A rendering of in vitro fertilization.
Imagine two men making a baby. Or two women. Or an infertile couple. Or an older woman whose eggs are no longer viable. None of these people could have a baby today without the help of an egg or sperm donor.
Cells scraped from the inside of your cheek could one day be manipulated to become either eggs or sperm.
But in the future, it may be possible for them to reproduce using only their own genetic material, thanks to an emerging technology called IVG, or in vitro gametogenesis.
Researchers are learning how to reprogram adult human cells like skin cells to become lab-created egg and sperm cells, which could then be joined to form an embryo. In other words, cells scraped from the inside of your cheek could one day be manipulated to become either eggs or sperm, no matter your gender or your reproductive fitness.
In 2016, Japanese scientists proved that the concept could be successfully carried out in mice. Now some experts, like Dr. John Zhang, the founder and CEO of New Hope Fertility Center in Manhattan, say it's just "a matter of time" before the method is also made to work in humans.
Such a technological tour de force would upend our most basic assumptions about human reproduction and biology. Combined with techniques like gene editing, these tools could eventually enable prospective parents to have an unprecedented level of choice and control over their children's origins. It's a wildly controversial notion, and an especially timely one now that a Chinese scientist has announced the birth of the first allegedly CRISPR-edited babies. (The claims remain unverified.)
Zhang himself is no stranger to controversy. In 2016, he stunned the world when he announced the birth of a baby conceived using the DNA of three people, a landmark procedure intended to prevent the baby from inheriting a devastating neurological disease. (Zhang went to a clinic in Mexico to carry out the procedure because it is prohibited in the U.S.) Zhang's other achievements to date include helping a 49-year-old woman have a baby using her own eggs and restoring a young woman's fertility through an ovarian tissue transplant surgery.
Zhang recently sat down with our Editor-in-Chief in his New York office overlooking Columbus Circle to discuss the fertility world's latest provocative developments. Here are his top ten insights:
Clearly [gene-editing embryos] will be beneficial to mankind, but it's a matter of how and when the work is done.
1) On a Chinese scientist's claim of creating the first CRISPR-edited babies:
I'm glad that we made a first move toward a clinical application of this technology for mankind. Somebody has to do this. Whether this was a good case or not, there is still time to find out.
Clearly it will be beneficial to mankind, but it's a matter of how and when the work is done. Like any scientific advance, it has to be done in a very responsible way.
Today's response is identical to when the world's first IVF baby was announced in 1978. The major news media didn't take it seriously and thought it was evil, wanted to keep a distance from IVF. Many countries even abandoned IVF, but today you see it is a normal practice. And it took almost 40 years [for the researchers] to win a Nobel Prize.
I think we need more time to understand how this work was done medically, ethically, and let the scientist have the opportunity to present how it was done and let a scientific journal publish the paper. Before these become available, I don't think we should start being upset, scared, or giving harsh criticism.
2) On the international outcry in response to the news:
I feel we are in scientific shock, with many thinking it came too fast, too soon. We all embrace modern technology, but when something really comes along, we fear it. In an old Chinese saying, one of the masters always dreamed of seeing the dragon, and when the dragon really came, he got scared.
Dr. John Zhang, the founder and CEO of New Hope Fertility Center in Manhattan, pictured in his office.
3) On the Western world's perception that Chinese scientists sometimes appear to discount ethics in favor of speedy breakthroughs:
I think this perception is not fair. I don't think China is very casual. It's absolutely not what people think. I don't want people to feel that this case [of CRISPR-edited babies] will mean China has less standards over how human reproduction should be performed. Just because this happened, it doesn't mean in China you can do anything you want.
As far as the regulation of IVF clinics, China is probably the most strictly regulated of any country I know in this world.
4) On China's first public opinion poll gauging attitudes toward gene-edited babies, indicating that more than 60 percent of survey respondents supported using the technology to prevent inherited diseases, but not to enhance traits:
There is a sharp contrast between the general public and the professional world. Being a working health professional and an advocate of scientists working in this field, it is very important to be ethically responsible for what we are doing, but my own feeling is that from time to time we may not take into consideration what the patient needs.
5) On how the three-parent baby is doing today, several years after his birth:
No news is good news.
6) On the potentially game-changing research to develop artificial sperm and eggs:
First of all I think that anything that's technically possible, as long as you are not harmful to other people, to other societies, as long as you do it responsibly, and this is a legitimate desire, I think eventually it will become reality.
My research for now is really to try to overcome the very next obstacle in our field, which is how to let a lady age 44 or older have a baby with her own genetic material.
Practically 99 percent of women over age 43 will never make a baby on their own. And after age 47, we usually don't offer donor egg IVF anymore.
But with improved longevity, and quality of life, the lifespan of females continues to increase. In Japan, the average for females is about 89 years old. So for more than half of your life, you will not be able to produce a baby, which is quite significant in the animal kingdom. In most of the animal kingdom, their reproductive life is very much the same as their life, but then you can argue in the animal kingdom unlike a human being, it doesn't take such a long time for them to contribute to the society because once you know how to hunt and look for food, you're done.
"I think this will become a major ethical debate: whether we should let an older lady have a baby at a very late state of her life."
But humans are different. You need to go to college, get certain skills. It takes 20 years to really bring a human being up to become useful to society. That's why the mom and dad are not supposed to have the same reproductive life equal to their real life.
I think this will become a major ethical debate: whether we should let an older lady have a baby at a very late state of her life and leave the future generation in a very vulnerable situation in which they may lack warm caring, proper guidance, and proper education.
7) On using artificial gametes to grant more reproductive choices to gays and lesbians:
I think it is totally possible to have two sperm make a baby, and two eggs make babies.
If we have two guys, one guy to produce eggs, or two girls, one would have to become sperm. Basically you are creating artificial gametes or converting with gametes from sperm to become egg or egg to become a sperm. Which may not necessarily be very difficult. The key is to be able to do nuclear reprogramming.
So why can two sperm not make offspring now? You get exactly half of your genes from each parent. The genes have their own imprinting that say "made in mom," "made in dad." The two sperm would say "made in dad," "made in dad." If I can erase the "made in dad," and say "made in mom," then these sperm can make offspring.
8) On how close science is to creating artificial gametes for clinical use in pregnancies:
It's very hard to say until we accomplish it. It could be very quick. It could be it takes a long time. I don't want to speculate.
"I think these technologies are the solid foundation just like when we designed the computer -- we never thought a computer would become the iPhone."
9) On whether there should be ethical red lines drawn by authorities or whether the decisions should be left to patients and scientists:
I think we cannot believe a hundred percent in the scientist and the patient but it should not be 100 percent authority. It should be coming from the whole of society.
10) On his expectations for the future:
We are living in a very exciting world. I think that all these technologies can really change the way of mankind and also are not just for baby-making. The research, the experience, the mechanism we learn from these technologies, they will shine some great lights into our long-held dream of being a healthy population that is cancer-free and lives a long life, let's say 120 years.
I think these technologies are the solid foundation just like when we designed the computer -- we never thought a computer would become the iPhone. Imagine making a computer 30 years ago, that this little chip will change your life.
This Jarvik-7 artificial heart was used in the first bridge operation in 1985 meant to replace a failing heart while the patient waited for a donor organ.
What might surprise you is that the origin of the artificial heart dates back decades before, when an inventive television actor teamed up with a famous doctor to design and patent the first such device.
A man of many talents
Paul Winchell was an entertainer in the 1950s and 60s, rising to fame as a ventriloquist and guest-starring as an actor on programs like "The Ed Sullivan Show" and "Perry Mason." When children's animation boomed in the 1960s, Winchell made a name for himself as a voice actor on shows like "The Smurfs," "Winnie the Pooh," and "The Jetsons." He eventually became famous for originating the voices of Tigger from "Winnie the Pooh" and Gargamel from "The Smurfs," among many others.
But Winchell wasn't just an entertainer: He also had a quiet passion for science and medicine. Between television gigs, Winchell busied himself working as a medical hypnotist and acupuncturist, treating the same Hollywood stars he performed alongside. When he wasn't doing that, Winchell threw himself into engineering and design, building not only the ventriloquism dummies he used on his television appearances but a host of products he'd dreamed up himself. Winchell spent hours tinkering with his own inventions, such as a set of battery-powered gloves and something called a "flameless lighter." Over the course of his life, Winchell designed and patented more than 30 of these products – mostly novelties, but also serious medical devices, such as a portable blood plasma defroster.
| Ventriloquist Paul Winchell with Jerry Mahoney, his dummy, in 1951 |
A meeting of the minds
In the early 1950s, Winchell appeared on a variety show called the "Arthur Murray Dance Party" and faced off in a dance competition with the legendary Ricardo Montalban (Winchell won). At a cast party for the show later that same night, Winchell met Dr. Henry Heimlich – the same doctor who would later become famous for inventing the Heimlich maneuver, who was married to Murray's daughter. The two hit it off immediately, bonding over their shared interest in medicine. Before long, Heimlich invited Winchell to come observe him in the operating room at the hospital where he worked. Winchell jumped at the opportunity, and not long after he became a frequent guest in Heimlich's surgical theatre, fascinated by the mechanics of the human body.
One day while Winchell was observing at the hospital, he witnessed a patient die on the operating table after undergoing open-heart surgery. He was suddenly struck with an idea: If there was some way doctors could keep blood pumping temporarily throughout the body during surgery, patients who underwent risky operations like open-heart surgery might have a better chance of survival. Winchell rushed to Heimlich with the idea – and Heimlich agreed to advise Winchell and look over any design drafts he came up with. So Winchell went to work.
Winchell's heart
As it turned out, building ventriloquism dummies wasn't that different from building an artificial heart, Winchell noted later in his autobiography – the shifting valves and chambers of the mechanical heart were similar to the moving eyes and opening mouths of his puppets. After each design, Winchell would go back to Heimlich and the two would confer, making adjustments along the way to.
By 1956, Winchell had perfected his design: The "heart" consisted of a bag that could be placed inside the human body, connected to a battery-powered motor outside of the body. The motor enabled the bag to pump blood throughout the body, similar to a real human heart. Winchell received a patent for the design in 1963.
At the time, Winchell never quite got the credit he deserved. Years later, researchers at the University of Utah, working on their own artificial heart, came across Winchell's patent and got in touch with Winchell to compare notes. Winchell ended up donating his patent to the team, which included Dr. Richard Jarvik. Jarvik expanded on Winchell's design and created the Jarvik-7 – the world's first artificial heart to be successfully implanted in a human being in 1982.
The Jarvik-7 has since been replaced with newer, more efficient models made up of different synthetic materials, allowing patients to live for longer stretches without the heart clogging or breaking down. With each new generation of hearts, heart failure patients have been able to live relatively normal lives for longer periods of time and with fewer complications than before – and it never would have been possible without the unsung genius of a puppeteer and his love of science.
She figured the pain would go away. But instead, it intensified that night. Kamil's husband drove her to the Cedars-Sinai hospital, where she was admitted to the coronary care unit. It turned out she wasn't having a heart attack after all. Instead, she was diagnosed with a much less common but nonetheless dangerous heart condition called takotsubo syndrome, or broken heart syndrome.
A heart attack happens when blood flow to the heart is obstructed—such as when an artery is blocked—causing heart muscle tissue to die. In takotsubo syndrome, the blood flow isn't blocked, but the heart doesn't pump it properly. The heart changes its shape and starts to resemble a Japanese fishing device called tako-tsubo, a clay pot with a wider body and narrower mouth, used to catch octopus.
"The heart muscle is stunned and doesn't function properly anywhere from three days to three weeks," explains Noel Bairey Merz, the cardiologist at Cedar Sinai who Kamil went to see after she was discharged.
"The heart muscle is stunned and doesn't function properly anywhere from three days to three weeks."
But even though the heart isn't permanently damaged, mortality rates due to takotsubo syndrome are comparable to those of a heart attack, Merz notes—about 4-5% of patients die from the attack, and 20% within the next five years. "It's as bad as a heart attack," Merz says—only it's much less known, even to doctors. The condition affects only about 1% of people, and there are around 15,000 new cases annually. It's diagnosed using a cardiac ventriculogram, an imaging test that allows doctors to see how the heart pumps blood.
Scientists don't fully understand what causes Takotsubo syndrome, but it usually occurs after extreme emotional or physical stress. Doctors think it's triggered by a so-called catecholamine storm, a phenomenon in which the body releases too much catecholamines—hormones involved in the fight-or-flight response. Evolutionarily, when early humans lived in savannas or forests and had to either fight off predators or flee from them, these hormones gave our ancestors the needed strength and stamina to take either action. Released by nerve endings and by the adrenal glands that sit on top of the kidneys, these hormones still flood our bodies in moments of stress, but an overabundance of them could sometimes be damaging.
Elaine Kamil
A recent study by scientists at Harvard Medical School linked increased risk of takotsubo to higher activity in the amygdala, a brain region responsible for emotions that's involved in responses to stress. The scientists believe that chronic stress makes people more susceptible to the syndrome. Notably, one small study suggested that the number of Takotsubo cases increased during the COVID-19 pandemic.
There are no specific drugs to treat takotsubo, so doctors rely on supportive therapies, which include medications typically used for high blood pressure and heart failure. In most cases, the heart returns to its normal shape within a few weeks. "It's a spontaneous recovery—the catecholamine storm is resolved, the injury trigger is removed and the heart heals itself because our bodies have an amazing healing capacity," Merz says. It also helps that tissues remain intact. 'The heart cells don't die, they just aren't functioning properly for some time."
That's the good news. The bad news is that takotsubo is likely to strike again—in 5-20% of patients the condition comes back, sometimes more severe than before.
That's exactly what happened to Kamil. After getting her diagnosis in 2013, she realized that she actually had a previous takotsubo episode. In 2010, she experienced similar symptoms after her son died. "The night after he died, I was having severe chest pain at night, but I was too overwhelmed with grief to do anything about it," she recalls. After a while, the pain subsided and didn't return until three years later.
For weeks after her second attack, she felt exhausted, listless and anxious. "You lose confidence in your body," she says. "You have these little twinges on your chest, or if you start having arrhythmia, and you wonder if this is another episode coming up. It's really unnerving because you don't know how to read these cues." And that's very typical, Merz says. Even when the heart muscle appears to recover, patients don't return to normal right away. They have shortens of breath, they can't exercise, and they stay anxious and worried for a while.
Women over the age of 50 are diagnosed with takotsubo more often than other demographics. However, it happens in men too, although it typically strikes after physical stress, such as a triathlon or an exhausting day of cycling. Young people can also get takotsubo. Older patients are hospitalized more often, but younger people tend to have more severe complications. It could be because an older person may go for a jog while younger one may run a marathon, which would take a stronger toll on the body of a person who's predisposed to the condition.
Notably, the emotional stressors don't always have to be negative—the heart muscle can get out of shape from good emotions, too. "There have been case reports of takotsubo at weddings," Merz says. Moreover, one out of three or four takotsubo patients experience no apparent stress, she adds. "So it could be that it's not so much the catecholamine storm itself, but the body's reaction to it—the physiological reaction deeply embedded into out physiology," she explains.
Merz and her team are working to understand what makes people predisposed to takotsubo. They think a person's genetics play a role, but they haven't yet pinpointed genes that seem to be responsible. Genes code for proteins, which affect how the body metabolizes various compounds, which, in turn, affect the body's response to stress. Pinning down the protein involved in takotsubo susceptibility would allow doctors to develop screening tests and identify those prone to severe repeating attacks. It will also help develop medications that can either prevent it or treat it better than just waiting for the body to heal itself.
Researchers at the Imperial College London recently found that elevated levels of certain types of microRNAs—molecules involved in protein production—increase the chances of developing takotsubo.
In one study, researchers tried treating takotsubo in mice with a drug called suberanilohydroxamic acid, or SAHA, typically used for cancer treatment. The drug improved cardiac health and reversed the broken heart in rodents. It remains to be seen if the drug would have a similar effect on humans. But identifying a drug that shows promise is progress, Merz says. "I'm glad that there's research in this area."