The parents of a 2-year-old girl write that their daughter “could die within the next year” because a genetic mutation is causing her heart to fail.
“Time is quickly running out for me,” writes a man in his mid-30s whose DNA harbors a genetic mistake certain to destroy his brain within a matter of years.
“Watching my sons disintegrate before my eyes is heartbreaking,” writes a mother with two children affected by a faulty gene that affects cognition, speech and mobility. One of her sons, she writes, is still walking and in college, but “it is only a matter of time before he will be in a wheelchair and his cognition will decline.”
Stories of human tragedies like these arrive in my inbox with increasing, painful regularity. People write to see if I can build a medication to fix their genes and stave off an early, imminent death. Their wish is not futuristic: Many scientists, including me, build DNA fixes for a living.
Over the past decade, thousands of people have agreed to be genetically engineered in experimental trials to develop these treatments — and to save their lives. Famously proposed 50 years ago, such fixes, or gene therapies, began earnest development in 1989. After fits and starts, the first real cures for children born with no functioning immune system arrived in the early 2000s.
Several approved gene therapy medicines now exist. All involve taking a virus, replacing its harmful contents with a disease-treating gene, and injecting it into a person (or exposing the person’s cells to that virus in a dish and putting them back). Though effective, these treatments remain cumbersome to build and jaw-droppingly expensive: One recently approved gene therapy for people with an inherited bleeding disorder costs a record-breaking $3.5 million for a single-use vial, making it the most expensive drug in the world.
Gene editing is much newer technology and builds on the gains of gene therapy. Instead of using a virus, however, gene editing relies on a molecular machine called CRISPR, which can be instructed to repair a mutation in a gene in nearly any organism, right where that “typo” occurs. Impressively versatile, potential applications for CRISPR range from basic science to agriculture and climate change. In medicine, CRISPR gene editing allows physicians to directly fix typos in the patients’ DNA. And so much substantive progress has been made in the field of genetic medicine that it’s clear scientists have now delivered on a remarkable dream: word-processor-like control over DNA.
The first person to be gene-edited with CRISPR was treated only three years ago for a disorder of red blood cell production, and since then, the technology has been used to treat congenital blindness, sickle cell disease, heart disease, nerve disease, cancer and H.I.V. While not all diseases have a single-gene basis, most have a genetic component. Early studies suggest that conditions like heart disease, chronic pain and Alzheimer’s disease could all be treated with CRISPR. Dr. Jennifer Doudna, a winner of the 2020 Nobel Prize in Chemistry for CRISPR gene editing along with Dr. Emmanuelle Charpentier, aptly described it as a “profound opportunity to change health care for many people.”
Scientists like me can now visualize an ideal scenario for the future of CRISPR medicines: When a 3-month-old starts to develop antibiotic-resistant infections, her primary care doctor orders a DNA test, and 48 hours later, the faulty gene that is preventing the development of a normal immune system is identified. “Not a problem. We will refer your child for corrective CRISPR therapy,” says the physician to the devastated parents. “The treatment will be covered by insurance and take all of two months.”
Here’s what will happen in those two months: A dedicated CRISPR cures center at a university-affiliated hospital then takes the diagnosis and morphs it into an order form for a manufacturing facility to create the medication that will repair the faulty gene. After a month of testing and data review by hospital clinicians and university scientists, the physician does a simple IV injection of the resulting CRISPR medicine, and after a three-day stay at the hospital to confirm the gene editing went according to plan, the child is sent home.
Just as CRISPR once seemed to be something out of science fiction, so might everything in the preceding paragraphs — but every step of that process is technically feasible today.
Examples from across the world illustrate the possibilities of what CRISPR can accomplish. In China, it was recently used to treat two children ages 7 and 8 with a genetic condition related to sickle cell disease called beta-thalassemia. Before treatment, the children were unable to create normal red blood cells and required blood transfusions every two to three weeks. Within a month after receiving gene-edited cells, the transfusions ended. Eighteen months later, the children remained free of disease symptoms.
In the United States and in Europe, progress has also been formidable. The biotechnology companies CRISPR Therapeutics and Vertex have cured 31 people with sickle cell disease, who no longer experience the debilitating episodes of pain that characterize their condition. Another biotechnology company, Intellia Therapeutics, teamed up with Regeneron and used CRISPR to inactivate a typo-laden toxic gene in the livers of 15 people. A mere month after this injection, 93 percent of the toxin was gone from the bloodstreams of patients who received the highest dose of CRISPR medicine. Verve Therapeutics is developing a CRISPR treatment for heart disease, with an initial focus on a severe genetic form. Should Verve meet its ambitious goal of expanding this approach to patients with the common type of heart disease, one gene edit could replace daily medications such as statins. Physicians elsewhere are using CRISPR to test a treatment for people who carry H.I.V. by cutting out the virus’s DNA from their immune system. If they succeed, it’s possible that about 40 million people could benefit.
But the question is: Will they?
There are up to 400 million people worldwide affected by one of the 7,000 diseases caused by mutations in single genes. Scientists owe them and their families honesty about the chasm between a test tube in a lab and an IV line in a hospital. The greatest obstacles are not technical but legal, financial and organizational.
Take the young girl whose parents told me she could die in the next year. In the “CRISPR cures on demand” vision described above, after reading her parents’ email, I would follow a well-practiced protocol using widely available software to engineer a CRISPR medicine for her.
First, I would enter the name of her typo-laden gene into a human genome browser. Click. Next, I would zoom in on the stretch of DNA with the typo and — click — run a piece of software that designs a CRISPR to repair the mutation. Click. I would review the options and pick the most promising one. Click. On my screen would appear a string of RNA: GGACGUGAGUUUCAGCACGC. This is our guide: a nucleic acid that would lead CRISPR to repair this girl’s mutation.
Pasting this string into an order form on the website of one of many companies that can synthesize such a CRISPR guide on demand could result in the key component of a potentially lifesaving medicine in three days.
However, from more than 15 years of experience building such gene-editing medicines and advancing them to clinical trials, I know this process is only the first step in a four-year journey likely to cost at least $8 million to $10 million.
According to U.S. and European law, a detailed process is in place to ensure safety and efficacy of the experimental medicine. It starts with meticulous studies using human cells in a dish and in animals. This takes at least two years, and if everything checks out, scientists embark on the most expensive leg of the trip: making the CRISPR medicine, which has to be synthesized to comply with a regulatory standard known as good manufacturing practice. Designed to protect patients from faulty medicines, this U.S. federal requirement stretches out the making of clinic-grade CRISPR to a year and over $1 million, followed by over a year of animal testing. All of this happens beforeyou can use it to treat a human being.
Given these realities, the 2-year-old girl with the genetic mutation stands little chance of timely treatment. Who will invest $10 million to build a medicine to correct a specific mutation that can then be used to treat only one person? Even if the money were available, people with such rare diseases would be likely to die by the time the necessary experiments are complete — infuriatingly rendering my ability to engineer the CRISPR medicine of zero help to the people who write to me and millions more in similar predicaments.
I cannot imagine responding: “I’m sorry to say that while we can use CRISPR to repair your mutation in a test tube, we cannot repair it in you because this is not commercially viable.” Instead, I often try to connect patients with physicians who may specialize in their condition.
A case study from gene therapy with viruses highlights the problem. Dr. Donald Kohn at U.C.L.A. built a therapy for a devastating genetic disease called severe combined immune deficiency. Partnering with clinicians at University College London, he used this therapy to treat 50 children doomed to die. Forty-eight were cured by the therapy; the other two survived after receiving a bone-marrow transplant.
But public universities are not in the business of commercializing medicines they build. For this reason, U.C.L.A. licensed this miracle drug to a for-profit biotechnology company. After the company failed to make a profit on it, U.C.L.A. took back the license and obtained funding from the State of California to treat a small number of children in an academic setting. No children were treated in the four years it was under for-profit purview.
Across the entire sector of for-profit companies building gene therapy medicines, a sobering process is playing out. Even when they create a treatment that works, companies price it exorbitantly (around $2 million to $3 million per patient), arguing that a one-time cure saves the health care system years of costly supportive care.
For diseases with fewer than 100 patients, such prices are still not enough for these efforts to make commercial sense, as demonstrated by a biotechnology company, bluebird bio. After 20 years of engineering such gene therapies and significant success in the clinic, bluebird bio now struggles to remain solvent — even as it priced its most recent approved medicine at $3 million. Another gene-editing biotechnology company recently halted clinical trials for a rare disease with 300 patients in the United States, saying it couldn’t make the economic case to continue the experiments. For a disease that affects one person, the current for-profit system thus makes building a gene therapy or a gene editing cure a daunting challenge.
To make CRISPR cures a reality, the biomedical community needs to start with regulation. For treatments developed for genetic diseases that affect tens of thousands of people (or, say, if a company tries to take on heart disease, which affects millions), the Food and Drug Administration has a well-established, yearslong review process. But the F.D.A. needs to consider a new regulatory process that could create a more streamlined path for bringing much-needed CRISPR medicine tailored to patients with a one-of-a-kind genetic typo. There is precedent for this: Starting in the late 1990s, the F.D.A. facilitated regulatory pathways for innovation of a then-new class of genomic medicines for cancer — CAR-T therapy — which is now widely used clinically. The same can be done for CRISPR.
Streamlining regulation won’t be enough, though. Where will the funding for developing cures for single patients come from? Biotechnology companies are unlikely to voluntarily take this on, given the financial cost, though the for-profit sector could make a significant contribution by sharing technologies and resources that would accelerate this effort. Tapping into federal and state funding could provide a path forward. Recently, the F.D.A. greenlit a clinical trial designed by my colleagues at U.C. Berkeley’s Innovative Genomics Institute, in collaboration with physicians at U.C.L.A. and U.C.S.F., for a gene editing approach to sickle cell disease. My sense of pride in this achievement is diluted by the realization that ours is the only suchall-academic trial in the entirety of the gene editing space. To truly realize the potential of this technology, there should be dozensof such efforts underway.
This approach poses a difficult but essential question: Why should the average taxpayer contribute to building medicines for rare diseases? Would the money be better spent on finding treatments for common ailments?
Investing public funding in CRISPR cures for rare diseases not only will help us treat people with uncommon mutations (a global community numbering hundreds of millions of people) but also can provide insights that can be infused into CRISPR clinical innovation for common diseases.
But for the next few years, devastating genetic ailments and cancer are where CRISPR clinical trials must remain; ethical considerations over the safety of patients being exposed to new technology dictate that. Today’s tools are also the cognate of the first iPod — at the time, an exhilarating advance but still low tech compared with present-day smartphones. Everything we learn about how to gene-edit people from this work, coupled with continued CRISPR innovation in the academic and for-profit sector, will provide a foundation for more deeply understanding how to safely edit DNA to treat and potentially prevent dire common diseases.
The invention of CRISPR gene editing gave us remarkable treatment powers, yet no one should do a victory lap. Scientists can rewrite a person’s DNA on demand. But now what? Unless things change dramatically, the millions of people CRISPR could save will never benefit from it. We must, and we can, build a world with CRISPR for all.
Fyodor Urnov is a professor of molecular and cell biology at the University of California, Berkeley, and a gene editor at its Innovative Genomics Institute.
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