Biotechnology And Health

At first glance, it looks like the start of a human pregnancy: A ball-shaped embryo presses gently into the receptive lining of the uterus and then grips tight, burrowing in as the first tendrils of a future placenta appear. 

This is implantation—the moment that pregnancy officially begins.

Only none of it is happening inside a body. These images were captured in a Beijing laboratory, inside a microfluidic chip, as scientists watched the scene unfold.

COURTESY OF THE RESEARCHERS

In three papers published this week by Cell Press, scientists are reporting what they call the most accurate efforts yet to mimic the first moments of pregnancy in the lab. They’ve taken human embryos from IVF centers and let these merge with “organoids” made of endometrial cells, which form the lining of the uterus.

The reports—two from China and a third involving a collaboration among researchers in the United Kingdom, Spain, and the US—show how scientists are using engineered tissues to better understand early pregnancy and potentially improve IVF outcomes.

“You have an embryo and the endometrial organoid together,” says Jun Wu, a biologist at the University of Texas Southwestern Medical Center, in Dallas, who contributed to both Chinese reports. “That’s the overarching message of all three papers.”

According to the papers, these 3D combinations are the most complete re-creations of the first days of pregnancy yet and should be useful for studying why IVF treatments often fail.

In each case, the experiments were stopped when the embryos were two weeks old, if not sooner. That is due to legal and ethical rules that typically restrict scientists from going any further than 14 days.

In your basic IVF procedure, an egg is fertilized in the lab and allowed to develop into a spherical embryo called a blastocyst—a process that takes a few days. That blastocyst then gets put into a patient’s uterus in the hope it will establish itself there and ultimately become a baby.

COURTESY OF THE RESEARCHERS

But that’s a common failure point. Many patients will learn that their IVF procedure didn’t work because an embryo never attached.

In the new reports, it’s that initial bond between mother and embryo that is being reproduced in the lab. “IVF means in vitro fertilization, but now this is the stage of in vitro implantation,” says Matteo Molè, a biologist at Stanford University whose results with collaborators in Europe are among those published today. “Considering that implantation is a barrier [to pregnancy], we have the potential to increase the success rate if we can model it in the laboratory.”

Normally implantation is entirely hidden from view because it occurs in someone’s uterus, says Hongmei Wang, a developmental biologist at the Beijing Institute for Stem Cell and Regenerative Medicine, who co-led the effort there. Wang often studies monkeys because she can interrupt their pregnancies to collect the tissues she needs to see. “We’ve always hoped to understand human embryo implantation, but we have lacked a way to do so,” she says. “It’s all happening in the uterus.”

In the Beijing study, researchers tested about 50 donated IVF embryos, but they also ran a thousand more experiments using so-called “blastoids.” The latter are mimics of early-stage human embryos manufactured from stem cells. Blastoids are easy to make in large numbers and, since they aren’t true embryos, don’t have as many ethical rules on their use.

“The question was, if we have these blastoids, what can we use them for?” says Leqian Yu, the senior author of the report from the Beijing Institute. “The obvious next step was implantation. So how do you do that?”

For the Beijing team, the answer was to build a soft silicone chamber with tiny channels to add nutrients and a space to grow the uterine organoid. After that, blastoids—or real embryos—could be introduced through a window in the device, so the “pregnancy” could start.

“The key question we want to try to answer is what is the first cross-talk between embryo and mother,” says Yu. “I think this is maybe the first time we can see the entire process.”

Medical Applications

This isn’t the first time researchers have tried using organoids for this kind of research. At least two startup companies have raised funds to commercialize similar systems—in some cases presenting the organoids as a tool to predict IVF success. In addition to Dawn Bio, a startup based in Vienna, there is Simbryo Technologies, in Houston, which last month said it would begin offering “personalized” predictions for IVF patients using blastoids and endometrial organoids.

To do that test, doctors will take a biopsy of a patient’s uterine lining and grow organoids from it. After that, blastoids will be added to the organoids to gauge whether a woman is likely to be able to support a pregnancy or not. If the blastoids don’t start to implant, it could mean the patient’s uterus isn’t receptive and is the reason IVF isn’t working.

The Beijing team thinks the pregnancy organoids could also be used to identify drugs that might help those patients. In their paper, they describe how they made organoids out of tissue taken from women who’ve had repeated IVF failures. Then they tested 1,119 approved drugs on those samples to see if anything improved.

Several seemed to have helpful effects. One chemical, avobenzone, an ingredient in some types of sunblock, increased the chance that a blastoid would start implanting from just 5% of the time to around 25% of the time. Yu says his center hopes to eventually start a clinical trial if they can find the right drug to try. 

Artificial womb?

The Beijing group is working on ways to improve the organoid system so that it’s even more realistic. Right now, it lacks important cell types, including immune cells and a blood supply. Yu says a next step he’s working on is to add blood vessels and tiny pumps to his chip device, so that he can give the organoids a kind of rudimentary circulation.

That means, in the near future, blastoids or embryos could likely be grown longer, raising questions about how far scientists will be able to take pregnancy in the lab. “I think this technology does raise the possibility of growing things longer,” says Wu, who says some view the research as an initial step toward creating babies entirely outside the body.

However, Wu says incubating a human to term in the laboratory remains impossible, for the time being. “This technology is certainly related to ectogenesis, or development outside the body,” he says. “But I don’t think it’s anywhere near an artificial womb. That’s still science fiction.”

Source Link Researchers are getting organoids pregnant with human embryos

At some point next month, a handful of volunteers will be injected with two experimental gene therapies as part of an unusual clinical trial. The drugs are potential longevity therapies, says Ivan Morgunov, the CEO of Unlimited Bio, the company behind the trial. His long-term goal: to achieve radical human life extension.

The 12 to 15 volunteers—who will be covering their own travel and treatment costs—will receive a series of injections in the muscles of their arms and legs. One of the therapies is designed to increase the blood supply to those muscles. The other is designed to support muscle growth. The company hopes to see improvements in strength, endurance, and recovery. It also plans to eventually trial similar therapies in the scalp (for baldness) and penis (for erectile dysfunction).

But some experts are concerned that the trial involves giving multiple gene therapies to small numbers of healthy people. It will be impossible to draw firm conclusions from such a small study, and the trial certainly won’t reveal anything about longevity, says Holly Fernandez Lynch, a lawyer and medical ethicist at the University of Pennsylvania in Philadelphia.

Unlimited Bio’s muscle growth therapy is already accessible at clinics in Honduras and Mexico, says Morgunov—and the company is already getting some publicity. Khloe Kardashian tagged Unlimited Bio in a Facebook post about stem-cell treatments she and her sister Kim had received at the Eterna clinic in Mexico in August. And earlier this week, the biohacking influencer Dave Asprey posted an Instagram Reel of himself receiving one of the treatments in Mexico; it was shared with 1.3 million Instagram followers. In the video, Eterna’s CEO, Adeel Khan, says that the therapy can “help with vascular health systemically.” “I’m just upgrading my system for a little while to reduce my age and reduce my vascular risk,” Asprey said.

Genes for life

Gene therapies typically work by introducing new genetic code into the body’s cells. This code is then able to make proteins. Existing approved gene therapies have typically been developed for severe diseases in which the target proteins are either missing or mutated.

But several groups are exploring gene therapies for healthy people. One of these companies is Minicircle, which developed a gene therapy to increase production of follistatin, a protein found throughout the body that has many roles and is involved in muscle growth. The company says this treatment will increase muscle mass—and help people live longer. Minicircle is based in Próspera, a special economic zone in Honduras with its own bespoke regulatory system. Anyone can visit the local clinic and receive that therapy, for a reported price of $25,000. And many have, including the wealthy longevity influencer Bryan Johnson, who promoted the therapy in a Netflix documentary.

Unlimited Bio’s Morgunov, a Russian-Israeli computer scientist, was inspired by Minicircle’s story. He is also interested in longevity. Specifically, he’s committed to radical life extension and has said that he could be part of “the last generation throughout human history to die from old age.” He believes the biggest “bottleneck” slowing progress toward anti-aging or lifespan-extending therapies is drug regulation. So he, too, incorporated his own biotech company in Próspera.

“A company like ours couldn’t exist outside of Próspera,” says Unlimited Bio’s chief operating officer, Vladimir Leshko.

There, Morgunov and his colleagues are exploring two gene therapies. One of these is another follistatin therapy, which the team hopes will increase muscle mass. The other codes for a protein called vascular endothelial growth factor, or VEGF. This compound is known to encourage the growth of blood vessels. Morgunov and his colleagues hope the result will be increased muscle growth, enhanced muscle repair, and longer life. Neither treatment is designed to alter a recipient’s DNA, and therefore it won’t be inherited by future generations.

The combination of the two therapies could benefit healthy people and potentially help them live longer, says Leshko, a former electrical engineer and professional poker player who retrained in biomedical engineering. “We would say that it’s a preventive-slash-enhancing indication,” he says. “Potentially participants can experience faster recovery from exercise, more strength, and more endurance.”

Of the 12 to 15 volunteers who participate in the trial, half will receive only the VEGF therapy. The other half will receive both the VEGF and the follistatin therapies. The treatments will involve a series of injections throughout large muscles in the arms and legs, says Morgunov.

He is confident that the VEGF therapy is safe. It was approved in Russia over a decade ago to treat lower-limb ischemia—a condition that can cause pain, numbness, and painful ulcers in the legs and feet. Morgunov reckons that around 10,000 people in Russia have already had the drug, although he says he hasn’t “done deep fact-checking on that.”

Other researchers aren’t convinced.

Limited bio

VEGF is a powerful compound, says Seppo Ylä-Herttuala, a professor of molecular medicine at the University of Eastern Finland who has been studying VEGF and potential VEGF therapies for decades. He doesn’t know how many people have had VEGF gene therapy in Russia. But he does know that the safety of the therapy will depend on how much is administered and where. Previous attempts to inject the therapy into the heart, for example, have resulted in edema, a sometimes fatal buildup of fluid. Even if the therapy is injected elsewhere, VEGF can travel around the body, he says. If it gets to the eye, for example, it could cause blindness. Leshko counters that the VEGF should remain where it is injected, and any other circulation in the body, if it occurs, should be short-lived. 

And while the therapy has been approved in Russia, there’s a reason it hasn’t been approved elsewhere, says Ylä-Herttuala: The clinical trials were not as rigorous as they could have been. While “it probably works in some patients,” he says, the evidence to support the use of this therapy is weak. At any rate, he adds, VEGF will only support the growth of blood vessels—it won’t tackle aging.  “VEGF is not a longevity drug,” he says.

Leshko points to a 2021 study in mice, which suggested that a lack of VEGF activity might drive aging in the rodents. “We’re convinced it qualifies as a potential longevity drug,” he says.

There is even less data about follistatin. Minicircle, the company selling another follistatin gene therapy, has not published any rigorous clinical trial data. So far, much of the evidence for follistatin’s effects comes from research in rodents, says Ylä-Herttuala.

Clinical trials like this one should gather more information, both about the therapies and about the methods used to get those therapies into the body. Unlimited Bio’s VEGF therapy will be delivered via a circular piece of genetic code called a plasmid. Its follistatin therapy, on the other hand, will be delivered via an adeno-associated virus (AAV). Plasmid therapies are easier to make, and they have a shorter lifespan in the body—only a matter of days. They are generally considered to be safer than AAV therapies. AAV therapies, on the other hand, tend to stick around for months, says Ylä-Herttuala. And they can trigger potentially dangerous immune reactions.

It’s debatable whether healthy people should be exposed to these risks, says Fernandez Lynch. The technology “still has serious questions about its safety and effectiveness,” even for people with life-threatening diseases, she says. “If you are a healthy person, the risk of harm is more substantial because it’ll be more impactful on your life.”

But Leshko is adamant. “Over 120,000 humans die DAILY from age-related causes,” he wrote in an email. “Building ‘ethical’ barriers around ‘healthy’ human (in fact, aging human) trials is unethical.” Morgunov did not respond to a request for comment.

Some people want to take those risks anyway. In his video, the biohacker influencer Asprey—who has publicly stated that he’s “going to live to 180”—described VEGF as a “longevity compound,” and Eterna’s CEO Khan, who delivered the treatment, described it as “the ultimate upgrade.” Neither Asprey nor Khan clinic responded to requests for comment. 

Michael Gusmano, a professor of health policy at Lehigh University in Bethlehem, Pennsylvania, worries that this messaging might give trial participants unrealistic expectations about how they might benefit. There is “huge potential for therapeutic misconception when you have some kind of celebrity online influencer touting something about which there is relatively sparse scientific evidence,” he says. In reality, he adds, “the only thing you can guarantee is that [the volunteers] will be contributing to our knowledge of how this intervention works.”

“I would certainly not recommend that anyone I know enter into such a trial,” says Gusmano.

A penis project

The muscle study is only the first step. The Unlimited Bio team hopes to trial the VEGF therapy for baldness and erectile dysfunction, too. Leshko points to research in mice that links high VEGF levels to larger, denser hair follicles. He hopes to test a series of VEGF therapy injections into the scalps of volunteers. Morgunov, who is largely bald, has already started to self-experiment with the approach.

An erectile dysfunction trial may follow. “That one we think has great potential because injecting gene therapy into the penis sounds exciting,” says Leshko. A protocol for that trial has not yet been finalized, but he imagines it would involve “five to 10” injections.

Ylä-Herttuala isn’t optimistic about either approach. Hair growth is largely hormonal, he says. And injecting anything into a penis risks damaging it (although Leshko points out that a similar approach was taken by another company almost 20 years ago). Injecting a VEGF gene therapy into the penis would also risk edema there, Ylä-Herttuala adds.

And he points out that we already have some treatments for hair loss and erectile dysfunction. While they aren’t perfect, their existence does raise the bar for any potential future therapies—not only do they have to be safe and effective, but they must be safer or more effective than existing ones.

That doesn’t mean the trials will flop. No small trial can be definitive, but it could still provide some insight into how these drugs are working. It is possible that the therapies will increase muscle mass, at least, and that this could be beneficial to the healthy recipients, says Ylä-Herttuala. 

Before our call, he had taken a look at Unlimited Bio’s website, which carries the tagline “The Most Advanced Rejuvenation Solution.” “They promise a lot,” he said. “I hope it’s true.”

Source Link This company is developing gene therapies for muscle growth, erectile dysfunction, and “radical longevity”