by Jamie Metzl
Responding to this progress, the FDA and National Institutes of Health jointly announced in August 2018 that they would significantly reduce the special oversight processes for gene therapies because “there is no longer sufficient evidence to claim that the risks of gene therapy are entirely unique and unpredictable—or that the field still requires special oversight that falls outside our existing framework for ensuring safety.”21
This rapid coming of age of gene therapies is being matched by other developments pushing the gene-editing revolution forward. A Silicon Valley start-up named Synthego, for example, sells custom CRISPR-edited human and other cells lines delivered to researchers within days. Another company, Inscripta, is trying to make all of the tools needed for CRISPR just an easy click away. These new companies, Wired noted in May 2018, are betting that “biology will be the next great computing platform, DNA will be the code that runs it, and CRISPR will be the programming language.”22 Although the current generation of genetic health-care interventions is not passed on to future generations of the people being treated, the popular acceptance of and demand for these treatments will play an important role making the general public more comfortable with the concept of human genetic alteration.
It would be impossible to capture in this or any book the breadth and speed of the experimental advances with major health-care implications using precision gene editing being made almost daily, but here are a few examples of the intensifying stream of progress made in recent years alone:
•In 2013, researchers in the Netherlands used CRISPR-Cas9 on human stem cells to repair a defect that contributes to the appearance of cystic fibrosis.23
•In 2014, scientists used CRISPR-Cas9 to correct liver cells in mice modeling the human disease hereditary tyrosinemia.24
•In 2015, researchers deployed CRISPR-Cas9 to edit endogenous beta-globin genes in human cells which, when mutated, result in beta-thalassemia blood disorders.25
•In 2016, scientists used CRISPR-Cas9 to extract HIV from human immune cell DNA and prevent the reinfection of unedited cells.26
•In 2017, researchers first used CRISPR-Cas9 on a human embryo successfully to correct a defect in the MYBPC3 gene that causes hypertrophic cardiomyopathy.27
•In 2018, scientists showed how a novel CRISPR gene-editing technique could potentially correct most of the three thousand mutations causing Duchenne muscular dystrophy by cutting single points along a patient’s DNA.28
•In 2019, researchers showed how CRISPR-Cas9 could be combined with special guide RNA to more accurately than ever before edit human cells to correct the genetic mutation causing sickle cell disease.
Because these breakthroughs are happening so rapidly as ideas and innovations cross-fertilize, it is certain that more CRISPR miracles will be announced after the final edits of this book are submitted. It is also certain that new gene-editing tools more precise than CRISPR will arrive in the coming years. “Gene therapy will become a mainstay in treating, and maybe curing, many of our most devastating and intractable diseases,” FDA Commissioner Scott Gottlieb presciently declared in 2018.29
Getting comfortable with editing people’s cells to cure terrible diseases will provide a level of comfort with and confidence in our ability to use CRISPR and other tools to precisely and safely edit the human genome. As this comfort level increases, scientists, doctors, and prospective parents will begin to ask why these tools can’t also be used to prevent these diseases in the first place.
Mitochondria are the tiny power packs of the cell. Floating in the cell’s cytoplasm (if the cell were an egg, the nucleus would be the yolk and the cytoplasm the white), they are the legacy of symbiotic bacteria incorporated into our cells hundreds of millions of years ago. Nearly all our twenty-one thousand or so genes are located in the cell’s nucleus, but a far smaller number, just thirty-seven, are in the mitochondria.* Unlike nuclear DNA, which is the combination of the DNA from both parents, mitochondrial DNA (mtDNA) is passed almost entirely from mother to child.
Most people have healthy mitochondria that allow their body to get the energy it needs from their cells. But about one in two hundred people has a disease-causing mtDNA mutation, and about one in sixty-five hundred develop symptoms of mitochondrial disease. These dangerous mutations primarily target children, who often suffer systemic organ failure. The symptoms generally get more severe with age and can increasingly damage cells in the brain, liver, heart, and other bodily systems.
If everyone with mitochondrial disease died young, this disease would have been eradicated from the human gene pool long ago. But a mother’s mitochondrial problems tend to be distributed unevenly among her offspring, allowing some of the children to live healthy lives, others to live managing the diseases, and others to die terrible, early deaths.
For millennia, parents with mitochondrial disease had no idea why their children were suffering; they blamed fate. But fate was not a good enough answer for the Swedish endocrinologist Dr. Rolf Luft, who first diagnosed a patient with mitochondrial disease in 1962. Although huge progress was made in understanding mitochondrial disease in the early years, little was achieved in finding a cure or preventing it from being passed mother to child.
In the 1990s, Jacques Cohen and his colleagues at the Institute for Reproductive Medicine and Science in New Jersey pioneered a process of injecting fluid from the cytoplasm of a healthy egg into an egg where problems in the cytoplasm were believed to be causing infertility. Although seventeen babies born through this procedure were mitochondrial disease-free, two fetuses indicated a severe genetic disorder.30 In response, the FDA in 2001 started requiring clinics to apply for approval to carry out the procedure. Because of the imperfect safety record, few applied. No approvals were granted.
Nevertheless, the underlying science continued to advance. Over the past decade, teams in the United Kingdom and the United States developed two new mitochondrial transfer procedures. In one, the healthy nucleus taken from an egg of the intended mother carrying faulty mitochondria is removed and placed inside the denucleated egg of a donor woman without mitochondrial disease—it’s like keeping the egg yolk but replacing the white with a donated one. In the other procedure, the same process happens to the early-stage embryo after the egg is fertilized; scientists remove the nucleus and place it into the denucleated embryo donor parents provide.
As prospective mothers carrying mitochondrial disease learned of this new approach, many were interested. But some observers were worried. Mitochondrial transfer is a heritable treatment. A daughter born with donor mitochondria will pass that mitochondrial DNA to her daughter, and down the line forever. (This is why women who get their ancestral history through DNA tests can learn about their mother’s mother’s mother’s mother, all the way back to our human female common ancestor, “mitochondrial Eve,” from around 160,000 years ago.) Even though the total amount of donor DNA in a child born with the mitochondrial transfer treatment would be small, scientifically altering human DNA for all future generations is a big deal.
The United Kingdom has done more than any other country to thoughtfully consider mitochondrial therapies and their implications. Soon after the “test tube” miracle baby, Louise Brown, was born in Manchester in 1978, the United Kingdom created a Committee of Inquiry into Human Fertilisation and Embryology. The committee produced a major 1984 report on the future of assisted reproduction and then a 1987 White Paper outlining a legislative agenda for going forward. This critically important work culminated in the 1990 Human Fertilisation and Embryology Act that created, you guessed it, the Human Fertilisation and Embryology Authority, HFEA. Since then, the HFEA has done incredible work overseeing and regulating reproductive technologies across Britain.
Although the 1990 act didn’t consider, and therefore couldn’t expressly authorize, mitochondrial therapies, the issue was raised in 2010 when researchers asked the UK Department of Health and Social Care to amend its regulations to allow mitochondrial transfer. Rather than just consid
ering this a simple regulatory decision, the UK government launched an intensive five-year consultation process, including a series of expert panels, public forums, comment opportunities on draft legislation, and cost-benefit analyses by the department of health. In 2015, the issue of whether the HFEA should be allowed to authorize clinical trials was put to a full vote of both Houses of Parliament and passed unanimously. The HFEA then waited for results from additional studies and convened even more expert panels on the safety and efficacy of these procedures.31
In March 2017, Britain’s HFEA granted its first license to doctors to use the mitochondrial transfer technique on a human embryo to be implanted in prospective mothers. After the first two clinical applications were approved on February 1, 2018, the first British child born using mitochondrial transfer will all but certainly be delivered in 2019.32 Moving forward with this first ever case of state-sponsored, heritable genetic engineering was a monumental step not just for the United Kingdom but also for humanity—and the British handled the process responsibly.
In America, the process of considering mitochondrial transfer has been much more bureaucratic. The FDA effectively banned mitochondrial transfer in a 2001 extension of its authorities, and then in 2016 Congress forbade the FDA from even authorizing clinical trials of mitochondrial replacement therapy. Although a series of expert panels on the issue have been held, the FDA has yet to authorize clinical trials partly because the contentious politics of abortion in the United States makes any discussion of manipulating embryos extremely complicated. Even after a 2016 U.S. National Academies of Science, Engineering, and Medicine report concluded that some limited application of mitochondrial transfer treatments could be justified for male embryos (to make sure no genetic changes could be passed on to future generations), the effective U.S. ban on mitochondrial transfer treatments remains in place.
But before the first British license was granted, and while the procedure was still banned in the United States, a Jordanian couple approached New York–based physician John Zhang about having it done. Because mitochondrial transfer was still illegal in the United States, Zhang agreed to travel to Mexico, which at the time had no rules governing the procedure. By the time this birth was officially announced in September 2016, the Jordanian baby was already a healthy five-month-old. Zhang returned to New York without repercussion and soon announced the creation of his new company, aptly named Darwin Life, which he described as “pushing the boundaries of Assisted Reproductive Technology.”33 In January 2017, doctors in Ukraine transferred the nucleus of an early-stage embryo with mitochondrial disease to a denucleated donor embryo without it, resulting in the birth of another healthy baby.34
Potential mothers who carry mitochondrial disease in the few places where mitochondrial transfer is allowed have a full range of options. Of course, they can always adopt. But if they want to have a fully biologically related child, they have the option of rolling the dice by getting pregnant, testing the embryo after ten weeks of pregnancy, and facing the option of abortion. Or they can just have the child and see if their naturally born and unscreened children will be born with a deadly form of mitochondrial disease. An alternative option would be for the mother to have her eggs extracted and fertilized using IVF and then genetically screened with PGT.35 But mitochondrial disease does not fully show up in early-stage embryos, so an embryo screened prior to implantation could still be a carrier of mitochondrial disease.36
If a mother in one of these jurisdictions wanted to be certain her child would not carry mitochondrial disease, she could swap out the cytoplasm of her egg prior to insemination during IVF, or of her early-stage embryo just after the egg was fertilized—all for the price of 0.1 percent of the child’s total DNA becoming inherited from the mitochondrial donor.
But what about women living in parts of the world where mitochondrial transfer is banned or unavailable? They can adopt, too. Of course, they can roll the hereditary dice. They can also do IVF and PGT if they are in a jurisdiction where that is legal, but they would still run the risk of passing the disease to future generations. They can travel to a place like Ukraine. But that’s expensive, uncomfortable, and inconvenient. Another option would be to band together with other prospective parents with the disease to form a lobby group to try to make mitochondrial transfer legal at home.
That’s exactly what the mitochondrial disease community has done in the United States. “We strongly support further scientific investigation of oocyte MRT [mitochondrial replacement therapy] as well as constructive debate towards the clinical approval of this therapy in women with mtDNA-related diseases,” the Pittsburgh-based United Mitochondrial Disease Foundation, UMDF, publicly declared. “If demonstrated to be safe and efficacious, this technique should be made available as an option to families who carry mtDNA point mutations.”37
As evidence of the safety and efficacy of mitochondria transfer in places like the United Kingdom continues to grow, pressure on other governments to fund research and ultimately allow heritable mitochondrial therapies by advocacy groups in those countries will increase. Politicians in those countries will have a hard time telling mothers terrified of passing potentially deadly mitochondrial disease to their children and influential single-issue lobby groups that they can’t have access to the mitochondrial replacement procedure that has been proven safe and effective under the highest level of government scrutiny in the United Kingdom. Over time, mitochondrial transfer will likely become the first relatively widely accepted heritable genetic manipulation.
Once this happens, parents afraid of passing other deadly genetic diseases to their future children will not sit by idly while their future children face potential genetic death sentences. Instead, they will demand that the most advanced precision gene-editing technologies be used to make the targeted changes that will save their future children from suffering. As scientists continue provide an increasing set of new potential possibilities to gene edit embryos to prevent disease and enhance health, parental demand will only increase.
Almost every significant genetic disease has its own social network, and many also have politically influential lobby groups. Disease advocacy groups spend many millions of dollars annually lobbying the U.S. government. Each thousand dollars invested in this type of outreach is estimated to correlate to a $25,000 increase the following year in National Institutes of Health funding for a specific disease.38 It is hard to imagine the U.S. government, itself driven largely by the interests of special-interest pressure groups, not eventually supporting research into and clinical trials of the most promising treatments for genetic diseases, even those that involve making heritable changes to preimplanted embryos.
The major strides toward making gene editing of preimplanted human embryos possible will add more fuel to this rocket.
In April 2015, scientists from Sun Yat-sen University in Guangzhou, China, shocked the world by disclosing they had used CRISPR-Cas9 to genetically alter genes in human embryos in vitro linked to the often-fatal blood disorder beta-thalassemia.39 The embryos were nonviable because they had been fertilized by two sperm cells instead of the usual one, and the accuracy rate of the edits was dismal. But this first reported direct application of CRISPR to the nuclear DNA of human embryos crossed an ethical Rubicon in the minds of many observers.
Soon after, United Kingdom regulators approved an application by Kathy Niakan. A researcher at London’s Francis Crick Institute, Niakan wanted to CRISPR-edit the genes of viable human embryos and examine how a gene called OCT4 regulates the development of fetuses, a first step to better understand a particular cause of infertility. Two months later, another team of Chinese scientists announced they had used CRISPR to try to make early-stage, unimplanted human embryos resistant to HIV.40
Then, in July 2017, the path-breaking and controversial U.S. scientist Shoukhrat Mitalipov of Oregon Health and Science University became the first American researcher to use CRISPR-Cas9 to genetically alter human sex cells and unimplanted embryos. M
italipov injected a CRISPR-Cas9 genetic scissors into the sperm of a man carrying a faulty MYBPC3 gene, which can cause hypertrophic cardiomyopathy, a heritable disease that can lead to sudden heart failure in children. When this gene-edited sperm was used to fertilize the eggs of twelve healthy donor women, two-thirds of the embryos were created disease free—a big increase over previous efforts. When Mitalipov’s team tried the same thing but only injected the unedited sperm and the CRISPR-Cas9 separately—so that the sperm editing happened simultaneous to egg fertilization—the success rate increased to 72 percent. Seventy-two percent efficacy is still not nearly good enough, and the embryos were all destroyed within three days, but a marker had clearly been set down on the path to the heritable gene editing of nuclear DNA in humans.41
“We’ve always said in the past gene editing shouldn’t be done, mostly because it couldn’t be done safely,” MIT researcher Richard Hynes told the New York Times after Mitalipov’s findings were released. “That’s still true, but now it looks like it’s going to be done safely soon.”42 When this happens, the irresistible attraction of using our most advanced technologies to eliminate our most deadly diseases will draw us into the genetic age.
The amazingly rapid transfer of advanced gene-editing tools from laboratories to farms and ranches and then to our hospitals and fertility clinics is already well underway with a momentum of its own. Almost every day, a new application is announced that, once available, some group of humans will demand. The very real benefits of these technologies to a growing group of potential beneficiaries will eventually outweigh the abstract aspirations of a dwindling number of genetic traditionalists.
