He Wants to Eliminate Inherited Diseases in Embryos. Congress Just Said No (Again).
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.
Biologist Shoukhrat Mitalipov is famous—and controversial--in the world of cutting-edge fertility treatments. A decade ago, he pioneered mitochondrial replacement therapy, paving the way for the world's first "three-parent" babies to be born free of a devastating inherited disease.
He sees his work toward embryo gene therapy as not only moral, but necessary.
In 2017, he shocked the world again when his group at Oregon Health and Science University became the first to repair a genetic mutation causing heart disease in dozens of human embryos. The embryos were later destroyed a part of the experiment; current policy in the U.S. prohibits such research from moving into clinical trials.
And that policy doesn't look like it's going to change anytime soon, despite recent political wavering. Last month, a House subcommittee dropped the ban that has blocked the Food and Drug Administration since 2015 from considering any clinical trials of genetically altered embryos intended to create a baby. The move raised the hopes of supporters who want to see such research move forward and angered critics who feel that the science is getting ahead of the ethics. But yesterday, a House committee decided to restore the ban on gene-edited babies after all.
As for Mitalipov, he told leapsmag that he sees his work toward embryo gene therapy as not only moral, but necessary. This interview has been edited and condensed for clarity.
What motivates you to pursue this line of research, even though it is highly controversial?
It's my expertise, I'm an embryologist. We study early development in humans -- sperm, egg, and the first five days of development -- and try to use our knowledge to treat human diseases, particularly in that early stage. This is how IVF started, as a treatment for infertility. It's a very successful cell therapy treatment, with millions of children born. [Now the idea is] to actually to use this IVF platform not as much to treat infertility, but also to treat heritable genetic diseases, because this is a very important stage when gametes from either dad or mom will transmit mutations. This is the bottleneck where we could actually interfere and repair that mutation.
Many people are hesitant to support embryo editing because of "designer babies," yet polls do show that Americans are more open to embryo editing for the purpose of disease prevention. Where should society draw a line?
Yeah, I agree with most Americans that we don't have to edit -- meaning you could make all kind of changes. Instead we do gene repair, which is a therapeutic application.
Gene repair is quite different than gene editing. It involves [focusing on] already known disease-causing mutations and how we can turn them back to normal.
Thousands of gene mutations cause human diseases, like Crohn's, for example, or mutations causing cancer, heart disease. These are well-described, well-studied cause-and-effect diseases and we need to do something about it because otherwise it's impossible to treat once the mutation is already passed to a child.
Early intervention is the best in any disease, but in genetics, "early" means you have to do it at the time of fertilization. That's when we are dealing with one copy of the mutation or maybe two, versus when you have a whole body with billions of cells in solid tissues that we cannot really access and target. So this is the most efficient way of preventing thousands and thousands of genetic diseases. I understand that we have to make sure that it's very safe, of course, and efficient as well. But at the same time, I think this is the future. We have to work toward developing these technologies.
"If we continue banning the research everywhere and not funding it, maybe 100 years will not be enough."
What's your opinion of Dr. He Jiankui and the Chinese CRISPR'ed babies?
This is a case where he was doing gene editing, not gene repair. He hasn't corrected anything, he induced a mutation to normal human genes, hoping that this would somehow confer resistance to HIV, which is still unclear.
I think such straightforward editing is unacceptable specifically for human embryos. He's approach has also never been tested in an animal model. That's why the reaction from the public and scientists was very negative, because this is the case where the doctor does this without any expertise in this area, without knowing probably much about what he is doing, and he acquired it without any oversights, which is troubling. And of course, it negatively affects the legitimate research that is going on in some labs.
What might the future of embryo gene therapy look like?
Hopefully in 10 years from now, thousands and thousands of families that know they carry germline mutations…could go through IVF and we would correct it, and they could have healthy children.
Right now, we have some tools. We cannot correct, but we can select. So what happens is the parents become pregnant and then at about three months along, we can biopsy the amniotic fluid and say, "Hey unfortunately you passed on this mutation." And that means this child, if it's born, will be affected, so we give parents a choice of terminating the pregnancy.
Or we could do it much earlier, so parents go to the IVF clinic where we retrieve about ten eggs, after stimulating a woman's ovaries. Each of them will be fertilized so we have ten embryos that develop. We have a five-day window where we can keep them in the lab. And we basically reap a few cells, we do a biopsy from each of these ten, and we say, "Hey embryo number 1 and number 4 are not mutant, but the others are."
Then we can take these two and the other eight usually will be thrown away. That's the technology that we have now. Some ethicists argue on religious grounds that we have this selection technology available, so why do we need germline gene therapy [i.e. repairing the disease-causing mutations in an embryo]?
I don't understand the moral argument there, because all the available technology is based on selective destruction of the embryo.
With [IVF gene therapy], we will take ten embryos and every embryo we'll make healthy because we can get rid of the mutations. How could embryo destruction be morally superior?
How long do you think it will take for this technology to be available to prospective parents?
It depends how many legitimate labs with expertise can get into this field and resolve all the scientific questions. If we continue banning the research everywhere and not funding it, maybe 100 years will not be enough.
So far, I think that my lab is the only one legitimately working on it. But we would like five, 10, maybe 100 labs in this country and Europe really working. Because we have scientific challenges that we need to resolve before we could say, "Hey now we know how to correct [a given mutation] and now this could be efficient, and there are no side effects or very little." And then we could say, "Okay, I think we've done everything we could in petri dishes and in animals, and now we are ready to transplant this embryo in a patient and see what happens."
"There's just no way you could sink your head into the sand and say, 'Oh, we just ban it and then hopefully everything will go away.'"
Does banning emerging technology actually work?
Banning it usually means it will leak out to a gray area where there's no regulation and many private IVF clinics will just use it while it is still premature. So I think we have to regulate the clinical testing. There's just no way you could sink your head into the sand and say, "Oh, we just ban it and then hopefully everything will go away." That's not going to happen.
If this technology does become feasible and legal in the future, do you think that more and more couples will choose IVF and gene therapy versus the natural method of rolling the dice?
As sequencing technology is becoming available, like 23andMe, more and more parents will realize what kind of mutations they carry. And if your spouse carries the same mutation on the same locus, now you have very high chance of transmitting it. Most of the time today, we find out these families carry it once they have one or two children with that condition.
Of course, parents can just do it naturally in the bedroom and have a chance of transmitting or not transmitting mutations, but hopefully eventually we can say, "Hey, because of your condition, you don't want to play this Russian Roulette. Let's just do IVF." And hopefully the government will cover that kind of treatment because right now IVF is not covered in most states. And we do this therapy and then they have a healthy child.
We have 10,000 different mutations in the human population. That means probably billions of people carry mutations. And unless they go through this gene therapy through IVF, they will keep transmitting them. And we're going to keep having millions and millions of children with diseases. We have to do something about it.
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.
Scientists aim to preserve donkeys, one frozen embryo at a time
Every day for a week in 2022, Andres Gambini, a veterinarian and senior lecturer in animal science at the University of Queensland in Australia, walked into his lab—and headed straight to the video camera. Trained on an array of about 50 donkey embryos, all created by Gambini’s manual in vitro fertilization, or IVF, the camera kept an eye on their developmental progress. To eventually create a viable embryo that could be implanted into a female donkey, the embryos’ cells had to keep dividing, first in two, then in four and so on.
But the embryos weren’t cooperating. Some would start splitting up only to stop a day or two later, and others wouldn’t start at all. Every day he came in, Gambini saw fewer and fewer dividing embryos, so he was losing faith in the effort. “You see many failed attempts and get disappointed,” he says.
Gambini and his team, a group of Argentinian and Spanish researchers, were working to create these embryos because many donkey populations around the world are declining. It may sound counterintuitive that domesticated animals may need preservation, but out of 28 European donkey breeds, 20 are endangered and seven are in critical status. It is partly because of the inbreeding that happened over the course of many years and partly because in today’s Western world donkeys aren’t really used anymore.
“That's the reason why some breeds begin to disappear because humans were not really interested in having that specific breed anymore,” Gambini says. Nonetheless, in Africa, India and Latin America millions of rural families still rely on these hardy creatures for agriculture and transportation. And the only two wild donkey species—Equus africanus in Africa and Equus hemionus in Asia—are also dwindling, due to losing their habitats to human activities, diseases and slow reproduction rates. Gambini’s team wanted to create a way to preserve the animals for the future. “Donkeys are more endangered than people realize,” he says.
There’s much more to donkeys' trouble though. For the past 20 or so years, they have been facing a huge existential threat due to their hide gelatin, a compound derived from their skins by soaking and stewing. In Chinese traditional medicine, the compound, called ejiao, is believed to have a medicinal value, so it’s used in skin creams, added to food and taken in capsules. Centuries ago, ejiao was a very expensive luxury product available only for the emperor and his household. That changed in the 1990s when the Chinese economy boomed, and many people were suddenly able to afford it. “It went from a very elite product to a very popular product,” says Janneke Merkx, a campaign manager at The Donkey Sanctuary, a United Kingdom-based nonprofit organization that keeps tabs on the animals’ welfare worldwide. “It is a status symbol for gift giving.”
Having evolved in the harsh and arid mountainous terrains where food and water were scarce, donkeys are extremely adaptable and hardy. But the Donkey Sanctuary documented cases in which an entire village had their animals disappear overnight, finding them killed and skinned outside their settlement.
The Chinese donkey population was quickly decimated. Unlike many other farm animals, donkeys are finicky breeders. When stressed and unhappy, they don’t procreate, so growing them in large industrial settings isn’t possible. “Donkeys are notoriously slow breeders and really very difficult to farm,” says Merkx. “They are not the same as other livestock like sheep and pigs and cattle.” Within years the, the donkey numbers in China dropped precipitously. “China used to have the largest donkey population in the world in the 1990s. They had 11 million donkeys, and it's now down to less than 3 million, and they just can't keep up with the demand.”
To keep the ejiao conveyor going, some producers turned to the illegal wildlife trade. Poachers began to steal and slaughter donkeys from rural villages in Africa. The Donkey Sanctuary documented cases in which an entire village had their animals disappear overnight, finding them killed and skinned outside their settlement. Exactly how many creatures were lost to the skin trade to-date isn’t possible to calculate, says Faith Burden, the Donkey Sanctuary’s director of equine operations. Traditionally a poor people’s beast of burden, donkey counts are hard to keep track of. “When an animal doesn't produce meat, milk or eggs or whatever edible product, they're often less likely to be acknowledged in a government population census,” Burden says. “So reliable statistics are hard to come by.” The nonprofit estimates that about 4.8 million are slaughtered annually.
During their six to seven thousand years of domestication, donkeys rarely got the full appreciation for their services. They are often compared to horses, which doesn’t do them justice. They’re entirely different animals, Burden says. Built for speed, horses respond to predators and other dangers by running as fast as they can. Donkeys, which originate from the rocky, mountainous regions of Africa where running is dangerous, react to threats by freezing and assessing the situation for the best response. “Those so-called stubborn donkeys that won’t move as you want, they are actually thinking ‘what’s the best approach,’” Burden says. They may even choose to fight the predators rather than flee, she adds. “In some parts of the world, people use them as guard animals against things like coyotes and wolves.”
Scientists believe that domestic donkeys take their origin from Equus africanus or African wild ass, originally roaming where Kenya, Ethiopia and Eritrea are today. Having evolved in the harsh and arid mountainous terrains where food and water were scarce, they are extremely adaptable and hardy. Research finds that they can go without water for 72 hours and then drink their fill without any negative consequences. Their big jaws let them chew tough desert shrubs, which horses can’t exist on. Their large ears help dissipate heat. Their little upright hooves are a perfect fit for the uneven rocky or other dangerous grounds. Accustomed to the mountain desert climate with hot days and cold nights, they don’t mind temperature flux.
“The donkey is the most supremely adapted animal to deal with hostile conditions,” Burden says. “They can survive on much lower nutritional quality food than a cow, sheep or horse. That’s why communities living in some of the most inhospitable places will often have donkeys with them.” And that’s why losing a donkey to an illegal skin trade can devastate a family in places like Eritrea. Suddenly everything from water to firewood to produce must be carried by family members—and often women.
Workers unloading donkeys at the Shinyanga slaughterhouse in Tanzania. Fearing a future in which donkeys go extinct, scientists have found ways to cryopreserve a donkey embryo in liquid nitrogen.
TAHUCHA
One can imagine a time when worldwide donkey populations may dwindle to the point that they would need to be restored. That includes their genetic variability too. That’s where the frozen embryos may come in handy. We may be able to use them to increase the genetic variability of donkeys, which will be especially important if they get closer to extinction, Gambini says. His team had already created frozen embryos for horses and zebras, an idea similar to a seed bank. “We call this concept the Frozen Zoo.”
Creating donkey embryos proved much harder than those of zebras and horses. To improve chances of fertilization, Gambini used the intracytoplasmic sperm injection or ICSI, in which he employed a tiny needle called a micropipette to inject a donkey sperm into an egg. That was a step above the traditional IVF method, in which the egg and a sperm are left floating in a test tube together. The injection took, but during the incubating week, one after the other, the embryos stopped dividing. Finally, on day seven, Gambini finally spotted the exact sight he was hoping to see. One of the embryos developed into a burgeoning ball of cells.
“That stage is called a blastocyst,” Gambini says. The clump of cells had a lot of fluids mixed within them, which indicated that they were finally developing into a viable embryo. “When we see a blastocyst, we know we can transfer that into a female.” He was so excited he immediately called all his collaborators to tell them the good news, which they later published in the journal of Theriogenology.
The one and only embryo to reach that stage, the blastocyst was cryopreserved in liquid nitrogen. The team is waiting for the next breeding season to see if a female donkey may carry it to term and give birth to a healthy foal. Gambini’s team is hoping to polish the process and create more embryos. “It’s our weapon in the conservation ass-enal,” he says.
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.
Too much of this ingredient leads to autoimmune diseases, new research shows. Here's how to cut back.
For more than a century, doctors have warned that too much salt in your diet can lead to high blood pressure, heart disease and stroke - and many of the reasons for these effects are well known. But recently scientists have been looking deeper, into the cellular level, and they are finding additional reasons to minimize sodium intake; it is bad for immune cells, creating patterns of gene expression and activity seen in a variety of autoimmune diseases such as multiple sclerosis, lupus, rheumatoid arthritis, and type-1 diabetes.
Salt is a major part of the ocean from which life evolved on this planet. We carry that legacy in our blood, which tastes salty. It is an important element for conducting electrical signals along nerves and balancing water and metabolites transported throughout our bodies. We need to consume about 500 milligrams of salt each day to maintain these functions, more with exercise and heavy sweating as that is a major way the body loses salt. The problem is that most Americans eating a modern western diet consume about 3400 milligrams, 1.5 teaspoons per day.
Evidence has been accumulating over the last few years that elevated levels of sodium can be harmful to at least some types of immune cells. The first signal came in monocytes, which are immune cells that travel to various tissues in the body, where some of them turn into macrophages, a subset of white blood cells that can directly kill microorganisms and make chemical signals that bring other types of immune cells into play.
Two years ago, Dominik N. Müller from the Max-Delbrueck-Center in Berlin, Germany and Markus Kleinewietfeld, an immunologist at Hasselt University in Belgium, ran a study where they fed people pizza and then measured their immune cell function. “We saw that in any monocytes, metabolic function was down, even after a single salty meal,” Kleinewietfeld says. It seemed to be the cellular equivalent of the sluggish feeling we get after eating too much. The cells were able to recover but more research is needed to answer questions about what dose of sodium causes impairment, how long the damage lasts, and whether there is a cumulative effect of salt toxicity.
Kleinewietfeld and his colleagues have hypothesized that too much salt could be a significant factor in the increased number of autoimmune diseases and allergies over the last few generations.
The latest series of experiments focused on a type of T cell called T regulatory cells, or Tregs. Most T cells release inflammatory mediators to fight pathogens and, once that job is done, Tregs come along to calm down their hyperactive brethren. Failure to do so can result in continued inflammation and possibly autoimmune diseases.
In the lab, Kleinewietfeld and his large team of international collaborators saw that high levels of sodium had a huge effect on Tregs, upregulating 1250 genes and downregulating an additional 1380 genes so that they looked similar to patterns of gene expression seen in autoimmune diseases.
Digging deeper, they found that sodium affected mitochondria, the tiny organelles inside of cells that produce much of its energy. The sodium was interfering with how the mitochondria use oxygen, which resulted in increased levels of an unstable form of oxygen that can damage cell function. The researchers injected those damaged Tregs into mice and found that they impaired the animals' immune function, allowing the inflammation to continue rather than shutting it down.
That finding dovetailed nicely with a 2019 paper in Nature from Navdeep Chandel's lab at Northwestern University, which showed in mice that inhibiting the mitochondrial use of oxygen reduced the ability of Tregs to regulate other T cells. “Mitochondria were controlling directly the immunosuppressive program, they were this master regulator tuning the right amount of genes to give you proper immunosuppression,” Chandel said. “And if you lose that function, then you get autoimmunity.”
Kleinewietfeld's team studied the Treg cells of humans and found that sodium can similarly decrease mitochondrial use of oxygen and immunosuppressive activity. “I would have never predicted that myself,” Chandel says, but now researchers can look at the mitochondria of patients with autoimmune disease and see if their gene expression also changes under high salt conditions. He sees the link between the patterns of gene expression in Tregs generated by high salt exposure and those patterns seen in autoimmune diseases, but he is cautious about claiming a causal effect.
Kleinewietfeld and his colleagues have hypothesized that too much salt could be a significant factor in the increased number of autoimmune diseases and allergies over the last few generations. He says a high salt diet could also have an indirect effect on immune function through the way it affects the gut microbiome and the molecules made by microbes when they break down food. But the research results are too preliminary to say that for sure, much less parse out the role of salt compared with other possible factors. “It is still an exciting journey to try to understand this field,” he says.
Additionally, it is difficult to say precisely how this research in animals and human cell cultures will translate into a whole human body. Individual differences in genetics can affect how the body absorbs, transports, and gets rid of sodium, such that some people are more sensitive to salt than are others.
So how should people apply these research findings to daily life?
Salt is obvious when we sprinkle it on at the table or eat tasty things like potato chips, but we may be unaware of sodium hidden in packaged foods. That's because salt is an easy and cheap way to boost the flavor of foods. And if we do read the labeled salt content on a package, we focus on the number for a single serving, but then eat more than that.
Last September, the U.S. Food and Drug Administration (FDA) began a process to update labels on the content of food, including what is meant by the word “healthy” and how food manufacturers can use the term. Many in the food industry are resisting those proposed changes.
Chandel cautions against trying to counter the effects of salt by reaching for foods or supplements full of antioxidants, which, in theory, could reduce the harmful effects on mitochondria caused by a heavy hand with the salt shaker.
Until labels are updated, it would be prudent to try to reduce sodium intake by cutting down on packaged foods while making your own food at home, where you know just how much salt has been added. The Mayo Clinic offers guidance on how to become more aware of the sodium in your diet and eat less of it.
Chandel thinks many people will struggle with minimizing salt in their diets. It’s similar to the challenge of eating less sugar, in that the body craves both, and it is difficult to fight that. He cautions against trying to counter the effects of salt by reaching for foods or supplements full of antioxidants, which, in theory, could reduce the harmful effects on mitochondria caused by a heavy hand with the salt shaker. “Dietary antioxidants have failed in just about every clinical trial, yet the public continues to take them,” Chandel says. But he is optimistic that research will lead us to a better understanding of how Tregs function, and uncover new targets for treating autoimmune diseases.