I can extract side effects

"Since it has been proved that the species barrier can be broken and cell competition has failed in mice, the next step is to attack pigs."

Looking at the mouse experiment records in front of him, Huang Qin couldn't help smiling when he thought that he was about to face the piglet he was most familiar with.

Ding Mian's face was not so good-looking, he stared at the few lines of numbers on the report, and fell into deep thought.

"The overall chimerism rate under genetic modification is only 22%, which does not seem to be ideal."

Huang Qin said disapprovingly, "I'm sure. The study of heterogeneous chimeras is not as easy as everyone imagined."

"The main human stem cells do not match the development of mouse embryos. Human cells and mouse cells cannot interact well, so the survival rate is so low."

"Besides, the development speed of heterogeneous cells is inconsistent, and the developmental program is also different. Even if the overall embryo chimerism is improved, some tissues may have very low chimerism or no chimerism."

"Generally speaking, the heart, muscle, pancreas and other organs have a relatively high chimerism rate, and the content of human cells in the tissue is very high, but blood vessels, brains, limbs, and bones are quite few."

"So when it is spread out evenly, it can reach more than 20%, which is already very amazing."

"When there was cell competition before, the chimerism rate was only one in 10,000, or even one in 100,000. We have improved it by a full two thousand times, which is a qualitative leap."

"Don't you want a 100% chimerism rate, how is that possible?"

"Even the overall chimerism between rats and mice has only reached 20%-30%."

"Through complementation, their chimerism in certain organs can reach more than 90%. But that's also because rats and mice are two close species, both of which belong to rodents, and their developmental programs are relatively similar, just like humans and mice. Gorillas have the same relationship.”

"However, the evolutionary relationship between humans and mice is very far away. Normally, human cells may not receive compatible developmental signals during the development of mouse embryos."

"I know, I'm just a little disappointed with the effect of cell competition." Ding Mian said with a serious face.

"The genetic similarity between humans and mice is higher than that of pigs, so the next human-pig chimera may not have such a high number."

"What we are going to do next, in addition to testing the overall chimerism, the most important thing is the chimerism in some important organs."

"Hopefully they can also reach the satisfactory data of 90%."

Huang Qin said in surprise, "You are too optimistic."

"Even if it is complementary between mice, the only successful organ is the pancreas."

"Other organs, such as the kidney, although it has been reported that mouse stem cells can generate kidneys in rat embryos, are smaller in size than contemporaneous rat kidneys, and their function has not been fully tested."

"These all show that this field is still in the exploratory stage, and it is still far away from clinical application."

"But they didn't solve the problem of cell competition. But we did."

Ding Mian took it for granted and said: "So we will definitely be able to enter the clinic successfully, you have to have confidence in me."

Huang Qin was silent for a moment, and after a while, he said: "Then what are you going to do?"

As soon as he talked about his plan, Ding Mian immediately became excited, and his body sat upright, no longer the lazy posture before.

He seemed to have been prepared for a long time, and he confided the plan with confidence.

"From chimera research to the eventual realization of organ transplantation, generally speaking, there should be such a roadmap."

"The first is to solve the technical problem of low overall embryo chimerism rate, how to make cross-species pluripotent stem cells more effectively enter the early developing embryos of another species, and be able to participate in the early development of various organs."

"If this problem is solved, the next step is how to control it, especially to prevent human embryonic stem cells from entering organs that we don't want them to enter. This is an ethical issue, and it is also a technical issue."

"The third point is whether the function of xenochimeric organs is similar to that of human organs. This may require some transplantation experiments."

"Of course, monkeys may be used for testing in the early stage, and human organs from pigs are transplanted into monkeys and other primates. After verification, they can be applied to human clinical practice."

"The fourth and final point is to make a whole organ."

"Because even if the chimerism of some organs is as high as 90%, the resulting organ is not a complete organ. For example, some of the blood vessels, nerves and interstitial cells are still from the host."

"After these tissues enter the human body, as foreign cells, there will still be immune rejection."

Huang Qin asked curiously: "Is there no way to replace these things with human's own?"

Ding Mian shook his head unwillingly, heaved a long sigh.

"It's very difficult. Even if we knock out the genes related to the pig's kidney or pancreas, artificially create an empty niche, and then use human stem cells to fill the gap, there is no way to control the specific development process of this organ in the embryo. .”

"An important reason is that the embryos of different animals develop at different speeds. We humans, as primates, have embryos that take ten months to fully develop."

"But it only takes 3 months for pigs and 20 days for mice. Can humans catch up with this cell differentiation speed?"

"Overall, the rate at which cells differentiate, human cells are much slower than mouse, rat and pig cells."

"Not to mention the size factor, even if the mouse grows an organ composed of human cells, can you use the islets as small as soybeans for transplantation?"

"However, in terms of body size, pigs are still better. The size of their internal organs is not much different from that of humans. Moreover, the internal organs can only be used for transplantation when they grow to maturity. They can also modify the growth genes to a certain extent. Considering all aspects, they are the most suitable animals. .”

"That's why we chose pigs."

"Uh, why did you make it sound pessimistic." Huang Qin said disapprovingly, "I think it's fine, I'll learn from nature and make do with it."

Ding Mian laughed, and said: "Yes, if we can reach the fourth step, it means that we are already one step away from success."

"It's time to worry about it. The most urgent thing is to get the first three steps done."

After confirming the work plan, the two immediately lifted their spirits.

When they came to the laboratory, they took out the prepared pig embryos and injected them with genetically modified human pluripotent stem cells.

The fluorescent protein GFP was added to this batch of human pluripotent stem cells, which can track the traces of the cells and their progeny.

Subsequently, the cell culture fluids of the two were mixed together to increase the adaptability of human stem cells in pig embryos.

In this way, in the case of suppressing the competition of heterogeneous cells, human-pig chimeric embryos were finally successfully cultivated.

Since the first test is only to test the overall chimerism, from an ethical point of view, such as worrying about human cells entering the reproductive system and brain, or developing parts similar to humans.

The embryos developed in the pigs for only 3 to 4 weeks before they were terminated.

The final results showed that the human-pig chimera did not show obvious cell competition, and the overall chimerism reached 28%, which was 6 percentage points higher than that of the human-mouse chimera.

The degree of chimerism of different tissues and organs is also quite different, which is no different from that of mice.

For example, the chimerism of heart and muscle is significantly higher than that of other tissues, and the chimerism of pancreas and kidney is also higher than that of lung and liver.

From the whole embryo, there are more than 20,000 human cells in about every 100,000 pig cells.

And after testing, the human cells in the pig's liver and kidney have certain functionality.

Such a result is enough to surprise people.

If it were possible to concentrate these human cells in several locations such as the heart, lungs, liver and kidneys...

Just thinking about it, the two of them were already excited about this prospect.

"The first step is achieved, as high as 28% chimerism, which is not much different from the same species."

"The second step is to make human cells concentrate on certain organs, then we have to start making niches for the corresponding organs in pigs."

Ding Mian said with a smile, a trace of excitement could not be concealed in his voice.

Huang Qin nodded, patted his chest, and said, "Let's look at me next. Genetic modification of pig egg cells is my specialty."

"Heart, kidney, liver, pancreas, let's start with these four."

Ding Mian pondered and said: "Make a batch of pig egg cells, about 100, in a group of 20, each of the four groups knocks out the gene related to an organ to create a niche."

"The remaining group does not move, and it is kept as a control group."

"Five days after fertilization, blastocysts will be formed, then injected with human pluripotent stem cells, and then put into sows for development."

"Wait for 3 to 4 weeks, you can observe the early development of the embryo, and you can know whether it will succeed or not."

"Understood." Huang Qin responded without saying much. The people in his department are experienced and able to do this kind of work with ease, so there is no need to tell too many details.

The first batch of samples is just to test whether this method is useful and to what extent it can be achieved.

If it succeeds, that is of course very good. If it fails, it is also due to learn from experience and lessons, and continue to make a batch.

There are not so many scientific researches that can be achieved overnight. It is only through continuous failure, summarization and continuous progress that we can reach the end.

Human-pig chimera embryos like this one have a long development period, and the chances of them growing up smoothly are not too high. He is mentally prepared to inject thousands of pig blastocysts.

However, the experimental results greatly exceeded his expectations.

Of the 80 chimeric embryos that made organ niches, only half aborted.

Of the remaining 40 human-pig chimeras born alive from sows, another third died within 1 week.

In the end, about 20 piglets lived for a month and were identified as human-pig chimeras through PCR sequence inspection.

"The first batch of samples had a 25% survival rate, which is really surprising."

Seeing this result, Huang Qin couldn't help being overjoyed.

Ding Mian raised his eyebrows, stood in front of the cage, looked at the lively little piglet inside, and couldn't help being moved by it.

These piglets look the same as normal pigs on the outside, but there are human hearts beating one by one inside, or human kidneys are on dialysis, or human livers are detoxifying.

It is the mediocrity of this appearance that forms a stark contrast with the miracle that happened under the skin, which makes people amazed.

"This is the miracle of life, and it's not what I want."

He muttered to himself: "Is the xenotransplantation finally going to be successful?"

"Am I the one destined to accomplish this great mission?"

When Huang Qin heard this, his face darkened immediately, he turned his head, and kindly reminded: "Brother, don't forget, there is me, Xiao Huang."

"Haha, I'll just say it casually." Ding Mian laughed, avoiding the other party's gaze with a guilty conscience.

Not long after, the results of the internal organ biopsy of the chimera came out.

Almost all of the 20 piglets have produced a human organ, but the degree of chimerism of the organs generated in each pig is different, which is related to their individual development.

The chimerism of human organs in some pigs is as high as 92%, while in others it is only over 80%.

The lowest is about 79%, which is also a very impressive figure.

In addition, traces of human cells also appeared in other tissues of these piglets, but the number was not large, about one in ten thousand.

Overall, the scheme to artificially create organ niches to grow human organs has been very successful.

"By the way, I forgot to tell you." Huang Qin patted his head and reminded: "It's been a month now, and we can do primate transplants on macaques or baboons in about two months."

"Because some organs, pigs are bigger than monkeys, so pigs can't grow too big. Young pigs around 2 months old are the most suitable."

"Let's test the function of the transplanted organ. If it can be used normally, it means that the research has entered the third step."

"Yes." Ding Mian nodded, observed Huang Qin's face, and couldn't help joking.

"Why, before you saw human cells in mice, you felt horrified, but you didn't react when you saw pigs grow human organs."

Huang Qin smiled innocently and said, "Don't they all say that I think too much?"

"Actually, you are right. We are all biologists. We should understand that everyone is an independent body of consciousness composed of cells. From a macro perspective, everyone is unique."

"But microscopically speaking, the human body is also a group of co-evolved and co-developed cell communities. The human-pig chimera is no more weird and disgusting than the symbiotic bacteria all over our intestines."

"Having realized this, I've become comfortable with any human-animal chimera."

"Of course," he paused, and added: "My cells and genes must never appear in any animals such as mice, pigs, and cows. Anyway, I can't bear it."

Ding Mian was speechless for a moment: "You are good at double standards. You are very frank and straightforward, which is simply typical."

"There is a classic famous saying by a celebrity, how do you say it?" Huang Qin said with a big smile.

"Engineers have an instinct to build, biologists have an instinct to cultivate."

"Humans, on the other hand, have a double-standard instinct! Hahaha~"

Ding Mian's eyes became confused: "Which celebrity said this? Why haven't I heard of it?"

Huang Qin patted his chest and said loudly, "Of course I, Huang, said it."

"We have achieved organ xenotransplantation. I, Huang, will definitely enter the hall of human science and become a great scientist, leaving a name in history."

"What I say is naturally a famous saying." (End of this chapter)