The Japanese "human-beast embryo experiment" that brushed the screen did not just appear, and the concern about "half-human, half-beast" has a long history. Why do scientists brave ethical pressures and technical challenges to create chimeric organisms?
Text/Reporter Ding Lin New Media Editor/Lu Bingxin
In recent days, the news about "Japan approved the world's first human-animal hybrid embryo experiment" has attracted widespread attention. Many netizens feel that their hearts are full of mixed feelings, and some people even discuss with great interest "what should people and pigs have reproductive isolation?" "
△ The nature website reported on this incident
The news goes like this: "Japan's Ministry of Education, Culture, Sports, Science and Technology last week provisionally approved a proposal by researchers at the University of Tokyo to create animal embryos containing human cells and transfer them into surrogate animals." The aim of this study is to use animals to produce human organs that can be transplanted. The relevant experiments need to be formally approved after one month. "
With regard to the above text, a few points that need to be clarified are:
1. The Japanese government approved the experiment of "animal embryos containing human cells", which is actually a title party to say that "hybrid embryos" are deliberately made people think otherwise;
2. Japan will be the first country to support such research, but similar studies have been conducted for many years under strict supervision, and these pioneering studies may contribute to a change in the attitude of the Japanese government;
3. Although Japan approved that mixed embryos can be conceived until term, scientists do not intend to do so immediately, and relying on existing technology, it is not yet possible to produce decent human organs, let alone "half-orcs".
"After 10 years of preparation, we can finally start serious research now." Nakauchi Hiromitsu, a researcher at the University of Tokyo Medical School who was approved this time, said in an interview with Japan's Asahi Shimbun. "We are not prepared to build human organs right away, but the support of the government allows us to build on the research that has been done."
△ Nakauchi Kaiko
In the past 10 years, the Nakanai team has achieved remarkable scientific research results, but it is also facing difficulties that are difficult for scientists in other fields to understand.
<h1 class="ql-align-center" > biological "chimeras" are not uncommon </h1>
In 2010, the Nakauchi team at the University of Tokyo published a landmark study in the journal Cell in which they successfully differentiated stem cells from rats into pancreas in mouse embryos with pancreatic developmental defects. The "Chimera" mice thus bred have pancreas composed entirely of rat cells.
△ Source: Cell Press
"Chimera" refers to organisms containing cells of different genetic origins. This life form also exists in nature — during embryonic development, multiple twins communicate with each other and become chimeras; humans with leukemia also become chimeras carrying donor cells after bone marrow transplantation.
In academic research, the concept of "chimera" is also crucial. Before the emergence of emerging gene editing technologies such as CRISPR, researchers could artificially create "chimeric mice" and eventually obtain mouse offspring that knock out specific genes for use in various biological and medical research.
△ The 2007 Nobel Prize in Physiology or Medicine was awarded to three scientists who have made outstanding contributions in the field (Source: nobelprize.org)
In addition, many genetically modified lab mice are used to simulate testing the human immune system, while others are implanted in human tumor cells to test drugs — they are all "interspecific chimeras." Human transplantation of pig heart valves has a history of many years, and China has also approved bioengineerated corneas modified with pig corneas in recent years. Those who receive xenotransplantations are also chimeras.
Even if chimeras are a familiar face in the field of biomedical research, they are still very strange to the public, and even a little abominable. According to feedback received by the National Institutes of Health (NIH) in the survey, a considerable number of people mistakenly believe that human embryos are used in "human-animal" chimeric embryo experiments.
The human cells used in chimeric embryos are actually "pluripotent stem cells" artificially induced by somatic cells.
△ The 2012 Nobel Prize in Physiology and Medicine, which recognized the breakthrough in the field of "induced pluripotent stem cells" (iPS) (source: nobelprize.org)
In 2013, the Nakanichi team published a new study in the Proceedings of the National Academy of Sciences. They had induced pluripotent stem cells derived from one pig eventually develop into a functional pancreas in another pig embryo with a defective pancreas.
As long as the method continues to be concocted, the Nakanai team seems to be not far from cultivating transplantable human organs...
< h1 class="ql-align-center" > continue research on the other side of the ocean </h1>
Organ transplantation is a great achievement of modern medicine. But it is also because of advances in medicine, coupled with safer transportation, fewer traffic accidents, fewer organs available for transplantation – but not fewer people needing organ transplants. Because of the progress of the times, many people have fallen into the process of waiting for transplanted organs.
In addition to the limited number of organ donors, can we create entirely new organs? Some scientists believe that induced pluripotent stem cells made with their own somatic cells have the potential to "tailor" organs — after all, all organs are differentiated from a very small number of embryonic stem cells during conception. Organs made with their own cells should not be at risk of immune rejection.
Although stem cell technology has been pinned on high hopes, scientists have never been able to grow stem cells into working, transplantable organs — stem cells may be able to develop into cardiomyocytes in a culture bottle, but a bottle of suspended cardiomyocytes is different from a real heart. The success of the "chimeric pancreas" seems to point to a clear path.
However, the next step of the "human-animal" chimeric embryo experiment was not easy in Japan at that time. According to Japanese research regulations, it is only allowed to mix stem cells of humans and animals in vitro for no more than 14 days, while conducting such research in living organisms is prohibited. This "14-day principle" originated in the United States in 1979 and the United Kingdom in 1984, where bioethical policy teams in both countries believe that the 14-day embryo has stabilized (and will no longer split into twins), but at this time the embryonic nervous system has not yet developed, so it does not feel pain.
After decades of widespread use, scientists have gained a deeper understanding of embryonic development, and the rule has been called for change. In June 2014, the Bioethics Committee of the Science and Technology Policy Council, Japan's top scientific advisory group, finally recommended that the above restrictions be slowed down.
However, Keimitsu Nakauchi believes that it will take longer for the ban to actually be lifted (it can now be seen that his intuition is correct). So he decided to open a lab across the ocean, in the less tightly regulated United States. He received a six-year, $6.2 million grant from the California Institute for Regenerative Medicine and established a laboratory at Stanford University to conduct research.
△ Keimitsu Nakauchi in his Stanford laboratory (Source: stanford.edu)
Unexpectedly, in September of the following year, the National Institutes of Health issued an interim ban, stopping funding for related research. Fortunately, the above ban only involves government funding, and Nakanori can still legally carry out his research. In later years, he had to rely on funding from the California Institute of Regenerative Medicine to continue his work.
<h1 class="ql-align-center" > "man-pig" chimera make history </h1>
In January 2017, scientists at the Salk Institute, a collaboration with The Kaiguang Laboratory in Nakauchi, published an article in Cell, announcing the creation of the first "human-pig" chimeric embryo in history.
The Salk Institute's approach is similar to that of the Naka-Nei team, but "human-pig" chimeras are actually more difficult than "mouse-rat" chimeras and "pig-pig" chimeras —mice and rats are genetically more similar, but in comparison, human and pig genes are quite different; on the other hand, pig embryos can develop in less than 4 months, much faster than human embryos.
In this study, the researchers found that only stem cells at specific stages of development were ultimately able to survive in pig embryos. Although the proportion of human cells is only about 0.001% and scattered, it is still early to become a "human organ", but it has already made history.
△ 4 weeks chimeric embryos, green fluorescently labeled are human cells (Source: Salk Institute)
Due to ethical regulatory constraints, the researchers only allowed chimeric embryos to develop for up to 28 days. In the final embryos, the development of human cells is not ideal, but they seem to have an impact on the development of pig embryos.
Within the same week that the Salk Institute published the paper, Keiguang Nakauchi's Stanford team also published a study in Nature: They grew the pancreas of mice in rats, transplanted islets into mice, and successfully suppressed their type I diabetes symptoms and stabilized their blood sugar.
In fact, in a breakthrough study in 2010, they successfully let the rat pancreas grow in mice. But these rat pancreass are only "mouse size" and not enough for transplantation. So in 2017 they did the opposite, validating that chimeric organs could be used for transplants. The researchers also found that five days after transplanting islets, the experimental mice did not take immunosuppressants, and the new organs were not rejected by the immune system; the pancreas produced by pluripotent stem cells did not become cancerous after a long time. All this allows researchers to see the potential of the application of the technology.
In early 2018, stanford's lab in The Middle Ages announced the success of creating a "human-sheep" chimera and increasing the proportion of human cells to 0.01% (these cells are still only scattered and do not produce human pancreas). Researchers believe that sheep embryos are better compatible with human stem cells and that the in vitro fertilization process is easier than that of pigs.
<h1 class="ql-align-center" > controversy and research peers </h1>
These studies opened the door to new fields, but they also immediately met with a lot of opposition.
The public has expressed a wide variety of concerns, with some arguing that chimeras cross "boundaries" between species and create confusing moral dilemmas (e.g., "can chimeric livestock eat them"); others feel that the existence of chimeric organisms is inherently an insult to human dignity. Brock Bastian, a social psychologist at the University of Melbourne, points out that many people sneer at chimeric creatures or feel sick to their stomachs, not out of concern for these experimental creatures, but out of concern for their existence, which offends the "purity" of human beings.
△ Injecting human induced pluripotent stem cells into pig blastocysts (Source: Salk Institute)
Zhang Suchun's research group at the University of Wisconsin has previously found that if the precursors of neuronal cells differentiated from human embryonic stem cells (hESCs) are implanted into newborn mice, these cells will eventually integrate into the mouse brains and respond to external stimuli. Some people think: if human stem cells are implanted into monkey embryos, the resulting monkey brain is mainly composed of human nerve cells, what should be done? What if these human cells entered the animal's reproductive system?
Even if scientists such as Nakanaka claim to be cautious and tightly controlled, there is no guarantee that human stem cells implanted in pig embryos will develop into something. As long as the research continues, the debate will follow like a shadow. In response, Pablo Ross, a researcher who published the "man-sheep" chimera experiment, said: "We understand people's ethical concerns. But conducting research alone can inject more rational insight into these concerns. "
So far, the risk of an ethical crisis in chimera studies has not been estimated, and there is no evidence to support the claim that Pandora's box was opened. Without research, thousands of lives are withering away in such a way. Recognizing the enormous potential and ethical risks of chimeric technology, the International Association for Stem Cell Research (ISSCR) recommends banning "human-animal" chimera studies that have the potential to generate human germ cells in the latest edition (2016 edition) of the Stem Cell Research and Clinical Translation Guidelines, but supports those that are reasonably regulated.
To make up for the shortage of transplantable organs, there are some scientists around the world working on mechanically driven artificial hearts, some scientists working on 3D printed organs; some scientists trying to eliminate the boundaries between pigs and humans through gene editing, and others creating chimeras. Ross said: "All of these studies are controversial and none of them are perfect. But they give hope that people waiting in hospital beds will survive. "
△ Mouse-developing heart, containing rat cells (Source: Salk Institute)
But these people may have to wait a long time. First of all, the 0.01% human cell ratio is still far from the standard of transplantability, let alone the monster that people imagine as "half-human, half-pig"; secondly, even if a functional human pancreas is produced, the clinical test to monitor the safety of the technology will take another 5 to 10 years; finally, in terms of transplanted organs, the islet islet is not complicated. Scientists still have a long way to go to create transplanted organs such as hearts and lungs.
Speaking to Vice News, Wu Jun, a scientist on Salko's research team, said: "If there is some kind of organ-generating technology that does not require animals in the future, I will naturally fully support it; but at the moment we have no other choice - people waiting for organs have no more time." "
Resources:
https://www.nature.com/articles/d41586-019-02275-3
https://theconversation.com/whats-the-benefit-in-making-human-animal-hybrids-72179
http://stanmed.stanford.edu/2018winter/caution-surrounds-research-into-growing-human-organs-in-animals.html
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