China vs. the West: Who Will Lead the Way in Embryo Editing Research?
The U.S. metaphorically boxing with China over biomedical research.
Junjiu Huang and his team performed a miracle. A few miracles, actually. The researchers at Sun Yat-sen University in Guangzhou, China used the precise new DNA editing tool called CRISPR-CAS9 to edit a human embryo, replacing a single base. In doing so, they edited out beta-thalassemia, a blood disorder that reduces the production of hemoglobin, which can result in pale skin, fatigue, higher risk of blood clots, and other symptoms.
The race is on, and it's one everyone is going to try to win.
Huang's group, which did not respond to an email requesting comment for this story, injected 86 embryos and observed them for 48 hours. After that period -- a time long enough for CRISPR to split the DNA, other molecules to replace the base, and the embryos to grow to eight cells -- they tested 54 of the 71 that survived. Of those, only a few had the replacement base, according to a report of the study published in Protein & Cell. The experiment stopped there as the embryos, which had been acquired from local fertility clinics, were non-viable and not implanted.
But procreation was not the point. Far from it, in fact. The point was to demonstrate that it could be done, that in some far off (or not so far off) future, doctors could use CRISPR to eliminate diseases like Tay-Sachs, Huntington's, and cystic fibrosis that are caused by genetic mutations. Going a step further, perhaps they could eventually even tailor embryos that will develop into adults with specific traits like height and IQ.
Experts agree that we are far from that point, years if not decades away from leveraging CRISPR to cure diseases and decades if not centuries from being able to build designer babies. In that frame, Huang's achievement is just a small step, a blip on the timeline of human achievement. But seen in another light, it's yet another sign that we need to start talking about DNA modification now, establishing protocols, procedures, and plans that guide the subject before we get so far down the road that momentum is impossible to stop.
"The Chinese generally don't have the religious objections to embryo research that have held back research in the West."
It's essential to do so now because the idea of DNA modification -- a realization that humanity can control its evolution -- is compelling and attractive. Imagine a world where doctors and scientists could get rid of disease before it begins or ensure a baby would arrive with an Einstein-level IQ. That's intriguing, and also terrifying. What are the rules? How do we know when to stop? What guides the process? And how can we prevent mistakes or unwanted mutations? To borrow from another famous quotation, with great power comes great responsibility.
These aren't questions for Huang and the Chinese scientific community alone. A team from Oregon recently edited viable human embryos, eliminating a mutation that can lead to heart failure while preventing any unintended consequences. Just as importantly, every embryo they edited produced the intended genetic changes, a vital step since a partial success rate, known as mosaicism, could have devastating consequences to a future child.
In London at the Francis Crick Institute, researcher Kathy Niakan used CRISPR-CAS9 to "turn off" a gene that produces the protein OCT4. Without the protein, the fertilized egg could not produce a blastocyst, which is a key structure in early mammalian development that gives rise to an embryo and placenta. The recent study wasn't designed to go further, but the use of CRISPR was important. "One way to find out what a gene does in the developing embryo is to see what happens when it isn't working," said Dr. Niakan, who was the first scientist in the world to be granted regulatory approval to edit the genes of a human embryo for research. "Now that we have demonstrated an efficient way of doing this, we hope that other scientists will use it to find out the roles of other genes. If we knew the key genes that embryos need to develop successfully, we could improve IVF treatments and understand some causes of pregnancy failure. It may take many years to achieve such an understanding. Our study is just the first step."
The point is, CRISPR is here and it's not going anywhere. Scientists will continue to use it to learn about how humans develop. Yet different rules regarding CRISPR and embryo research in countries around the world will impact who gets there first. "I've heard the U.S.-China gene editing research parallel paths as Sputnik 2.0," said Kevin Doxzen, Science Communications Specialist at the University of California, Berkeley's Innovative Genomics Institute. The race is on, and it's one everyone is going to try to win.
Based on number of researchers and ease of regulations, the Chinese are the favorites to advance the science the furthest, the fastest.
Based on number of researchers and ease of regulations, the Chinese are the favorites to advance the science the furthest, the fastest. "The Chinese generally don't have the religious (predominantly Christian) or moral objections to embryo research that have held back research in the West," said Dr. Julian Savulescu, the Uehiro Professor of Practical Ethics and Director of the Oxford Martin Programme on Collective Responsibility for Infectious Disease at the University of Oxford. "This kind of research should be done, with the right sort of ethical oversight. The concern over China leading the way is that institutional oversight mechanisms are probably not as developed as in the West but so far, there is no evidence of breaches in standards of research ethics around the published research."
Or, put another way by bioethicist Dr. Arthur Caplan, founding director of NYU Langone Health's Division of Medical Ethics: "The Chinese, because they don't care and don't have moral reservations about embryo work, are doing what they want." This lack of aversion to working with embryos manifests itself in a couple of ways. The absence of moral qualms is one. Funding is another. Huang's study, and others like it, receive funding from the government. His, for example, was supported by two grants from the National Basic Research Program and three from the National Natural Science Foundation of China.
The U.S., on the other hand, bans any federal funding for research using human embryos. A law passed in 1996 states that federal dollars can't be used for: "research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses." This restriction can shift incentives as many private institutions or commercial enterprises may have financial motivations or other goals beyond furthering basic research for the sake of general knowledge.
Embryo gene modification recently performed in the U.K. would merit 15 years in prison in Australia.
The embryo research ban is even more strict elsewhere. The Oviedo Convention, enacted in 1997, effectively prohibits germline engineering in members of the European Union. "In Italy, you can't destroy an embryo for any reason," said Alessandro Bertero, a postdoctoral fellow at the University of Washington's Department of Pathology who used to study in Italy. "It's illegal, and you'll go to jail." Later, Bertero was one of the researchers who worked with Dr. Niakan in London, an investigation that was allowed by the UK's Human Fertilisation and Embryology Authority. (In Australia, Niakan and her colleagues would face 15 years in jail due to the 2002 Prohibition of Human Cloning Act, which prohibits altering the genomes of embryonic cells.)
Despite the moral and legal reservations in the Western world, every person I spoke with for this story believed that better, more advanced studies and learning is happening in the U.S. and Europe. "The best studies in my opinion are from the labs in California and Oregon," Bertero said. "The quality of the work [in the Chinese study] – not being critical, but to be scientifically critical -- was just quick and dirty. It was, 'Let's just show that we have done it and get it out.' That doesn't mean that the quality of the work was good."
"If the Chinese or someone else starts beating our brains out, we're not going to want to stand by idly and not do these things."
How long that remains the case, however, is an open question. A significant number of groups in China are working on germline editing in human embryos. The concern is that the Chinese will emerge as a leader sooner rather than later because they can do research with embryos more easily than their Western counterparts.
For Caplan, the NYU professor, the embryo ban in the U.S. isn't based on science; it's rooted in something else. "It's 96 percent political," he said, laughing. "It has basically ground to a halt because no one wants to see repercussions take place if federal funding is involved. The NIH isn't involved. And they won't be."
What, in his mind, would get Americans to start realizing the benefits that embryo research would provide? "The perception that other countries were moving quickly to get the advantages of CRISPR and other gene modification techniques, finding more industrial and more medical purposes," he said. "If the Chinese or someone else starts beating our brains out, we're not going to want to stand by idly and not do these things."
Doing so would involve difficult conversations about the role of embryos in research. But these are philosophical questions that need to be approached at some point. From a U.S. perspective, doing so sooner while the American scientists still hold the technological and informational edge, is vital. Ignoring the issue doesn't make it go away.
Experts think a few changes should be made. The ban on federal funding should be lifted. Scientists and regulators should push for things like allowing federal funds to be used for the creation of new embryos for research purposes and the use of spare IVF embryos for research when the embryo would not be implanted into a woman. (Privately funded scientists can proceed in states that encourage embryonic stem cell research, like New York, New Jersey, and California, but not in restrictive ones like Louisiana and South Dakota, which prohibit creating or destroying embryos for research.) Policymakers could ban reproductive gene editing for now but look at it again after a certain period. A highly anticipated report issued earlier this year from an international guidance committee left the door open to eventual clinical trials with edited embryos. As of now, however, Congress will not allow the Food and Drug Administration to consider such trials. This is the future and it's the scientific community's responsibility to develop the ethical framework now.
"The US and Europe have the technological history and capacity to lead this research and should do so, ethically. We ought to be revising our laws and ethical guidelines to facilitate this kind of research," Professor Savulescu said. "But the challenge is to think constructively and ethically about this new technology, and to be leaders, not followers."
Gene Transfer Leads to Longer Life and Healthspan
In August, a study provided the first proof-of-principle that genetic material transferred from one species to another can increase both longevity and healthspan in the recipient animal.
The naked mole rat won’t win any beauty contests, but it could possibly win in the talent category. Its superpower: fighting the aging process to live several times longer than other animals its size, in a state of youthful vigor.
It’s believed that naked mole rats experience all the normal processes of wear and tear over their lifespan, but that they’re exceptionally good at repairing the damage from oxygen free radicals and the DNA errors that accumulate over time. Even though they possess genes that make them vulnerable to cancer, they rarely develop the disease, or any other age-related disease, for that matter. Naked mole rats are known to live for over 40 years without any signs of aging, whereas mice live on average about two years and are highly prone to cancer.
Now, these remarkable animals may be able to share their superpower with other species. In August, a study provided what may be the first proof-of-principle that genetic material transferred from one species can increase both longevity and healthspan in a recipient animal.
There are several theories to explain the naked mole rat’s longevity, but the one explored in the study, published in Nature, is based on the abundance of large-molecule high-molecular mass hyaluronic acid (HMM-HA).
A small molecule version of hyaluronic acid is commonly added to skin moisturizers and cosmetics that are marketed as ways to keep skin youthful, but this version, just applied to the skin, won’t have a dramatic anti-aging effect. The naked mole rat has an abundance of the much-larger molecule, HMM-HA, in the chemical-rich solution between cells throughout its body. But does the HMM-HA actually govern the extraordinary longevity and healthspan of the naked mole rat?
To answer this question, Dr. Vera Gorbunova, a professor of biology and oncology at the University of Rochester, and her team created a mouse model containing the naked mole rat gene hyaluronic acid synthase 2, or nmrHas2. It turned out that the mice receiving this gene during their early developmental stage also expressed HMM-HA.
The researchers found that the effects of the HMM-HA molecule in the mice were marked and diverse, exceeding the expectations of the study’s co-authors. High-molecular mass hyaluronic acid was more abundant in kidneys, muscles and other organs of the Has2 mice compared to control mice.
In addition, the altered mice had a much lower incidence of cancer. Seventy percent of the control mice eventually developed cancer, compared to only 57 percent of the altered mice, even after several techniques were used to induce the disease. The biggest difference occurred in the oldest mice, where the cancer incidence for the Has2 mice and the controls was 47 percent and 83 percent, respectively.
With regard to longevity, Has2 males increased their lifespan by more than 16 percent and the females added 9 percent. “Somehow the effect is much more pronounced in male mice, and we don’t have a perfect answer as to why,” says Dr. Gorbunova. Another improvement was in the healthspan of the altered mice: the number of years they spent in a state of relative youth. There’s a frailty index for mice, which includes body weight, mobility, grip strength, vision and hearing, in addition to overall conditions such as the health of the coat and body temperature. The Has2 mice scored lower in frailty than the controls by all measures. They also performed better in tests of locomotion and coordination, and in bone density.
Gorbunova’s results show that a gene artificially transferred from one species can have a beneficial effect on another species for longevity, something that had never been demonstrated before. This finding is “quite spectacular,” said Steven Austad, a biologist at the University of Alabama at Birmingham, who was not involved in the study.
Just as in lifespan, the effects in various organs and systems varied between the sexes, a common occurrence in longevity research, according to Austad, who authored the book Methuselah’s Zoo and specializes in the biological differences between species. “We have ten drugs that we can give to mice to make them live longer,” he says, “and all of them work better in one sex than in the other.” This suggests that more attention needs to be paid to the different effects of anti-aging strategies between the sexes, as well as gender differences in healthspan.
According to the study authors, the HMM-HA molecule delivered these benefits by reducing inflammation and senescence (cell dysfunction and death). The molecule also caused a variety of other benefits, including an upregulation of genes involved in the function of mitochondria, the powerhouses of the cells. These mechanisms are implicated in the aging process, and in human disease. In humans, virtually all noncommunicable diseases entail an acceleration of the aging process.
So, would the gene that creates HMM-HA have similar benefits for longevity in humans? “We think about these questions a lot,” Gorbunova says. “It’s been done by injections in certain patients, but it has a local effect in the treatment of organs affected by disease,” which could offer some benefits, she added.
“Mice are very short-lived and cancer-prone, and the effects are small,” says Steven Austad, a biologist at the University of Alabama at Birmingham. “But they did live longer and stay healthy longer, which is remarkable.”
As for a gene therapy to introduce the nmrHas2 gene into humans to obtain a global result, she’s skeptical because of the complexity involved. Gorbunova notes that there are potential dangers in introducing an animal gene into humans, such as immune responses or allergic reactions.
Austad is equally cautious about a gene therapy. “What this study says is that you can take something a species does well and transfer at least some of that into a new species. It opens up the way, but you may need to transfer six or eight or ten genes into a human” to get the large effect desired. Humans are much more complex and contain many more genes than mice, and all systems in a biological organism are intricately connected. One naked mole rat gene may not make a big difference when it interacts with human genes, metabolism and physiology.
Still, Austad thinks the possibilities are tantalizing. “Mice are very short-lived and cancer-prone, and the effects are small,” he says. “But they did live longer and stay healthy longer, which is remarkable.”
As for further research, says Austad, “The first place to look is the skin” to see if the nmrHas2 gene and the HMM-HA it produces can reduce the chance of cancer. Austad added that it would be straightforward to use the gene to try to prevent cancer in skin cells in a dish to see if it prevents cancer. It would not be hard to do. “We don’t know of any downsides to hyaluronic acid in skin, because it’s already used in skin products, and you could look at this fairly quickly.”
“Aging mechanisms evolved over a long time,” says Gorbunova, “so in aging there are multiple mechanisms working together that affect each other.” All of these processes could play a part and almost certainly differ from one species to the next.
“HMM-HA molecules are large, but we’re now looking for a small-molecule drug that would slow it’s breakdown,” she says. “And we’re looking for inhibitors, now being tested in mice, that would hinder the breakdown of hyaluronic acid.” Gorbunova has found a natural, plant-based product that acts as an inhibitor and could potentially be taken as a supplement. Ultimately, though, she thinks that drug development will be the safest and most effective approach to delivering HMM-HA for anti-aging.
A new study provides key insights in what causes Alzheimer's: a breakdown in the brain’s system for clearing waste.
In recent years, researchers of Alzheimer’s have made progress in figuring out the complex factors that lead to the disease. Yet, the root cause, or causes, of Alzheimer’s are still pretty much a mystery.
In fact, many people get Alzheimer’s even though they lack the gene variant we know can play a role in the disease. This is a critical knowledge gap for research to address because the vast majority of Alzheimer’s patients don’t have this variant.
A new study provides key insights into what’s causing the disease. The research, published in Nature Communications, points to a breakdown over time in the brain’s system for clearing waste, an issue that seems to happen in some people as they get older.
Michael Glickman, a biologist at Technion – Israel Institute of Technology, helped lead this research. I asked him to tell me about his approach to studying how this breakdown occurs in the brain, and how he tested a treatment that has potential to fix the problem at its earliest stages.
Dr. Michael Glickman is internationally renowned for his research on the ubiquitin-proteasome system (UPS), the brain's system for clearing the waste that is involved in diseases such as Huntington's, Alzheimer's, and Parkinson's. He is the head of the Lab for Protein Characterization in the Faculty of Biology at the Technion – Israel Institute of Technology. In the lab, Michael and his team focus on protein recycling and the ubiquitin-proteasome system, which protects against serious diseases like Alzheimer’s, Parkinson’s, cystic fibrosis, and diabetes. After earning his PhD at the University of California at Berkeley in 1994, Michael joined the Technion as a Senior Lecturer in 1998 and has served as a full professor since 2009.
Dr. Michael Glickman