“Synthetic Embryos”: The Wrong Term For Important New Research
This fluorescent image shows a representative post-implantation amniotic sac embroid.
As a subject of research, an unusual degree of consensus appears to exist among scientists, politicians and the public about human embryos being deserving of special considerations. But what those special considerations should be is less clear. And this is where the subject becomes contentious and opinions diverge because, somewhat surprisingly, what really represents a human embryo has so far not been resolved.
"Prior to implantation, embryos must be given a different level of reverence than after implantation."
In 2002, Howard W. Jones Jr., widely considered the "father" of in vitro fertilization (IVF) in the U.S., argued in a widely acclaimed article titled "What is an embryo?" that a precondition for the definition of a human embryo was successful implantation. Only once implantation established a biological unit between embryo and mother, could a relatively small number of human cells be considered a human embryo.
Because he felt strongly that human embryos, indeed, deserve special considerations, and should receive those during IVF, he pointed out that, even inside a woman's body, most human embryos (in contrast to other species) never implant and, therefore, are never given a chance at human life. Consequently, he reasoned that prior to implantation, embryos must be given a different level of reverence than after implantation.
"One cannot help but wonder about the fog of misconceptions and misrepresentations that still surrounds what an embryo is."
This difference, he felt, should also be reflected in scientific language, proposing that embryos prior to implantation in daily IVF practice be called "pre-embryos," with the term "embryo" reserved for post-implantation-stage embryos. Then still unknown to Jones, recent research findings support this viewpoint, since genetic profiles of pre- and post-implantation stage embryos greatly differ.
In an analogy to nature, which in humans allows implantation of only a small minority of naturally generated pre-embryos, IVF centers around the world routinely discard large numbers of pre-embryos, judged inadequate for producing normal pregnancies. Jones' suggestion that only post-implantation embryos should be considered embryos deserving of special considerations, therefore, not only appears prescient and considerate of current IVF practices, but grounded in scientific reality. One, therefore, cannot help but wonder about the fog of misconceptions and misrepresentations that still surrounds what an embryo is.
"Much of the regulatory environment surrounding research on human embryos is guided by emotions rather than science and logical thinking."
In 1984, a British ethics committee issued the Warnock Report, which still today prohibits scientists worldwide from studying human embryos in a lab beyond 14 days from fertilization or past formation of the so-called primitive streak, whichever comes first. Well-meaning in its day, its intent was to apply special considerations to human pre-embryos by protecting them from the potential of "feeling pain," once the primitive streak arose on day-15 of development. Formation of the primitive streak signifies a process known as gastrulation, when a subset of cells from the inner cell mass of the pre-embryo are transformed into the three germ layers that comprise all tissues of the developing embryo: The ectoderm, which gives rise to the nervous system; the mesoderm, which gives rise to the circulatory system, muscle, and kidneys; and the endoderm which gives rise to the interior lining of the digestive and respiratory tracts, among other tissues.
That pre-embryos may feel pain at that stage of development was far-fetched in 1984; in view of what we have learned about early human embryology in the 33 years since, it remains untenable today. And, yet, scientists all over the world remain bound by the ethical constraints imposed by the Warnock Report.
A similar ethical paradox exists today for guidelines affecting huge numbers of so-called "abandoned" cryopreserved embryos, often stored ad infinitum in IVF centers all over the world. These are pre-embryos, whose "parents" are no longer responsive to queries from their IVF centers. Current U.S. guidelines allow the disposal of such pre-embryos but prohibit their use in research that may benefit mankind. One, however, wonders whether disposal of huge numbers of abandoned embryos is really more ethical than their use in potentially life-saving human research?
That much of the regulatory environment surrounding research on human embryos is, indeed, guided by emotions rather than science and logical thinking, is also demonstrated by recently expressed concern about so-called "artificial" or "synthetic" embryos. Though both of these terms suggest impending ability to create human embryos from synthetic building blocks, this is not what these terms are meant to describe (such abilities also are not on the horizon). They also do not describe abilities to create gametes (i.e., eggs and sperm) from somatic cells by reprogramming adult peripheral cells, which has already been successfully done in mice by Japanese investigators, leading to the creation of healthy embryos and births and three generations of healthy pubs. Such an approach is at least conceivable as an upcoming infertility treatment.
"A team of biologists and engineers at the University of Michigan recently received media attention after creating organoids from embryonic stem cells that resembled human embryos."
What all of this noise is really about is the discovery that, as several Rockefeller University investigators recently noted, "Cells have an intrinsic ability to self-assemble and self-organize into complex and functional tissues and organs." Investigators have taken advantage of this ability by creating in the lab so-called "organoids" from accumulations of individual embryonic stem cells. They are defined by three characteristics: (i) they contain a variety of cell types and tissue layers, all typical for a given organ; (ii) these cells are organized similarly to their organization in a specific organ; and (iii) the organoid mimics functions of the organ.
Several other biologists from the Cincinnati Children Hospital Medical Center recently noted that in the last five years, quite a variety of human stem cell-derived organoids, including all three germ layers, have been generated by different research groups around the world, thereby establishing new human model systems that can be used outside the body, in a dish, to investigate otherwise difficult-to-approach organs. Interestingly, they can also be used to investigate early stages of human embryological development.
A team of biologists and engineers at the University of Michigan recently received media attention after creating organoids from embryonic stem cells that resembled human embryos and, therefore, were given the name "embroids." Though clearly not embryos (the only thing they had in common with human embryos were cell types), they were nevertheless awarded in at least one article the identity of "artificial embryos," which "no one knows how to handle." As Howard Jones so correctly noted, with the word embryo often comes undeserved reverence.
"Any association with the term "embryo" should be avoided; it is not only misleading and irresponsible but scientifically incorrect."
Artificial embryos, therefore, do not exist. Organoids that resemble embryos (i.e., "embroids"), while potentially very useful research objects in studies of early human embryonic cell organization and lineage development, are not embryos--not even pre-embryos. Special considerations for "artificial" or "synthetic" embryos, as recently advocated by some scientists, therefore, appear ethically undeserved. How misdirected and forced some of these efforts are is probably best demonstrated by a recent publication in which a group of Harvard University investigators proposed the term "synthetic human entities with embryo-like features" or SHEEFS" in place of "organoids." Preferably, however, in describing these laboratory-created entities, any association with the term "embryo" should be avoided. It is not only misleading and irresponsible but scientifically incorrect.
Clinical reproductive medicine and reproductive biology, for valid ethical reasons, but also because of myths, misperceptions and, sometimes, outright misrepresentations of facts for political reasons, are under more public scrutiny than most other science areas. Yet, at least in the realm of biomedical research, nothing appears more important than better understanding the first few days of human embryo development. A recent study involving genetic editing of human embryos, reported by British investigators in Nature, once again confirmed what biologist have known for some time: No animal model faithfully recapitulates most of human developmental origins. The most important secrets nature still has to tell us, will not be revealed through mouse or other animal studies. We will discover them only through the study of early-stage human embryos – and we, therefore, should not limit the use of lab-grown organoids to help further that research.
Understanding early human development "will not only greatly enhance the biological understanding of our species; but also will open groundbreaking new therapeutic options in all areas of medicine."
As Howard Jones intuitively noticed, words matter. Appropriate and uniformly accepted definitions and terms are not only essential for scientific communications but, within the context of human reproduction, often elicit strong emotional reactions, and are easily misappropriated by those opposed to most interventions into human reproduction.
Who does not recall the early days of IVF in the late 1970s, when even reputable news outlets raised the specter of Frankenstein monsters created through the IVF process? Millions of IVF births later, a Nobel Prize in Medicine and Physiology was in 2010 finally awarded to the biologist Robert Edwards who, together with the gynecologist Patrick Steptoe, reported the first live birth through IVF on July 25, 1978. Many more awards are still waiting for recipients who through the study of early human embryo development will discover how cell fate is determined and cells acquire highly specific functions; how rapid cell proliferation takes place and, when required, stops; why chromosomal abnormalities are so common in early stage embryos and what their function may be.
Those who will discover these and many other important answers, will not only greatly enhance the biological understanding of our species; but also will open groundbreaking new therapeutic options in all areas of medicine. Learning how to control cell proliferation, for example, will likely revolutionize cancer therapy; I started my research career in biology with a study published in 1980 of "common denominators of pregnancy and malignancy." If regulatory prohibitions are not allowed to interfere in rapidly progressing research opportunities involving organoids and pre-embryos, we will, finally, see the circle closing, with the most rewarding benefits for mankind ever achieved through biological research.
Editor's Note: Read a different viewpoint here written by one of the world's top experts on the ethics of stem cell research.
Here's how one doctor overcame extraordinary odds to help create the birth control pill
Dr. Percy Julian had so many personal and professional obstacles throughout his life, it’s amazing he was able to accomplish anything at all. But this hidden figure not only overcame these incredible obstacles, he also laid the foundation for the creation of the birth control pill.
Julian’s first obstacle was growing up in the Jim Crow-era south in the early part of the twentieth century, where racial segregation kept many African-Americans out of schools, libraries, parks, restaurants, and more. Despite limited opportunities and education, Julian was accepted to DePauw University in Indiana, where he majored in chemistry. But in college, Julian encountered another obstacle: he wasn’t allowed to stay in DePauw’s student housing because of segregation. Julian found lodging in an off-campus boarding house that refused to serve him meals. To pay for his room, board, and food, Julian waited tables and fired furnaces while he studied chemistry full-time. Incredibly, he graduated in 1920 as valedictorian of his class.
After graduation, Julian landed a fellowship at Harvard University to study chemistry—but here, Julian ran into yet another obstacle. Harvard thought that white students would resent being taught by Julian, an African-American man, so they withdrew his teaching assistantship. Julian instead decided to complete his PhD at the University of Vienna in Austria. When he did, he became one of the first African Americans to ever receive a PhD in chemistry.
Julian received offers for professorships, fellowships, and jobs throughout the 1930s, due to his impressive qualifications—but these offers were almost always revoked when schools or potential employers found out Julian was black. In one instance, Julian was offered a job at the Institute of Paper Chemistory in Appleton, Wisconsin—but Appleton, like many cities in the United States at the time, was known as a “sundown town,” which meant that black people weren’t allowed to be there after dark. As a result, Julian lost the job.
During this time, Julian became an expert at synthesis, which is the process of turning one substance into another through a series of planned chemical reactions. Julian synthesized a plant compound called physostigmine, which would later become a treatment for an eye disease called glaucoma.
In 1936, Julian was finally able to land—and keep—a job at Glidden, and there he found a way to extract soybean protein. This was used to produce a fire-retardant foam used in fire extinguishers to smother oil and gasoline fires aboard ships and aircraft carriers, and it ended up saving the lives of thousands of soldiers during World War II.
At Glidden, Julian found a way to synthesize human sex hormones such as progesterone, estrogen, and testosterone, from plants. This was a hugely profitable discovery for his company—but it also meant that clinicians now had huge quantities of these hormones, making hormone therapy cheaper and easier to come by. His work also laid the foundation for the creation of hormonal birth control: Without the ability to synthesize these hormones, hormonal birth control would not exist.
Julian left Glidden in the 1950s and formed his own company, called Julian Laboratories, outside of Chicago, where he manufactured steroids and conducted his own research. The company turned profitable within a year, but even so Julian’s obstacles weren’t over. In 1950 and 1951, Julian’s home was firebombed and attacked with dynamite, with his family inside. Julian often had to sit out on the front porch of his home with a shotgun to protect his family from violence.
But despite years of racism and violence, Julian’s story has a happy ending. Julian’s family was eventually welcomed into the neighborhood and protected from future attacks (Julian’s daughter lives there to this day). Julian then became one of the country’s first black millionaires when he sold his company in the 1960s.
When Julian passed away at the age of 76, he had more than 130 chemical patents to his name and left behind a body of work that benefits people to this day.
Therapies for Healthy Aging with Dr. Alexandra Bause
My guest today is Dr. Alexandra Bause, a biologist who has dedicated her career to advancing health, medicine and healthier human lifespans. Dr. Bause co-founded a company called Apollo Health Ventures in 2017. Currently a venture partner at Apollo, she's immersed in the discoveries underway in Apollo’s Venture Lab while the company focuses on assembling a team of investors to support progress. Dr. Bause and Apollo Health Ventures say that biotech is at “an inflection point” and is set to become a driver of important change and economic value.
Previously, Dr. Bause worked at the Boston Consulting Group in its healthcare practice specializing in biopharma strategy, among other priorities
She did her PhD studies at Harvard Medical School focusing on molecular mechanisms that contribute to cellular aging, and she’s also a trained pharmacist
In the episode, we talk about the present and future of therapeutics that could increase people’s spans of health, the benefits of certain lifestyle practice, the best use of electronic wearables for these purposes, and much more.
Dr. Bause is at the forefront of developing interventions that target the aging process with the aim of ensuring that all of us can have healthier, more productive lifespans.
