treating the disease: to add a second modification to override the development of sickle hemoglobin at a different site. This imitates a common condition in which a person has 2 pairs of sickle hemoglobin genes but displays no symptoms of the disease. The explanation? Another mutation in the fetus hemoglobin gene which normally turns off when people mature in favour of adult hemoglobin but stays turned on and produces normal hemoglobin. “Having lost it twice they won the genetic lottery,” says Liu. Both methods have demonstrated positive outcomes for mice.
Liu, 47, chooses, like his co-founders Zhang and Joung, to concentrate on his academic and scientific interests instead of commercializing the technology. The trio likes to employ well-credential managers to run their businesses, such as Evans, who does have a successful track record of bringing laboratory precision medications to the market.
In 2009, Evans, who received Wharton’s MBA and University of Pennsylvania’s Masters in Biotechnology, was an early executive at Agios Pharmaceuticals, then a tiny biotech with a pre-clinical cancer metabolism target. He helped broker a groundbreaking partnership among Cambridge-based Agios and major biopharmaceutical firm Celgene the same year, potentially leading to two 10-year FDA approvals for acute myeloid leukaemia therapies, which seems like a long time but is significantly smoother than the normal timetable for drug growth.
“Celgene offered us $130 million in funding to pursue this field of biology and Agios was able to retain marketing assets, plus many other valuable things, and it was a very innovative deal,” says David Schenkein, Agios’ former CEO and general partner at Mountain View, California-based investment firm GV (previously known as Google Ventures), which invested in Beam.
Following eight years at Agios, Evans left for Arch Venture Partners, an angel investor in Beam, to become a business partner. He met Liu at his Cambridge office late in 2016 to debate the company, which at the time was in stealth mode. “Last night I did not sleep, I was so nervous about it,” Evans remembers.
Because base editing is a tool, instead of a single product, it will certainly work in others until the system works in one disorder. “That ease of retargeting will mean that as we get it ready to launch, we could get through and cure a whole bunch of illnesses very easily and produce a sort of viable supply of new medicines,” Evans says. He began at Beam in an interim CEO position, and in January 2018 finally took the top job.
Beam cannot combat any disease and Evans has established corporate collaborations and licence arrangements with other gene editing firms, like Editas, Prime and another company headquartered in Cambridge called Verve, which uses base editing to create treatments for heart disease. Joung is co-founder of Verve, and Evans sits on Prime and Verve boards. “It’s sort of a divide and conquer strategy, where we’re eliminating redundancy but now I think more illnesses and more people will actually benefit from the technologies than otherwise,” says Evans.
This is, of course, difficult to tell that Beam’s technical superiority with base editing would eventually triumph over older Crispr innovations with the first-mover advantage, notes Wedbush Securities biotechnology expert David Nierengarten. Yet what distinguishes Beam so far is “more effective” gene editing based on their research in mice, suggesting that “larger numbers of transformed cells” can get into patients, Nierengarten notes.
Beam is studying a variety of other unusual diseases with its precise gene editing technologies which it aims to treat, and even cure. Below are the seven which it has revealed.
- Sickle Cell Disease
- Approximate patients in U.S.: 100,000
- Inherited blood disorder causes serious pain.
- Approximate patients in U.S.: 1000-2000
- Inherited blood disease that causes serious anemia.
- T-Cell Acute lymphoblastic leukaemia
- Approximate patients in U.S.: 500-1,000 per year
- Blood cancer which is growing rapidly.
- Acute Myeloid Leukemia
- Approximate patients in U.S.: 20,000 per year
- Fast-growing blood cancer.
- Alpha-1 Antitrypsin Deficit
- Approximate patients in U.S.: 60,000
- Inherited disorder causes both lung and liver disease.
- Glycogen Storage Disorder 1a
- Approximate patients in U.S.: 1400
- Inherited disease where sugar can’t be stored by body.
- Stargardt disease
- Approximate patients in U.S.: 5500
- Inherited eye disease causes gradual loss of vision.
Beam has one major advantage: there is no need to break the DNA double helix with its methods, as with the first generation of Crispr technologies. It ensures higher precision, with less chance of accidental insertions and code removal.
Beam’s real test is coming next year, once the company expects to file for authorization from the U.S. FDA Food and Drug Administration to commence human clinical trials. Also at this early point, Dr. Francis Collins, manager of the National Institutes of Health, the $41.7 billion (2020 budget) federally funded research agency, admits he is “very optimistic” about the possibility of quantitative editing to fix 7,000 genetic diseases caused by DNA misspellings.
“By applying this sort of base editor to the correct tissue at the correct time, you can expect that all of these [serious diseases] are becoming treatable, or even curable,” says Collins, who works with Liu on an NIH-funded research study using simple editing (currently in mice) to fix the point mutation for progeria, a disorder that causes children to mature rapidly and die while they become teens. “I definitely never envisioned this kind of accurate ability to edit the genetic code in my wildest fantasies, where you can go and find a letter out of 3 billion that needed fixing, and provide the apparatus to do so with fairly little risk of causing problems elsewhere,” says Collins reflecting on his profession and the rapid progress made in gene editing over the recent years.
Yet one of the big technological obstacles ahead for multiple diseases will be to refine the transmission strategies of bringing foundation editors into the patient’s body successfully. Although sickle cell therapy could be performed outside the body and injected, the base editor may have to be injected straight into the recipient with certain disorders, such as progeria, and many approaches are being developed. “We need to come up with a distribution method that can take the base editing tool and send it to the cells in which it needs to do its work effectively and securely,” Collins says. “So this is a huge obstacle.”
The other challenge on the path is being kept available. Present gene therapies appear to be appallingly expensive. For instance, in 2019 Novartis made international headlines for charging 2.1 million US dollars for Zolgensma, a potential treatment for spinal muscle atrophy. Many adult patients with sickle cell do not yet have access to hydroxyurea which is the cheapest prescription drug on the market. “We really have a long way to go till we can actually conclude that such treatments will help a significant number of patients,” says Dr. Liem, who headed the American Society of Hematology’s recommendations for clinical practice on sickle cell disease. While gene therapies are promising, “the vast majority of people really need simple treatment out there,” says Liem.
Yet Evans believes Beam will shift the rules of interaction in a profound way. “In the very distant future, we will have significant effects on the lives of patients,” he notes, as patients involved in phase one could theoretically leave the sickle cell disease trial healed. “This is the best thing about such one-time treatments.”