Friends who pay attention to the mysterious issue of biotechnology will not be unfamiliar with the fact that whenever biotechnology takes a step forward, it will cause a lot of controversy in ethics. Today's article is also about the relationship between biotechnology and ethics.
The story begins with an experiment 4 years ago. In the summer of 2017, scientists at University College London in the United Kingdom took a small piece of tissue from the shoulder of science writer Philip Ball and conducted a special experiment with the cells of these tissues. After 8 months, the cells developed into a miniature brain: not only did the cell type change from skin cells to neurons, but the cells also formed the same neural connections in the brain that could transmit nerve signals. This suggests that the boundaries between the body's different tissue cells will become blurred. With the development of stem cells, gene editing, somatic cell cloning, tissue engineering and other technologies, such seemingly only possible in science fiction plots are or are about to become a reality, scientists can even convert cells into germ cells, creating artificial "sperm" and "eggs", further bringing good news to infertility, but it will also blur the boundaries between cells and life.
In How to Make a Man, PhilipPe Bauer takes readers to the forefront of today's developments in the field and brings philosophical thoughts: How will technology affect human life? If we could transform the cells in our arms into germ cells to "make" humans, what ethical dilemmas would this technology entail? How will such technology disrupt human reproductive behavior and culture? The following is authorized by the publishing house and excerpted from "How to Make a Man", with slight deletions.
How to Make a Man, by Philip Bauer, translated by Li Ke/Wang Yating, Xinsi Culture | CITIC Publishing Group, June 2021.
What is the principle of "artificial" sperm and egg technology?
One of the common causes of infertility in women is that the quality of the eggs declines with age. Today, a woman looking to conceive later may choose to collect her eggs at a young age and freeze them for later use. There is no indication that this approach poses a health risk to the children born, but in fact, it is too early to know whether these children will have health problems as adults.
But what if you didn't freeze your eggs early and you're almost 40 years old now, making it difficult to conceive naturally? What if you don't have eggs in your body at all (say, surgery to remove your ovaries because of ovarian cancer) ? You can use donor eggs, but these eggs are now in short supply, after all, egg collection is a painful process, so not many women are willing to donate eggs. Also, regardless of the situation, you may want a child who is related to you by blood.
There may be a silver lining – not now, but there may be a play in ten or twenty years. We might be able to make "artificial" eggs using induced pluripotent stem cells derived from a small patch of skin, just as we would make mini-brains from my induced pluripotent stem cells. In the embryo, some pluripotent stem cells will form germ cells that eventually become gametes, i.e. eggs and sperm. The process of gamete formation is somewhat peculiar, different from the formation of somatic cells, because gametes have only one set of chromosomes and are produced through a special way of cell division called meiosis. Nevertheless, there are no obvious indications that induced pluripotent stem cells cannot form gametes.
In fact, both "artificial" eggs and sperm can be made in Petri dishes in this way, and the need for both is urgent. At least half of infertility problems are caused by poor sperm quality in men, and the situation is getting worse: men's sperm counts fell by a staggering 50 to 60 percent between 1973 and 2011. This does not mean that the birth rate will decrease accordingly – even if the husband's sperm quality is poor, the wife may still become pregnant after a longer period of effort, in addition, there is an option to use donated sperm. But poor sperm quality is not just related to the difficulty of conceiving. Low sperm counts often also indicate other health problems that have just emerged or are already in place in men, including testicular cancer, heart disease, and obesity. Worryingly, no one knows the reason for the decline in sperm count, but it may be the result of a combination of environmental factors, including smoking, unhealthy diets, and intake of pollutants and chemicals that interfere with the development of the male reproductive system. In conclusion, a drop in sperm count may also be a sign of other health problems.
Stills from Blade Runner 2049.
Artificial sperm does not solve the above problems behind low sperm count, but it can treat infertility caused by low sperm count or quality. In vitro fertilization techniques can already help less fertile men because we can collect and concentrate their sperm and have those sperm bind to the egg. This technique can even be used for sperm that cannot "swim" (a common cause of poor sperm quality) by injecting sperm directly into the egg using intracytoplasmic sperm injection technique. But some men can't produce sperm at all. In this case, in time, we may be able to make artificial sperm by reprogramming stem cells, so that these men and their wives have a blood-related child.
"I'm amazed when I think about this application prospect," says Azim Surani, a developmental biologist at the University of Cambridge and one of the leading researchers in the field of artificial egg and sperm making. ”
For some, "making" a child with a part of an arm may sound inconceivable, offensive, or even blasphemous. Of course, there is a similar expression in the Bible, which gives the above idea a god-like power: the Lord God put him to sleep, and he slept; so he took off one of his ribs and put the flesh together in place. Then jehovah God created a woman out of the ribs taken from the man and brought her to the man.
But making gametes from stem cells is not as easy as making neurons, which require a reenactment of the natural process by which embryonic stem cells develop into gametes. After a few weeks of fertilization, the fate of a subset of embryonic stem cells is determined and will develop into germ cells. These cells first form so-called primordial germ cells and migrate in the embryo, reaching the area where they will develop into gonads (i.e., the testicles or ovaries). Only then does the gonads begin to show male or female features. If the sex of the embryo is male, then a subset of the original germ cells will express the SRY gene on the Y chromosome, which produces a transcription factor that causes the undifferentiated gonads to develop into the testes, otherwise the gonads will develop into the ovaries by default.
Once inside the gonads, the primordial germ cells receive signals from the surrounding tissues that prompt them to mature into gametes. After entering puberty, the primitive germ cells in the male body will continue to form sperm through meiosis. In women, diploid cells (cells with two sets of chromosomes) called "oocytes" produce haploid eggs. Oocytes begin to meiosis during the fetal period, but stagnate during the first meiosis until the girl reaches puberty more than a decade later. During ovulation, oocytes complete the first meiosis inside the follicles of the ovary and are then excreted from the follicles into the fallopian tubes. During meiosis, epigenetic modifications acquired by primitive germ cell chromosomes are removed, restoring the gene to its original pluripotent state.
So there are many steps that need to be repeated in vitro: first the stem cells need to be converted into primitive germ cells, and then they need to mature and form gametes through meiosis. But it can be done, at least the cells of mice. In 2011, biologist Toshiki Saito of Kyoto University in Japan, Katsuhiko Hayashi, a biologist at Kyushu University, and collaborators reprogrammed skin cells from adult mice into induced pluripotent stem cells and used those cells to create "artificial" sperm. By injecting induced pluripotent stem cells with a transcription factor called "BMP4," they transformed the cells into primitive germ cells. The researchers then transplanted these artificially induced primitive germ cells into the testicles of live mice. In the testicles, these cells can receive the signals needed to become sperm. The researchers used these sperm to fertilize the mouse's egg cells and implanted the embryos developed from the fertilized eggs into the female mouse's uterus, which eventually gave birth to live jumping mouse pups.
A similar process can be used to make gametes for females with slight modifications. Using the same method, Saito Toshiki's research team once induced pluripotent stem cells or embryonic stem cells to induce differentiation into primitive germ cells and transplanted these cells into the ovaries of mice. In the ovaries, these primitive germ cells successfully form eggs. The researchers also developed a method of making eggs entirely in vitro: They used an "artificial ovary" to give the egg the signal it needed to make it fully mature. This artificial ovary is made from mouse ovarian cells cultured in vitro.
In a topical experiment, Saito Tsuki's research team completed a complete generation cycle with mouse eggs without the participation of adult mice. They prepared eggs from mice in vitro with pluripotent stem cells, and then fertilized the eggs with the sperm of adult mice through in vitro fertilization techniques. The researchers cultured these fertilized eggs into blastocyst stages in a petri dish, then took new embryonic stem cells from the blastocysts and used them to prepare gametes to begin a new cycle.
Although the experiment used techniques that had been developed before, in a sense, it subverted the nature of sexuality and reproduction. This experiment means that we can continuously grow generation after generation of mice in a matter of days (usually about 20 days of gestation), without having to make an adult individual. In fact, no "mice" were produced in the above process. If there are enough sperm (and if you want, sperm can also be artificially made), we can use stem cells to get eggs, embryos, and stem cells again, and so on indefinitely. You might say that these cells are producing a family through sexual behavior and don't need a complete organism at all.
We still know little about the details of this process. Of course, biology doesn't care about that.
These advances are very useful if you want to treat infertility in mice (although my family doesn't want to help mice improve their fertility). What about making human gametes? We are still some distance from this goal. So far, researchers have been able to differentiate human pluripotent stem cells into primitive germ cells, but it is difficult to mature them further, because these cells also need the correct signals provided by gonadal cells.
However, the study found that these signals are not species-specific. The gonads of mice can also provide signals to human germ cells, at least in part. In 2018, Toshiki Saito and his collaborators published a study. In the study, the scientists cultured human primitive germ cells in vitro along with ovarian cells from mice, "coaxing" the former into developing to the next stage, forming oogonia. Saito admits that before that, he had thought that it was a bit whimsical to expect mouse gonads to induce the development of human germ cells, but he decided not to do it. Mice are not human, but as far as the cells of the two are concerned, in this case, the mouse and the human are still close enough. Researchers also need to now have the ovarian cells turn into oocytes before taking on the challenge of meiosis to make them fertilized egg cells.
Using a similar approach, it is also possible that human primitive germ cells will be converted into sperm in vitro by culturing these cells with testicular cells in mice. Scientists don't yet know whether fully mature sperm can be produced in this way, but sperm may not need to be fully mature: even immature sperm without a "tail" may fertilize an egg cell if it is injected directly into the egg cell.
How far are we from the maturity of "artificial" sperm and egg technology?
These technologies are still in their infancy. How similar are these artificial cells compared to primitive germ cells and oval cells in human embryos or in adults? We don't know yet. Nor do we know how thoroughly the epigenetic modifications of artificial germ cells are reset. If these cells also "remember" information about their original origin (such as from skin cells), then they may not develop properly when fertilized. (The human oocyte-like cells made by Saito's team do appear to have removed most of the epigenetic markers.) However, some mouse eggs produced from artificial primitive germ cells look a little odd and deformed, and these eggs are not as successful as "natural" eggs. In either case, no responsible researcher would approve of the use of such cells for human reproduction until such safety issues are scrutinized.
However, using artificial mouse gametes, researchers have been able to make very healthy mice. Hank Greely, a bioethicist at Stanford University, said he hadn't seen obvious "spoiler discoveries," so what works in mice should eventually apply to humans as well. Werner Neuhausser, a stem cell biologist at Harvard University, said: "Making human gametes from somatic cells in the lab is not a question of whether it can be done, it may just be a question of how much time and effort it takes." He also added that the clinical demand for this technology is immeasurable.
Son of Man movie poster.
Don't get your hopes up for the time being, though. "I've gotten a lot of emails from people saying, 'My husband is fertile and he dreams of having children', Sulani said. Well, nothing is impossible, but if these techniques are to be applied clinically, then the situation is very complicated. He also said that in order to confirm the feasibility and safety of this technology when used in human assisted reproduction, experiments with non-human primates are first needed. Not only are these experiments costly and slow to progress, but they are almost entirely impossible to carry out in some highly regulated countries.
"Even with all the safeguards in place, we still need to accept some residual risks." Neuhauser warned, "Ultimately, if the technology goes into clinical trials, some patients will have to have confidence even if they don't have confidence." Sulani thinks the technique is unlikely to be used in the clinic within 10 years, and Saito Tsuki's collaborator Kohiko Hayashi tends to warn those who contact him (who volunteer as volunteers for artificial gamete IN VIF) that human conception with these methods could be 50 years later.
The ethical problems faced by "single parents" reproduction, "multiple parents", and "making a person"
Reports of declining sperm counts have also had an impact on some dystopian novels. These novels are dedicated to exploring the fears that arise from them, including P. D. James. D. James's "Son of Man" and Margaret Atwood's "The Handmaid's Tale." In these novels, the human capacity to reproduce disappears. While there's no reason to think this will happen, some aspects of modernity — whether it's dietary and lifestyle changes, or environmental pollution — do seem to be contributing to fertility problems becoming more prevalent.
Richard Sharpe, a reproductive health expert at the University of Edinburgh in Scotland, said that if a man's sperm count continues to decline and the scientific community still lacks a deep understanding of its causes and there is no effective treatment, then one day, in vitro-made sperm may be more likely to fertilize eggs than natural sperm. We may hope that this option will never come in handy, but it's always good to be prepared. As bioethicist Ronald Green put it: "If all of humanity reaches its most dangerous moment, if our fertility is no longer sufficient, we may have to make humans." ”
However, beyond the tantalizing prospects of artificial gametes "ending infertility" and "democratizing fertility", there is the question of how to consider fertility itself. The philosopher Anna Smajdor has aggressively pointed out that such advances "may break down natural barriers to procreation," for example, by enabling postmenopausal (and even older) women and prepubertal children to have children. Indeed, as we saw earlier, even embryos can "procreate." Greeley admits that although he has been studying the field for years, he has been speechless more than once when confronted with the prospects for the technology's applications proposed by others. One such application is "uniparent" reproduction, in which a person (whether male or female) creates eggs and sperm from his own somatic cells and creates a child (a "single parent baby") out of those two cells. As a result of the chromosomal recombination that occurs during this process,
So single-parent babies are not strictly human clones. Another application is "multiplex parenting," in which three or more people mix their genes to get a child. In fact, Greeley said, this could mean that "two people want their own children and a third person to have children, but don't have to bother with Mr. Next child and raise him/her to adolescence".
Stills from The Handmaid's Tale.
If one day any part of our body (like the cells you leave behind on beer bottles and wine glasses) could be used to make gametes, it's easy to think of other worrying situations. It is not difficult to imagine that celebrities are about to start fighting lawsuits over parent-child issues.
Greeley concludes that the ideas "demonstrate how broad and unhurried the effects of new biotechnologies on human reproductive behavior" are. Faced with so many possibilities, even experts can get dizzy.
Most people probably find some of the above situations very weird. But security issues aside, ethical issues aren't as simple as you might think. An important reason is that no philosopher has yet been able to solve the question of right and wrong that allows or does not allow a person to exist. (If the existence of a person is prohibited, how can their rights be respected?) One thing seems self-evident: trying to make an absolute judgment about right and wrong may only hinder serious debate, and the latest scientific advances will always fail such attempts.
Therefore, the guiding principle for the application of new technologies should not be "What to do?" And it should be "Why do?" "Why do you do it?" "It should be based on the interests of children born in this way. Smyto doesn't think we should immediately embrace the options that are new or likely to emerge in the future. Instead, we must try to solve some of the thorny questions, including understanding what fertility, reproduction, and sexuality really mean, understanding how we examine the relationships between these things, and what kind of relationships they will be in the future.
The original author | Philip Ball
Excerpts | Xu Yuedong
Edit | Rodong
The introduction section proofreads | Dangerous