We Should Resist Making “Synthetic Embryos” Too Realistic

A rendering of emerging medical technology.
Ethics needs context. So does science – specifically, science that aims to create bioengineered models of early human embryo development in a dish (hereafter synthetic embryos). Even the term "synthetic embryos" begs for an explanation. What are these? And why would anyone want to create them?
"This knowledge may help scientists understand how certain birth defects are formed and why miscarriages often occur."
First the research context. Synthetic embryos are stem cell-derived simulations of human post-implantation embryos that are designed to mimic a stage of early development called gastrulation. That's the stage—around 14-15 days after fertilization – when embryos begin to form a very primitive body plan (basic dorsal-ventral and anterior-posterior axes, and distinct cell lineages). Researchers are starting to create synthetic embryos in the lab – albeit imperfect and incomplete versions – to learn how gastrulation might unfold in real human embryos embedded unseen in the womb. This knowledge may help scientists understand how certain birth defects are formed and why miscarriages often occur soon after implantation. As such, synthetic embryos are meant to be models of human embryo development, not themselves actually embryos. But will synthetic embryos ever get to the point where they are practically the same thing as "natural" human embryos? That is my concern and why I think researchers should avoid creating synthetic embryos capable of doing everything natural embryos can do.
It may not be too difficult to prevent this slide from synthetic to real. Synthetic embryos must be created using sophisticated 3D culture systems that mimic the complex architecture of human embryos. These complex culture systems also have to incorporate precise microinjection systems to chemically trigger the symmetry-breaking events involved in early body plan formation. In short, synthetic embryos need a heavy dose of engineering to get their biological processes going and to help keep them going. And like most engineered entities, designs can be built into the system early to serve well-considered goals – in our case, the goal of not wanting to create synthetic embryos that are too realistic.
"If one wants to study how car engines work, one can model an engine without also modeling the wheels, transmission, and every other car part together."
A good example of this point is found a report published in Nature Communications where scientists created a human stem cell-based 3D model that faithfully recapitulates the biological events around post-implantation amniotic sac development. Importantly, however, the embryo model they developed lacked several key structures and therefore – despite its partial resemblance to an early human embryo – did not have complete human form and potential. While fulfilling their model's aim of revealing a previously inaccessible early developmental event, the team intentionally did not recreate the entire post-implantation human embryo because they did not want to provoke any ethical concerns, as the lead author told me personally. Besides, creating a complete synthetic embryo was not necessary or scientifically justified for the research question they were pursuing. This example goes to show that researchers can create a synthetic embryo to model specific developmental events they want to study without modeling every aspect of a developing embryo. Likewise – to use a somewhat imprecise but instructive analogy – if one wants to study how car engines work, one can model an engine without also modeling the wheels, transmission, and every other car part together.
A representative "synthetic embryo," which in some ways resembles a post-implantation embryo around 14 days after fertilization.
(Courtesy of Yue Shao)
But why should researchers resist creating complete synthetic embryos? To answer this, we need some policy context. Currently there is an embryo research rule in place – a law in many nations, in others a culturally accepted agreement – that intact human embryos must not be grown for research in the lab for longer than 14 consecutive days after fertilization or the formation of the primitive streak (a faint embryonic band that signals the start of gastrulation). This is commonly referred to as the 14-day rule. It was established in the UK decades ago to carve out a space for meritorious human embryo research while simultaneously assuring the public that researchers won't go too far in cultivating embryos to later developmental stages before destroying them at the end of their studies. Many citizens accepting of pre-implantation stage human embryo research would not have tolerated post-implantation stage embryo use. The 14-day rule was a line in the sand, drawn to protect the advancement of embryo research, which otherwise might have been stifled without this clear stopping point. To date, the 14-day rule has not been revoked anywhere in the world, although new research in extended natural embryo cultivation is starting to put some pressure on it.
"Perhaps the day will come when scientists don't have to apply for research funding under such a dark cloud of anti-science sentiment."
Why does this policy context matter? The creation of complete synthetic embryos could raise serious questions (some of them legal) about whether the 14-day rule applies to these lab entities. Although they can be constructed in far fewer than 14 days, they would, at least in theory, be capable of recapitulating all of a natural embryo's developmental events at the gastrulation stage, thus possibly violating the spirit of the 14-day rule. Embryo research laws and policies worldwide are not ready yet to tackle this issue. Furthermore, professional guidelines issued by the International Society for Stem Cell Research prohibit the culture of any "organized embryo-like cellular structures with human organismal potential" to be cultured past the formation of the primitive streak. Thus, researchers should wait until there is greater clarity on this point, or until the 14-day rule is revised through proper policy-making channels to explicitly exclude complete synthetic embryos from its reach.
I should be clear that I am not basing my recommendations on any anti-embryo-research position per se, or on any metaphysical position regarding the positive moral status of synthetic embryos. Rather, I am concerned about the potential backlash that research on complete synthetic embryos might bring to embryo research in general. I began this essay by saying that ethics needs context. The ethics of synthetic embryo research needs to be considered within the context of today's fraught political environment. Perhaps the day will come when scientists don't have to apply for research funding under such a dark cloud of anti-science sentiment. Until then, however, it is my hope that scientists can fulfill their research aims by working on an array of different but each purposefully incomplete synthetic embryo models to generate, in the aggregate of their published work, a unified portrait of human development such that biologically complete synthetic embryo models will not be necessary.
Editor's Note: Read a different viewpoint here written by a leading New York fertility doctor/researcher.
Following the Footsteps of a 105-Year-Old Sprinter
No human has run a distance of 100 meters faster than Usain Bolt’s lightning streak in 2009. He set this record at age 22. But what will Bolt’s time be when he’s 105?
At the Louisiana Senior Games in November 2021, 105-year-old Julia Hawkins of Baton Rouge became the oldest woman to run 100 meters in an official competition, qualifying her for this year's National Senior Games. Perhaps not surprisingly, she was the only competitor in the race for people 105 and older. In this Leaps.org video, I interview Hawkins about her lifestyle habits over the decades. Then I ask Steven Austad, a pioneer in studying the mechanisms of aging, for his scientific insights into how those aspiring to become super-agers might follow in Hawkins' remarkable footsteps.
Following the Footsteps of a 105-Year-Old Sprinter
No human has run a distance of 100 meters faster than Usain Bolt’s lightning streak in 2009. He set this record at age 22. But what will Bolt’s time be when ...Matt Fuchs is the editor-in-chief of Leaps.org. He is also a contributing reporter to the Washington Post and has written for the New York Times, Time Magazine, WIRED and the Washington Post Magazine, among other outlets. Follow him on Twitter @fuchswriter.
Monkeypox produces more telltale signs than COVID-19. Scientists think that a “ring” vaccination strategy can be used when these signs appear to help with squelching the current outbreak of this disease.
A new virus has emerged and stoked fears of another pandemic: monkeypox. Since May 2022, it has been detected in 29 U.S. states, the District of Columbia, and Puerto Rico among international travelers and their close contacts. On a worldwide scale, as of June 30, there have been 5,323 cases in 52 countries.
The good news: An existing vaccine can go a long way toward preventing a catastrophic outbreak. Because monkeypox is a close relative of smallpox, the same vaccine can be used—and it is about 85 percent effective against the virus, according to the World Health Organization (WHO).
Also on the plus side, monkeypox is less contagious with milder illness than smallpox and, compared to COVID-19, produces more telltale signs. Scientists think that a “ring” vaccination strategy can be used when these signs appear to help with squelching this alarming outbreak.
How it’s transmitted
Monkeypox spreads between people primarily through direct contact with infectious sores, scabs, or bodily fluids. People also can catch it through respiratory secretions during prolonged, face-to-face contact, according to the Centers for Disease Control and Prevention (CDC).
As of June 30, there have been 396 documented monkeypox cases in the U.S., and the CDC has activated its Emergency Operations Center to mobilize additional personnel and resources. The U.S. Department of Health and Human Services is aiming to boost testing capacity and accessibility. No Americans have died from monkeypox during this outbreak but, during the COVID-19 pandemic (February 2020 to date), Africa has documented 12,141 cases and 363 deaths from monkeypox.
Ring vaccination proved effective in curbing the smallpox and Ebola outbreaks. As the monkeypox threat continues to loom, scientists view this as the best vaccine approach.
A person infected with monkeypox typically has symptoms—for instance, fever and chills—in a contagious state, so knowing when to avoid close contact with others makes it easier to curtail than COVID-19.
Advantages of ring vaccination
For this reason, it’s feasible to vaccinate a “ring” of people around the infected individual rather than inoculating large swaths of the population. Ring vaccination proved effective in curbing the smallpox and Ebola outbreaks. As the monkeypox threat continues to loom, scientists view this as the best vaccine approach.
With many infections, “it normally would make sense to everyone to vaccinate more widely,” says Wesley C. Van Voorhis, a professor and director of the Center for Emerging and Re-emerging Infectious Diseases at the University of Washington School of Medicine in Seattle. However, “in this case, ring vaccination may be sufficient to contain the outbreak and also minimize the rare, but potentially serious side effects of the smallpox/monkeypox vaccine.”
There are two licensed smallpox vaccines in the United States: ACAM2000 (live Vaccina virus) and JYNNEOS (live virus non-replicating). The ACAM 2000, Van Voorhis says, is the old smallpox vaccine that, in rare instances, could spread diffusely within the body and cause heart problems, as well as severe rash in people with eczema or serious infection in immunocompromised patients.
To prevent organ damage, the current recommendation would be to use the JYNNEOS vaccine, says Phyllis Kanki, a professor of health sciences in the division of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health. However, according to a report on the CDC’s website, people with immunocompromising conditions could have a higher risk of getting a severe case of monkeypox, despite being vaccinated, and “might be less likely to mount an effective response after any vaccination, including after JYNNEOS.”
In the late 1960s, the ring vaccination strategy became part of the WHO’s mission to globally eradicate smallpox, with the last known natural case described in Somalia in 1977. Ring vaccination can also refer to how a clinical trial is designed, as was the case in 2015, when this approach was used for researching the benefits of an investigational Ebola vaccine in Guinea, Kanki says.
“Since Monkeypox spreads by close contact and we have an effective vaccine, vaccinating high-risk individuals and their contacts may be a good strategy to limit transmission,” she says, adding that privacy is an important ethical principle that comes into play, as people with monkeypox would need to disclose their close contacts so that they could benefit from ring vaccination.
Rapid identification of cases and contacts—along with their cooperation—is essential for ring vaccination to be effective. Although mass vaccination also may work, the risk of infection to most of the population remains low while supply of the JYNNEOS vaccine is limited, says Stanley Deresinski, a clinical professor of medicine in the Infectious Disease Clinic at Stanford University School of Medicine.
Other strategies for preventing transmission
Ideally, the vaccine should be administered within four days of an exposure, but it’s recommended for up to 14 days. The WHO also advocates more widespread vaccination campaigns in the population segment with the most cases so far: men who engage in sex with other men.
The virus appears to be spreading in sexual networks, which differs from what was seen in previously reported outbreaks of monkeypox (outside of Africa), where risk was associated with travel to central or west Africa or various types of contact with individuals or animals from those locales. There is no evidence of transmission by food, but contaminated articles in the environment such as bedding are potential sources of the virus, Deresinski says.
Severe cases of monkeypox can occur, but “transmission of the virus requires close contact,” he says. “There is no evidence of aerosol transmission, as occurs with SARS-CoV-2, although it must be remembered that the smallpox virus, a close relative of monkeypox, was transmitted by aerosol.”
Deresinski points to the fact that in 2003, monkeypox was introduced into the U.S. through imports from Ghana of infected small mammals, such as Gambian giant rats, as pets. They infected prairie dogs, which also were sold as pets and, ultimately, this resulted in 37 confirmed transmissions to humans and 10 probable cases. A CDC investigation identified no cases of human-to-human transmission. Then, in 2021, a traveler flew from Nigeria to Dallas through Atlanta, developing skin lesions several days after arrival. Another CDC investigation yielded 223 contacts, although 85 percent were deemed to be at only minimal risk and the remainder at intermediate risk. No new cases were identified.
How much should we be worried
But how serious of a threat is monkeypox this time around? “Right now, the risk to the general public is very low,” says Scott Roberts, an assistant professor and associate medical director of infection prevention at Yale School of Medicine. “Monkeypox is spread through direct contact with infected skin lesions or through close contact for a prolonged period of time with an infected person. It is much less transmissible than COVID-19.”
The monkeypox incubation period—the time from infection until the onset of symptoms—is typically seven to 14 days but can range from five to 21 days, compared with only three days for the Omicron variant of COVID-19. With such a long incubation, there is a larger window to conduct contact tracing and vaccinate people before symptoms appear, which can prevent infection or lessen the severity.
But symptoms may present atypically or recognition may be delayed. “Ring vaccination works best with 100 percent adherence, and in the absence of a mandate, this is not achievable,” Roberts says.
At the outset of infection, symptoms include fever, chills, and fatigue. Several days later, a rash becomes noticeable, usually beginning on the face and spreading to other parts of the body, he says. The rash starts as flat lesions that raise and develop fluid, similar to manifestations of chickenpox. Once the rash scabs and falls off, a person is no longer contagious.
“It's an uncomfortable infection,” says Van Voorhis, the University of Washington School of Medicine professor. There may be swollen lymph nodes. Sores and rash are often limited to the genitals and areas around the mouth or rectum, suggesting intimate contact as the source of spread.
Symptoms of monkeypox usually last from two to four weeks. The WHO estimated that fatalities range from 3 to 6 percent. Although it’s believed to infect various animal species, including rodents and monkeys in west and central Africa, “the animal reservoir for the virus is unknown,” says Kanki, the Harvard T.H. Chan School of Public Health professor.
Too often, viruses originate in parts of the world that are too poor to grapple with them and may lack the resources to invest in vaccines and treatments. “This disease is endemic in central and west Africa, and it has basically been ignored until it jumped to the north and infected Europeans, Americans, and Canadians,” Van Voorhis says. “We have to do a better job in health care and prevention all over the world. This is the kind of thing that comes back to bite us.”