Exploring Artificial Sperm Ovum: When Skin Cells Can Become Germ Cells

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[Netease Smart News August 9 news] Let us call him BD, this is his wife in her infertility blog Shooting Blanks call him.

A few years ago, at the age of 36, he learned that he could not produce sperm, which meant that his body had no sperm at all.

In a recent telephone interview, I could hear the voice of his wife in the background.

She is 35 years old this year and is now facing a terrible countdown to what she described as "the life without sons and daughters." She wrote in her blog: "I can't live without children. It's impossible."

So far, BD's infertility has proved to be unreliable, despite taking drugs and vitamins for many years and undergoing a major operation.

However, he may still have a chance to become a father!

In 2012, BD went to Stanford University, where a technician performed a skin perforation surgery and removed a small piece of tissue from his shoulder. With a technique called "reprogramming," his skin cells are transformed into stem cells, which are likely to develop into various types of human cells. Then these cells were transplanted into the testes of rats. Will stem cells grow and develop in this environment and eventually form sperm? Two years later, scientists announced that they had found evidence of primitive human germ cells. This major discovery became a national news story.

"I heard this news on American Public Radio. I was thinking, 'Damn, isn't that talking to me?' BD recalled.

This experiment attempts to convert ordinary cells obtained from adults into functional germ cells, sperm or egg cells. No one has yet done this, but scientists say they are very likely to prove that this is possible. If they can develop a technology to make eggs and sperm in the lab, they can end many people's infertility problems. However, this technological progress has also caused deep anxiety and turmoil, because the technology can simplify the gestation process of life to be completed in the laboratory.

"I don't think that such things as in vitro fertilization are terrible." I saw a group of people (because of infertility) enduring pain.

This is part of a study of how cells determine their own destiny.

Become a neuron or a beating heart cell?

From the moment the egg is fertilized, new life forms, and a series of biochemical signals guide the fertilized egg to divide, grow, and develop toward different functions. The first goal of biologists studying life development is to understand each step and copy these steps into the laboratory if possible.

Moreover, cells cultivated in any laboratory have no greater impact on the scientific community and society than sperm and eggs. Recreating these can enable scientists to understand how the bonds of life are formed.

"What's more interesting than this? It's amazing," said Renee Reijo Pera, a scientist in charge of studying BD cells. “I know that some scientists are studying how life on earth started, or people who are committed to finding the boundaries of the universe.” But I don’t think these studies are more valuable than researching sperm and egg combinations because the latter can Create a human. And, for the most part, people have two arms and two legs. "This precision is amazing."

The development of "germ cells" has been accelerating. In Japan, scientists cultivate mice by using eggs grown from tail cells. Chinese scientists later claimed that they had determined the exact molecular signal sequence needed to make mouse sperm.

So far, the exact biochemical formulas that have prompted stem cells to develop into healthy eggs or sperm have not yet been solved. There is no successful precedent for the successful transformation of human skin cells into germ cells. However, many scientists believe that this is only a matter of time, and it may take only one or two years for them to find the right way. Recent developments are "very clear and shocking." George 燚aley said that he is a stem cell biologist who recently became dean of Harvard Medical School.

Researchers use CRISPR (Gene Editing Technology) to correct an embryonic gene that causes sudden heart failure.

Because the research controls the basic units of the reproductive process, this work attracted the attention of entrepreneurs, legal experts, bioethics scientists, and in vitro fertilization experts.

Some people believe that artificial insemination may be the greatest improvement since 1977 when humans first tried in vitro fertilization. Millions of people are unable to give birth because of cancer, accidents, age, or genetic factors. "You would think that if you have skin, that is if you are still alive, as long as you do this, you can have sperm," BD said.

But this technology may have destructive social consequences, and women may choose to have children regardless of their age. As long as there is a small piece of skin, it will turn into an egg.

If you can produce eggs and sperm in the lab, why not breed dozens of them, and then test them to select the seed players who have the lowest risk of disease or high IQ? Henry燝reely, one of the most influential bioethics thinkers in the United States, and a member of the Stanford Law School, believes that this kind of thing is very likely to happen.

Last year, in a book entitled The End of Sex, he predicted that by 2040, half of couples will cease natural reproduction and instead rely on the synthesis of skin or blood to breed life. .

Others said that laboratory-produced germ cells may be genetically engineered to eliminate disease risk. There are more possible opportunities coming soon. For example, scientists believe that it is possible to make eggs from male skin cells and obtain sperm from female skin cells, although the latter is more difficult because women lack the Y chromosome.

This process, known as "sexual reversal" (Sex燫eversal), can theoretically allow two people of the same sex to give birth to offspring. In addition, Greely also defines the concept of "sole parents": one uses his own sperm and eggs and has his own children. "These odd possibilities have become the main content of the latest progress in this area."

The BD recently heard a "Society Overview" program (All candle hings hot onsidered, NPR radio's one-stage show) discusses stealing a hair from George Clooney and then establishing a "Hollywood sperm bank." The possibility. Reijo燩ero, who currently serves as vice president of research at Montana State University, believes this speculation is misleading and harmful. "I don't think that such things as in vitro fertilization are terrible." "I saw a group of people suffering from infertility," she said. She believes that if people do not have other ways, they will not choose to choose a "laboratory baby." She said: "I think these remarks will make those who are unable to bear children feel sad."

“Because those people who have a healthy reproductive function do what they do, my thoughts may be naive, but I think the only way to have a healthy child is to get two people together and enjoy dinner and wine together,” she said. .

Reprogramming cells

In a postdoctoral researcher in the 1990s, Reijo Pera helped determine the genes that led to the complete loss of male sperm. A gene called DAZ that causes sperm loss is particularly interesting because it exists only in primates. This means that in addition to our fingers and intelligence, we also have some unique characteristics in reproduction.

The problem facing scientists is that many of these details are hidden from view. Scientists were allowed to incubate embryos in the laboratory for 14 days to study them. After this there will be a crucial period during which a small fraction of the cells (about 40) of the embryos begin their development towards the "genital ridge," and they will gradually develop into the ovaries or testes. During this journey, germ cells gained the ability to form a new life, and the mechanism of this process has not been uncovered.

For exploring this process, Reijo燩ero is also influenced by some personal emotions.

Early in her career, she was diagnosed with ovarian cancer, a rare, granular cell tumor. This disease makes her infertile. People would say, "Oh ok, adoption is easy, there are other options," she said. "I began to worry that in health care, the issue of infertility will become less respected."

She and her husband finally decided to adopt a Guatemalan child.

In 2006, she was studying Spanish and told Newsweek that she would be named the 20 most influential women in the United States. She will be a mother. However, Guatemala later no longer allowed foreigners to adopt children. At that time, she was 49 years old. "So we decided that we want to create a life. We both have a dog named Boo." "That's what we do," she said.

Although she abandoned her motherhood, she did not shelve this scientific issue. Instead, she seized the ultimate solution to possible infertility.

In 2006, a Japanese scientist named Shinya燳amanaka reported that he came up with a formula that could convert any adult cells, including skin and blood cells, into so-called induced pluripotent stem cells.

These cells, abbreviated as iPS, have similar symptoms of molecular memory loss. Like cells found in newly formed human embryos, they have no fixed identity but can become bone, fat, or any other part of the body's tissues.

It turns out that this technology is very simple and easy to use. Some people compare it to the collapse of a biological Berlin wall.

Just six years later, Yamanaka quickly won the Nobel Prize. While developing research on iPS cells, he also solved an ethical dispute. He found a way to explore the early stages of human development without fertilizing the embryo in a test tube. More importantly, iPS cells come from specific people. This means that the resulting cells will exactly match the patient. Scientists began to discuss how to create "personalized" neurons or heart cells for transplant surgery.

Reijo燩ero is one of those who understand the importance of genetically homogenized stem cells for the reproductive process. How else can you get a biologically related child through skin cells? However, although it was so straightforward to use Yamanaka's method to reshape cells, the development of these cells in an established trajectory proved to be challenging. Scientists still don't know what kind of chemicals are causing a cell to develop into a neuron, not part of a toenail.

The precise composition of matter required to guide cell growth and its development has become the biologically most vexing puzzle.

In June of this year, 3,900 developmental biologists, biotechnology executives and doctors gathered at a large conference center in Boston to attend the 15th International Stem Cell Research Society annual meeting. Yamanaka attended the meeting and he followed the staff of the Japanese TV station. Many of the participating scientists are working to create specific types of cells. One of the Harvard University professors said that he spent more than a decade to determine how to convert stem cells into pancreatic cells that respond to insulin, which he managed to achieve in 2014. He has two children with diabetes and he hopes to eventually cure them through cell transplantation. "We want to fully control the development of cells," Meloton told participants at the conference.

Life's "formula"

During the meeting, I tracked two Japanese scientists. Last November reported that they had turned mouse tail cells into iPS cells and then became eggs. This is a noteworthy development. For the first time in human history, artificial eggs have been created outside of animals. They used a synthetic egg to grow eight pups. These mice are not only healthy, but they can continue to reproduce. This discovery took more than five years to complete, and published a 17-page research report in the journal Nature.

Yamanaka called Saitou "genius."

The current goal of the two scientists is to allow human germ cells to reproduce in the same way. Saitou told me that Yamanaka personally guided him and told him how to generate human germ cells. “He personally asked me.” He thinks we should do this because it is very interesting scientific research,” he said. “We really want to know why these cells can become a new individual. ”

This is the ultimate way to control cell fate.

The team led by Yamanaka has been working hard to prove the practical use of "iPS cells": The discovery of treatments from the Nobel Prize in Japan has become an important national task. In 2014, Japanese researchers conducted the first test of cells generated by iPS for the treatment of blindness. However, Saitou said artificial breeding of germ cells has not yet been put on the agenda. "It's not just a lower priority in our task list, but it's on our task list with the headquarters." "It can't even compare to alternative cell therapy," he said. "I think it's hard to make humans out of in vitro cultured germ cells." But it's not impossible.

This is not only technically difficult: He is also nervous about some moral issues. He received letters from many infertile couples. However, in Japan, current research guidelines prohibit scientists from attempting to use such cells to make embryos. The Japanese cabinet is considering whether to relax control.

Technical obstacles may be overcome before legal issues are resolved. This is because there is already a race to perfect the laboratory method of making human eggs. This makes Saitou feel very uneasy. Saitou admits that he is now engaged in a "not so happy" competition with his former mentor, Azim University of Cambridge. They all want to be the first research team to make breakthroughs in this field. His former student, now Hayashi at Kyushu University, also participated in the competition. If any of them succeeds, other researchers may not hesitate to apply this result to IVF/IV.

When I asked how long it would take for a younger Japanese scientist, Hayashi, to learn how to make human germ cells, his answer was 10-20 years. "This is the most difficult problem because I'm experimenting, and it's not easy to do these experiments." He said: "I don't want to lie to you for as long as five years. Because after five years (if not) someone May blame me."

Scientists have been able to induce iPS cells to form primitive germ cells, just as BD tissues are grown in mice. What has not yet been resolved is how to convert these cells into normal sperm or eggs. In humans, this process did not end completely until puberty.

The iPS cells were induced by mouse, destroying aitou and Hayashi using mock ovaries, which were cultured in mouse embryonic tissues. It is impractical to make such incubators from human embryonic cells because these embryos are difficult to obtain on their own. Instead, he believes that he also needs to make supportive tissue from iPS cells. This extra challenge may extend the experiment time.

If they can really make human eggs or sperm, scientists will encounter another obstacle. This is because the only way to prove the authenticity of these cells is to create a human infant. Now, this is a step that Japanese scientists are unwilling or not ready to consider.

On the contrary, for the final step, Hayashi and Saitou also conducted experiments on monkeys. According to Hayashi, monkeys have many similarities with humans and they can be used to prove that this technique is "safe for primates."

"What we need to prove is that we can cultivate good eggs." "We need to prove this with new life," he said.

Embryo incubation

Business interests began to spin around scientists. In my conversation with Hayashi, we talked with Hardy 燢agimoto, CEO of a Japanese biotech company called Healios, who is looking to convert iPS cells into a way to treat blindness. In addition, Kagimoto also hopes to cooperate with Hayashi to study the manufacture of human germ cells in the laboratory. He said that an international network of in vitro fertilization doctors is also very interested in this. “An important thing is happening now, but the society has not yet realized this,” he said. "Do not misunderstand what I mean - we will continue to build on our consensus."

Although he has applied for a patent for his invention, Hayashi has not been willing to join any company so far. He said that in November last year, Japanese venture capitalists asked him to make human eggs. I refused. I refused because I can't do it yet. This is mainly because it is technically very difficult," he said. "But also because there is no definitive conclusion on what kind of contribution society will make. “A survey in Japan showed that about 30% of people accepted the idea of ​​nurturing infants in the laboratory. But couples who tried to insemination but failed failed to support this idea.

Some investors see a wider range of possibilities. If the egg can be made from human iPS cells, its supply will be unlimited and may lead to the so-called "embryo breeding." Kagimoto points to a picture in Hayashi's book. This photograph was taken with a microscope. It is a dozen laboratory-grown mouse eggs floating in a drop of water.

In this case, gene sequencing can be used to examine every embryo so that people can choose the "best" - those with ideal genes, or those without bad genes, such as those with schizophrenia Disease risk gene. This is the scenario predicted by legal scholar Greely. He believes that if parents can benefit from it, they will choose to breed artificially instead of sexually. "If you have 1,000 eggs, then you can make choices," he said.

Brave New World

At the Boston Stem Cell Conference, students stood at the door listening to lectures about the ethical issues brought about by new reproductive technologies. Daley’s Consultant Cai Yuxi’s “Courageous New World,” a book published in 932, describes a society that controls childbearing and hatches children in centralized facilities. Daly said that the scene depicted by Huxley was anti-utopia, but it was also "prescient." It indicates the in vitro fertilization technique.

"We only need to speculate. How long will it take for us to be able to completely cultivate ourselves outside the palace?" So the question becomes: Can you draw a line?

Daley believes that scientific advancement has made the picture described by Huxley a reality. In addition to Japan’s efforts to research and manufacture artificial germ cells, some scientists have also created gastroidis, a self-generated cell tissue whose appearance and behavior are similar. Very similar to human embryos.

At the same time, researchers are putting pressure on nature from another direction. In February of this year, doctors in Philadelphia removed fetus lambs from their mothers and kept them alive until they were born in a transparent sac. This pocket was called artificial uterus. The combination of these technologies shows that the entire breeding process from conception to birth can be done in the laboratory. Daly said: "What people need to predict is how long it will take before we can completely create life outside the mother."

"So the question has become: Can you draw boundaries?"

Daley paid particular attention to the research progress of converting iPS cells into eggs and sperm, which he called "a subversive technique." One reason is that he believes that artificial germ cell technology is likely to be combined with gene editing technology called CRISPR. CRISPR was developed four years ago and it makes it easier to change DNA in living cells.

This links artificial germ cell technology with the "baby-designed" debate, the so-called "reproductive genetic modification" technology. The debate on this issue was ignited in 2015. Before that, Chinese scientists reported that they had used CRISPR in the laboratory's petri dish to try to remove genes that cause thalassaemia in blood diseases. The report was initially closely watched, in part because of CRISPR and guaranteeing nothing: Experiments have shown that embryos may have been imperfectly edited, which would pose an unknown risk to infants who are trained on a method.

Although some critics believe that modifying the gene pool is an ethical boundary that should not be crossed, this is not the opinion of the scientific community (see “Making Perfect Baby”).

A report released this year by the National Academy of Sciences concluded that if this technique is used to eliminate serious diseases such as Huntington's disease, then editing human embryos should be allowed.

Although the committee did object to the use of genetic engineering to make pure improvements - such as acquiring blue eyes and better intelligence - the report did not explain whether it could be used to fight disease.

Scientists are studying how to edit future children's DNA. Should they stop before everything is too late?

The report pays special attention to the artificial generation of germ cells because editing in iPS cells can be very accurate. Once perfect iPS cells are available, they can be induced to create germ cells with specific genetic modifications.

The idea of ​​using CRISPR in stem cells has been successful in mice. In China, a scientist named Jinsong燣i edited mouse stem cells and removed genes that cause cataracts. When he created the sperm and then used it to fertilize it, he produced an edited organism, which was very efficient. This result gives scientists reason to believe that as the main reason for opposing GM technology - the technology will never become reliable, nor safe - is losing its foundation.

Richard 燞ynes, a professor at the Massachusetts Institute of Technology and one of the two senior authors of the National Academy of Sciences report, said: "Now it is impossible to say that this is not feasible."

Huge demand

At the Harvard Stem Cell Institute, a test-tube baby doctor named Werner Chaneuhausser is exploring how genome sequencing, stem cells, and genome editing can work together to change the reproductive process. In a large fertility center in Boston, he spent a day each week to meet with patients. He spends four days a week to verify and try to continue the scientific research harvested in Japan and elsewhere.

As a test-tube baby doctor, he told me that he "absolutely" saw the demand for sperm produced in the laboratory, and the demand for eggs was even greater. "If this becomes possible, it will be a big event," he said.

Like Kagimoto, Neuhausser believes that embryos will be measured and quantified: "We will correct all the embryos that have a higher risk of heart disease or mental illness than the normal population. Faced with the fact that you will do What kind of choice?"

But he thinks parents may not have to make a choice. Instead, he said, parents can choose to improve their germ cells. You can sort the future parents' genomes, and then you can ask: “What are the unfavorable factors that you can improve before you give birth?” This is something we have never thought about before. This will depend largely on risk, and there are many things we do not know. ""No one wants to use it on patients in the short term. ”

He has already started studying the gene editing of germ cells in Harvard's laboratory. The team is acquiring sperm from a man with a gene that causes amyotrophic lateral sclerosis, a destructive neurological disease that the team plans to use CRISPR to eliminate.

After correcting this error in his laboratory, it will sort the sperm cells to observe the results.

But he said that a more accurate approach would be to genetically engineer iPS cells. These cells multiply and multiply in the laboratory. Once they have been edited, they can create eggs or sperm from them.

"You can get the genome; you can change the genome at will." "Of course, this is controversial," he said. "But we should definitely study whether it will work."

For men like BD, this technology for producing germ cells is what they desperately need.

He told me that once he can use this technology to help with childbirth, he will become the "first candidate."

But his wish is unlikely to be realized soon.

He said that he and his wife recently set a date, after which they would give up their efforts to have children.

And that day was September 2019.

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