What’s next for IVF
Forty-eight years ago this July, Louise Joy Brown became the world’s first person born with the help of in vitro fertilization. Millions more IVF babies have entered the world since then. And that’s partly thanks to advances in technology that have made IVF safer and more effective.
But it’s still not perfect. The process can be slow, painful, and expensive—and that’s for the lucky people who are able to access it in the first place. And by at least one measure, IVF success rates have been declining in recent years.
Reproduction is complex, and there’s a lot that embryologists and gynecologists still don’t know and can’t control. They don’t know why many healthy-looking embryos don’t “stick” in the uterus, for example. They don’t always have an explanation for why their patients can’t get pregnant. And they can’t always account for vast differences in IVF success rates between individuals and between fertility clinics.
Scientists are working on all those questions and more. They’re wrestling with complex ethical questions about how new genetic tools will be used to analyze or even alter embryos. Meanwhile, technologies designed to standardize treatment, eliminate human error, boost success rates, and make IVF more accessible are already beginning to usher in a new era for assisted reproduction—one aided by AI and robots.
1. Helping embryos stick
Some of those technologies are being developed at the Carlos Simon Foundation in Valencia, Spain. When I visited in March, researchers gave me a tour of the labs and showed me a device that had been used to keep a human uterus alive outside the body for the first time.
While some members of the team dream of building artificial uteruses that might one day be able to carry a fetus to term, they first want to use such devices to learn more about implantation—the moment at which a fertilized egg makes contact with the lining of the uterus, burrows inside, and essentially “hatches,” triggering the start of a pregnancy.
Despite decades of advances in IVF, that process is still poorly understood. Even healthy-looking embryos stick no more than 40% to 60% of the time.
In IVF techniques used today, clinics can create early-stage embryos and wait until the uterus is deemed most receptive, but once they insert the embryo into the uterus, it’s on its own. Xavier Santamaria, senior clinical scientist at the Carlos Simon Foundation, and his colleagues are trialing a different approach. They’ve developed a device that, at the press of a button, injects the embryo into the uterine lining.
In a demonstration I watched with a prototype, Santamaria picked up his speculum and turned to face the vaginal opening of his “patient,” which in this case was just a model of the real thing—a plastic bottom with labia, a vagina, a uterus, and ovaries, two short stumps representing what would normally be a pair of legs held in stirrups.
He hunched over and peered inside. “Embryo,” he called. His colleague Maria Pardo, an embryologist, passed him a thin needle containing a mouse embryo she had recently collected from a petri dish.
Santamaria’s device allows for the embryo-containing needle to be connected to a delivery tube. This tube also has a camera, a light, and a sensor that lets the doctor know when the needle reaches the uterine lining. Once it has been fed into the uterus, the gynecologist can see the inside of the organ and direct the tube to the lining.
“When everything is ready, you just press the button,” Santamaria said as he activated it using a foot pedal, allowing the embryo to be injected. “There it goes.”
The team has just started a trial of the device; so far, fewer than 10 women have undergone the procedure, and none of those have become pregnant. But foundation director Carlos Simon is hopeful, noting that the inventors of IVF had to perform over 160 cycles before Louise Brown was born (between 1969 and 1978, that team performed 457 cycles in 250 people, resulting in only two live births). “The trial is ongoing,” he says.
2. Picking the “best” eggs, sperm, and embryos
One long-running challenge of IVF has been selection. Say you manage to collect 10 eggs from one partner and a decent-looking semen sample from the other. How do you choose which cells to use? The same question comes up once the resulting embryos have been cultured in a dish for a few days: Which should you transfer to the uterus?
Traditionally, these judgments have been made by eye. Embryologists literally pick the ones that look the best in terms of their shape or, in the case of sperm, how they move. But scientists have been working on alternatives. And over the last decade or so, many have turned to genetic testing to hint at which embryos have the best chances of creating a healthy baby.
The most commonly used test is called PGT-A, which stands for preimplantation genetic testing for aneuploidy. Aneuploidy essentially means having an “incorrect” number of chromosomes, and it is thought that embryos with such characteristics are more likely to be lost through miscarriage or potentially develop into babies with genetic conditions.
Once embryologists have created embryos in the lab, they can pinch off a few cells and test them for aneuploidies. The tests are especially beneficial for women over the age of 38, says Alan Penzias, a reproductive endocrinologist at Boston IVF. “You start to see an improvement: more babies and fewer miscarriages,” he says. The tests can shorten the time to pregnancy.
This type of genetic testing is possible thanks to multiple advances in technology—not just in genomics, but also in the ability to keep embryos alive in a dish for five to six days and the technique of freezing embryos while the cells undergo testing and thawing them once the results are in. And it has become hugely popular—some clinics do PGT-A tests on all their embryos.
But PGT-A won’t give you a perfect readout of a future baby’s genetics, says Sonia Gayete-Lafuente, a reproductive endocrinologist at the Center for Human Reproduction in New York City. And some of the abnormalities might be able to self-correct with time. Gayete-Lafuente and her colleagues have transferred some of those “abnormal” embryos into patients’ uteruses and seen them develop into perfectly healthy children, she says.
Other forms of PGT are even more controversial. PGT-P tests are designed to predict an embryo’s chances of developing complex traits that rely on multiple genes, including medical disorders but also physical characteristics like height or cognitive factors like IQ. These tests are new, and they are illegal in some countries, including the UK. But they are gaining ground in the US. Nucleus Genomics—a company that invites customers to “have [their] best baby”—promises to predict traits running the gamut from eye color and intelligence to left-handedness and risk of Alzheimer’s.
When I asked IVF practitioners how they might respond if a patient asked for this service, most dodged the question and told me there’s not enough evidence that any of these tests actually work. They also cautioned that selecting for one trait might inadvertently introduce new risks. None seemed especially keen on the idea of using genetic testing for anything other than preventing serious disease.
3. Speeding things up with AI
Some seemed more excited about the potential for AI. After all, AI tools are generally good at recognizing patterns. Many researchers have attempted to train tools to spot healthy sperm, eggs, and embryos.
And they’ve had some success. A team at Columbia University Medical Center in New York has developed a device that uses AI to examine semen samples from men who have only tiny numbers of healthy sperm. An embryologist might struggle to find a single healthy sperm in such a sample. But the Sperm Tracking and Recovery (STAR) system can analyze over a million microscope images in an hour. It has already been used to create healthy embryos. The team behind the work announced the first pregnancy resulting from the treatment in November last year.
Other teams are using AI tools to advance IVF in more dramatic ways. Around a decade ago, a reproductive endocrinologist named Alejandro Chavez-Badiola began developing an AI tool trained to rank embryos, another to rank eggs, and another to select sperm. He recalls being struck by a realization that these tools were “the brains that have the potential to drive robots in the future,” he says.
4. Using robots to standardize IVF
In the early 2020s, Chavez-Badiola and his colleagues decided to combine technologies and develop an automated system for IVF. In theory, a robotic system loaded up with AI tools could undertake most of the steps required in the IVF process: selecting the eggs and sperm, fertilizing eggs to create embryos, culturing those embryos in a dish, and selecting the “best” one for transfer. Such a system could “do everything in a standard way” without ever getting tired, he says.
Chavez-Badiola, who is now founder and chief medical officer at Conceivable, started building prototypes by motorizing regular IVF equipment and connecting it to computers. He and his colleagues started testing their system with animal cells before eventually moving on to human ones. “We were able to prove that integrating robots to automate different steps in IVF is doable,” he says.
The device is now being used to prepare sperm and eggs and create embryos. At least 19 children have been born following the automated IVF. It is early days, but Chavez-Badiola is hoping that future iterations of the machine could each process thousands of IVF cycles in a year, potentially making the procedure more affordable and accessible.
Many in the field are excited about the potential for automated devices like Conceivable’s. “This is all time saved for the embryologists,” says Laura Rienzi, a clinical embryologist and scientific director of the IVIRMA network of fertility centers in Italy. She also hopes it will help standardize IVF treatments. “Automation [will allow for] every patient to be treated in the same way in every single lab in the world,” she says.
5. Controversial edits are on the table
There’s a catch, however: All these technologies rely on the availability of at least some healthy sperm, eggs, and embryos at the outset. Embryologists and IVF patients have to work with what they’ve got. And sometimes, what they’ve got won’t result in a healthy baby.
That’s why some scientists are proposing a controversial idea: using gene-editing technologies like CRISPR to tinker with the genome of an IVF embryo before it is implanted. The biophysicist He Jiankui infamously took this approach to create embryos that resulted in the births of three children in the late 2010s. He was widely condemned by the scientific community and ultimately spent three years in a Chinese prison.
His former romantic partner Cathy Tie, who now leads startup Origin Genomics, is pursuing the technology as a potential way to prevent serious disease in children. At a recent event held at the Hastings Center for Bioethics, Tie made the case for using embryo editing to prevent diseases like cystic fibrosis, Huntington’s, and sickle-cell.
It won’t be straightforward from a technical, legal, or ethical perspective. Diseases that are known to be caused by single-gene mutations are good first candidates, but as the Center for Human Reproduction’s Gayete-Lafuente points out, most diseases are much more complicated than that. “I wish we could understand the genetic basis of every disease to be able to prevent it,” she says. So far, we can’t. Besides, most diseases can be influenced by our diets, behaviors, and environments as well as our genes.
As things stand, no one knows if editing a human embryo to eliminate the risk of one disease might increase a future child’s risk of some other disorder. And some scientists worry that such edits might be a slippery slope to genetic enhancement or eugenics.
Rienzi hopes that the technology might be developed in a safe way with regulatory oversight, and only for a specific list of diseases. “It has to be within a legal context,” she says. “But to me, it’s a dream.”
In the meantime, the field looks set to keep transforming with the development of new technologies that are already creating healthy babies. Watch this space.
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