Put He Jiankui, the Chinese scientist who developed gene-edited babies, out of your mind. Instead, think of Victoria Gray, the African-American woman who claims to have been cured of the sickle-cell disease through gene editing.
London is hosting the Third International Summit on Human Genome Editing this week. It’s the Super Bowl of gene editing, where scientists show off their impressive new abilities to alter DNA while ethicists fret over the implications.
Event organizers kicked things off on a Monday by reflecting on what they called 2018’s “misuse” of the technology to create designer babies in China. That situation was an ethical nightmare and prompted serious debate about whether or not we should intervene in the evolutionary process.
But the real story of how gene editing is changing people’s lives is through treatments used on adults with serious diseases; this is lost in the designer-baby debate.
According to a tally provided to MIT Technology Review by David Liu, a gene-editing specialist at Harvard University, there are currently more than 50 experimental studies using gene editing in human volunteers to treat everything from cancer to HIV and blood diseases.
CRISPR, the most flexible gene-editing method, was developed only a decade ago and is being used in roughly 40 of these studies.
Gray plays an important role here. She was one of the first people ever to be treated with a CRISPR procedure, and when she told her story to the London audience in 2019, she brought many to tears.
Because of the disease, Gray said, “I stand here before you today as proof miracles still happen,” as she overcame the excruciating pain and anemia that sickle cell anemia can bring.
Still, Gray’s situation highlights the challenges inherent in the initial wave of CRISPR therapies, also known as “CRISPR 1.0.” They will be extremely difficult to implement and costly, and they may be rendered obsolete by a newer, better generation of editing drugs.
Vertex Pharmaceuticals, the company working on Gray’s treatment, claims to have successfully treated over seventy-five people with sickle cell and beta-thalassemia in clinical trials, and that the therapy could be approved for sale in the United States within the next year. Many believe it will be the first CRISPR-based treatment available to the public.
Vertex hasn’t provided an estimate, but it’s safe to assume that it will be in the multi-millions.
Scientists are impressed by how quickly the technology is being adopted in the medical field. “I think CRISPR [has] outpaced every previous genomic therapy technology,” says Fyodor Urnov, a researcher at the University of California, Berkeley.
CRISPR has revolutionized genetic research because it allows precise cuts to be made in the genome. It consists of a slicing protein joined to a short gene sequence that acts as a GPS, allowing it to rapidly travel to a specific location in a person’s chromosomes.
And according to Jennifer Doudna, the Berkeley biochemist who co-invented the method and shared the Nobel Prize, altering that GPS sequence is a breeze. Reminding the summit attendees that “CRISPR is a technology that enables changes to DNA that are programmed,” she said.
There has been a wave of biotech companies, led by Vertex, that are banking on this technology to create effective treatments; these include Intellia, Beam Therapeutics, and Editas Medicine. The trials on Liu’s list are being conducted by many of them. However, not every test will prove fruitful.
San Francisco biotech Graphite Bio, for example, had to halt its own tests of a gene-editing treatment for sickle-cell anemia in January after the first patient experienced a dangerous drop in blood cell counts. The therapeutic procedure generated the issue. The future of Graphite is uncertain after its stock dropped by more than 90%.
Even with these advances, however, the challenge of delivering CRISPR to its intended site in the body persists. Not an easy task, to be sure. Doctors took bone marrow cells from Gray and modified them in the laboratory. Her remaining bone marrow was wiped out with harsh chemotherapy before the new cells were reintroduced.
A bone marrow transplant is the cornerstone of the Vertex treatment. In and of itself, that is a challenge for which not every patient is prepared. Vertex believes that 32,000 people across Europe and the United States constitute a market for the treatment’s efficacy in “severe” cases.
However, this won’t help patients if insurance companies and governments refuse to cover the costs. It’s a genuine danger. For instance, European governments refused to pay the $1.8 million price tag for a different gene therapy for beta-thalassemia developed by Bluebird Bio.
The Next Generation of CRISPR
Furthermore, there is a catch with the first-gen CRISPR therapies. Harvard biologist George Church famously coined the term “genome vandalism” to describe the practice of intentionally damaging DNA in order to silence genes.
One such treatment aims to zap HIV using a technique similar to those used in attempts to break genes. Gray was given a different one. Her therapy works because it breaks a particular DNA sequence, which releases a second form of the hemoglobin gene. As the sickle-cell disease is caused by a defective form of hemoglobin, reviving a spare copy of the protein is the only way to treat the condition.
Human gene editing trials
Researchers are aiming to “disrupt” genes in this way in about two-thirds of current studies, as calculated by Liu.
Liu’s lab is developing cutting-edge strategies for editing genes. The CRISPR protein is used in these tools as well, but it has been modified so that instead of cutting the DNA helix, it can be used to replace specific letters or make larger alterations. Base editors are what the name implies.
Although these new versions of CRISPR have “lower risk and better performance,” as gene scientist Llus Montoliu of Spain’s National Center for Biotechnology puts it, getting them “to the right target cell in the body” is still challenging.
Montoliu is using base editors to completely eradicate albinism in mice in his lab. He thinks it’s a first step towards a treatment that newborn humans could receive, though not to alter their skin tone. Instead, he fantasizes about injecting Liu’s molecules into their eyes to treat the severe vision problems that come with albinism.
In any case, the albinism study is not being conducted as a money-making venture at this time. This highlights one of the primary constraints on the long-term usefulness of CRISPR. Multiple companies are pursuing the same problems, and nearly all active CRISPR trials focus on either cancer or sickle-cell disease.
Urnov claims that this means thousands of additional inherited diseases that could be treated with CRISPR are being overlooked. The fact that most of them are too rare to be a commercial opportunity is a major factor, he says.
However, Urnov will be presenting his ideas on how treatments could be tested even for ultra-rare diseases, such as some genetic conditions so rare that they only affect one person, at the London meeting.
This is not a marketable application of CRISPR, but it is theoretically possible due to the tool’s flexibility in being directed to specific locations in the genome through programming. Urnov claims there is an “urgent need” to clear a “path to the clinic for all” now that gene editing has shown initial promise.