Fixing a Baby’s Abnormal Genes in the Womb May Soon Be Possible
A couple holds up a picture of their ultrasound.
By now you have probably heard something about CRISPR, the simple and relatively inexpensive method of precisely editing the genomes of plants, animals, and humans.
The treatment of disease in fetuses, the liminal category of life between embryos and humans, poses the next frontier.
Through CRISPR and other methods of gene editing, scientists have produced crops to be more nutritious, better able to resist pests, and tolerate droughts; engineered animals ranging from fruit flies to monkeys to make them better suited for scientific study; and experimentally treated the HIV virus, Hepatitis B, and leukemia in human patients.
There are also currently FDA-approved trials to treat blindness, cancer, and sickle cell disease in humans using gene editing, and there is consensus that CRISPR's therapeutic applications will grow significantly in the coming years.
While the treatment of human disease through use of gene editing is not without its medical and ethical concerns, the avoidance of disease in embryos is far more fraught. Nonetheless, Nature reported in November that He Jiankui, a scientist in China, had edited twin embryos to disable a gene called CCR5 in hopes of avoiding transmission of HIV from their HIV-positive father.
Though there are questions about the effectiveness and necessity of this therapy, He reported that sequencing has proven his embryonic gene edits were successful and the twins were "born normal and healthy," although his claims have not been independently verified.
More recently, Denis Rebrikov, a Russian scientist, announced his plans to disable the same gene in embryos to be implanted in HIV-positive women later this year. Futuristic as it may seem, prenatal gene editing is already here.
The treatment of disease in fetuses, the liminal category of life between embryos and humans, poses the next frontier. Numerous conditions—some minor, some resulting in a lifetime of medical treatment, some incompatible with life outside of the womb—can be diagnosed through use of prenatal diagnostic testing. There is promising research suggesting doctors will soon be able to treat or mitigate at least some of them through use of fetal gene editing.
This research could soon present women carrying genetically anomalous fetuses a third option aside from termination or birthing a child who will likely face a challenging and uncertain medical future: Whether to undergo a fetal genetic intervention.
However, genetic intervention will open the door to a host of ethical considerations, particularly with respect to the relationship between pregnant women and prenatal genetic counselors. Current counselors theoretically provide objective information and answer questions rather than advise their pregnant client whether to continue with her pregnancy, despite the risks, or to have an abortion.
In practice, though, prenatal genetic counseling is most often directive, and the nature of the counseling pregnant women receive can depend on numerous factors, including their religious and cultural beliefs, their perceived ability to handle a complicated pregnancy and subsequent birth, and their financial status. Introducing the possibility of a fetal genetic intervention will exacerbate counselor reliance upon these considerations and in some cases lead to counseling that is even more directive.
Some women in the near future will face the choice of whether to abort, keep, or treat a genetically anomalous fetus.
Future counselors will have to figure out under what circumstances it is even appropriate to broach the subject. Should they only discuss therapies that are FDA-approved, or should they mention experimental treatments? What about interventions that are available in Europe or Asia, but banned in the United States? Or even in the best case of scenario of an FDA-approved treatment, should a counselor make reference to it if she knows for a fact that her client cannot possibly afford it?
Beyond the basic question of what information to share, counselors will have to confront the fact that the very notion of fixing or "editing" offspring will be repugnant to many women, and inherent in the suggestion is the stigmatization of individuals with disabilities. Prenatal genetic counselors will be on the forefront of debates surrounding which fetuses should remain as they are and which ones should be altered.
Despite these concerns, some women in the near future will face the choice of whether to abort, keep, or treat a genetically anomalous fetus in utero. Take, for example, a woman who learns during prenatal testing that her fetus has Angelman syndrome, a genetic disorder characterized by intellectual disability, speech impairment, loss of muscle control, epilepsy, and a small head. There is currently no human treatment for Angelman syndrome, which is caused by a loss of function in a single gene, UBE3A.
But scientists at the University of North Carolina have been able to treat Angelman syndrome in fetal mice by reactivating UBE3A through use of a single injection. The therapy has also proven effective in cultured human brain cells. This suggests that a woman might soon have to consider injecting her fetus's brain with a CRISPR concoction custom-designed to target UBE3A, rather than terminate her pregnancy or bring her fetus to term unaltered.
Assuming she receives the adequate information to make an informed choice, she too will face an ethical conundrum. There will be the inherent risks of injecting anything into a developing fetus's brain, including the possibility of infection, brain damage, and miscarriage. But there are also risks specific to gene editing, such as so-called off-target effects, the possibility of impacting genes other than the intended one. Such effects are highly unpredictable and can be difficult to detect. So too is it impossible to predict how altering UBE3A might lead to other genetic and epigenetic changes once the baby is born.
There are no easy answers to the many questions that will arise in this space.
A woman deciding how to act in this scenario must balance these risks against the potential benefits of the therapy, layered on top of her belief system, resources, and personal ethics. The calculus will be different for every woman, and even the same woman might change her mind from one pregnancy to the next based on the severity of the condition diagnosed and other available medical options.
Her genetic counselor, meanwhile, must be sensitive to all of these concerns in helping her make her decision, keeping up to date on the possible new treatments, and carefully choosing which information to disclose in striving to be neutral. There are no easy answers to the many questions that will arise in this space, but better to start thinking about them now, before it is too late.
Breakthrough therapies are breaking patients' banks. Key changes could improve access, experts say.
Single-treatment therapies are revolutionizing medicine. But insurers and patients wonder whether they can afford treatment and, if they can, whether the high costs are worthwhile.
CSL Behring’s new gene therapy for hemophilia, Hemgenix, costs $3.5 million for one treatment, but helps the body create substances that allow blood to clot. It appears to be a cure, eliminating the need for other treatments for many years at least.
Likewise, Novartis’s Kymriah mobilizes the body’s immune system to fight B-cell lymphoma, but at a cost $475,000. For patients who respond, it seems to offer years of life without the cancer progressing.
These single-treatment therapies are at the forefront of a new, bold era of medicine. Unfortunately, they also come with new, bold prices that leave insurers and patients wondering whether they can afford treatment and, if they can, whether the high costs are worthwhile.
“Most pharmaceutical leaders are there to improve and save people’s lives,” says Jeremy Levin, chairman and CEO of Ovid Therapeutics, and immediate past chairman of the Biotechnology Innovation Organization. If the therapeutics they develop are too expensive for payers to authorize, patients aren’t helped.
“The right to receive care and the right of pharmaceuticals developers to profit should never be at odds,” Levin stresses. And yet, sometimes they are.
Leigh Turner, executive director of the bioethics program, University of California, Irvine, notes this same tension between drug developers that are “seeking to maximize profits by charging as much as the market will bear for cell and gene therapy products and other medical interventions, and payers trying to control costs while also attempting to provide access to medical products with promising safety and efficacy profiles.”
Why Payers Balk
Health insurers can become skittish around extremely high prices, yet these therapies often accompany significant overall savings. For perspective, the estimated annual treatment cost for hemophilia exceeds $300,000. With Hemgenix, payers would break even after about 12 years.
But, in 12 years, will the patient still have that insurer? Therein lies the rub. U.S. payers, are used to a “pay-as-you-go” model, in which the lifetime costs of therapies typically are shared by multiple payers over many years, as patients change jobs. Single treatment therapeutics eliminate that cost-sharing ability.
"As long as formularies are based on profits to middlemen…Americans’ healthcare costs will continue to skyrocket,” says Patricia Goldsmith, the CEO of CancerCare.
“There is a phenomenally complex, bureaucratic reimbursement system that has grown, layer upon layer, during several decades,” Levin says. As medicine has innovated, payment systems haven’t kept up.
Therefore, biopharma companies begin working with insurance companies and their pharmacy benefit managers (PBMs), which act on an insurer’s behalf to decide which drugs to cover and by how much, early in the drug approval process. Their goal is to make sophisticated new drugs available while still earning a return on their investment.
New Payment Models
Pay-for-performance is one increasingly popular strategy, Turner says. “These models typically link payments to evidence generation and clinically significant outcomes.”
A biotech company called bluebird bio, for example, offers value-based pricing for Zynteglo, a $2.8 million possible cure for the rare blood disorder known as beta thalassaemia. It generally eliminates patients’ need for blood transfusions. The company is so sure it works that it will refund 80 percent of the cost of the therapy if patients need blood transfusions related to that condition within five years of being treated with Zynteglo.
In his February 2023 State of the Union speech, President Biden proposed three pilot programs to reduce drug costs. One of them, the Cell and Gene Therapy Access Model calls on the federal Centers for Medicare & Medicaid Services to establish outcomes-based agreements with manufacturers for certain cell and gene therapies.
A mortgage-style payment system is another, albeit rare, approach. Amortized payments spread the cost of treatments over decades, and let people change employers without losing their healthcare benefits.
Only about 14 percent of all drugs that enter clinical trials are approved by the FDA. Pharma companies, therefore, have an exigent need to earn a profit.
The new payment models that are being discussed aren’t solutions to high prices, says Bill Kramer, senior advisor for health policy at Purchaser Business Group on Health (PBGH), a nonprofit that seeks to lower health care costs. He points out that innovative pricing models, although well-intended, may distract from the real problem of high prices. They are attempts to “soften the blow. The best thing would be to charge a reasonable price to begin with,” he says.
Instead, he proposes making better use of research on cost and clinical effectiveness. The Institute for Clinical and Economic Review (ICER) conducts such research in the U.S., determining whether the benefits of specific drugs justify their proposed prices. ICER is an independent non-profit research institute. Its reports typically assess the degrees of improvement new therapies offer and suggest prices that would reflect that. “Publicizing that data is very important,” Kramer says. “Their results aren’t used to the extent they could and should be.” Pharmaceutical companies tend to price their therapies higher than ICER’s recommendations.
Drug Development Costs Soar
Drug developers have long pointed to the onerous costs of drug development as a reason for high prices.
A 2020 study found the average cost to bring a drug to market exceeded $1.1 billion, while other studies have estimated overall costs as high as $2.6 billion. The development timeframe is about 10 years. That’s because modern therapeutics target precise mechanisms to create better outcomes, but also have high failure rates. Only about 14 percent of all drugs that enter clinical trials are approved by the FDA. Pharma companies, therefore, have an exigent need to earn a profit.
Skewed Incentives Increase Costs
Pricing isn’t solely at the discretion of pharma companies, though. “What patients end up paying has much more to do with their PBMs than the actual price of the drug,” Patricia Goldsmith, CEO, CancerCare, says. Transparency is vital.
PBMs control patients’ access to therapies at three levels, through price negotiations, pricing tiers and pharmacy management.
When negotiating with drug manufacturers, Goldsmith says, “PBMs exchange a preferred spot on a formulary (the insurer’s or healthcare provider’s list of acceptable drugs) for cash-base rebates.” Unfortunately, 25 percent of the time, those rebates are not passed to insurers, according to the PBGH report.
Then, PBMs use pricing tiers to steer patients and physicians to certain drugs. For example, Kramer says, “Sometimes PBMs put a high-cost brand name drug in a preferred tier and a lower-cost competitor in a less preferred, higher-cost tier.” As the PBGH report elaborates, “(PBMs) are incentivized to include the highest-priced drugs…since both manufacturing rebates, as well as the administrative fees they charge…are calculated as a percentage of the drug’s price.
Finally, by steering patients to certain pharmacies, PBMs coordinate patients’ access to treatments, control patients’ out-of-pocket costs and receive management fees from the pharmacies.
Therefore, Goldsmith says, “As long as formularies are based on profits to middlemen…Americans’ healthcare costs will continue to skyrocket.”
Transparency into drug pricing will help curb costs, as will new payment strategies. What will make the most impact, however, may well be the development of a new reimbursement system designed to handle dramatic, breakthrough drugs. As Kramer says, “We need a better system to identify drugs that offer dramatic improvements in clinical care.”
In today's podcast episode, law professor Gaia Bernstein talks about the challenges of keeping control over our thoughts and actions, even when some powerful forces are pushing in the other direction.
Each afternoon, kids walk through my neighborhood, on their way back home from school, and almost all of them are walking alone, staring down at their phones. It's a troubling site. This daily parade of the zombie children just can’t bode well for the future.
That’s one reason I felt like Gaia Bernstein’s new book was talking directly to me. A law professor at Seton Hall, Gaia makes a strong argument that people are so addicted to tech at this point, we need some big, system level changes to social media platforms and other addictive technologies, instead of just blaming the individual and expecting them to fix these issues.
Gaia’s book is called Unwired: Gaining Control Over Addictive Technologies. It’s fascinating and I had a chance to talk with her about it for today’s podcast. At its heart, our conversation is really about how and whether we can maintain control over our thoughts and actions, even when some powerful forces are pushing in the other direction.
Listen on Apple | Listen on Spotify | Listen on Stitcher | Listen on Amazon | Listen on Google
We discuss the idea that, in certain situations, maybe it's not reasonable to expect that we’ll be able to enjoy personal freedom and autonomy. We also talk about how to be a good parent when it sometimes seems like our kids prefer to be raised by their iPads; so-called educational video games that actually don’t have anything to do with education; the root causes of tech addictions for people of all ages; and what kinds of changes we should be supporting.
Gaia is Seton’s Hall’s Technology, Privacy and Policy Professor of Law, as well as Co-Director of the Institute for Privacy Protection, and Co-Director of the Gibbons Institute of Law Science and Technology. She’s the founding director of the Institute for Privacy Protection. She created and spearheaded the Institute’s nationally recognized Outreach Program, which educated parents and students about technology overuse and privacy.
Professor Bernstein's scholarship has been published in leading law reviews including the law reviews of Vanderbilt, Boston College, Boston University, and U.C. Davis. Her work has been selected to the Stanford-Yale Junior Faculty Forum and received extensive media coverage. Gaia joined Seton Hall's faculty in 2004. Before that, she was a fellow at the Engelberg Center of Innovation Law & Policy and at the Information Law Institute of the New York University School of Law. She holds a J.S.D. from the New York University School of Law, an LL.M. from Harvard Law School, and a J.D. from Boston University.
Gaia’s work on this topic is groundbreaking I hope you’ll listen to the conversation and then consider pre-ordering her new book. It comes out on March 28.
