Stem cell research opens up the second battlefield to clone sheep.

The leap from sheep to monkey

Without the two papers published on November 20th, Shaukolet Mitalipov (ShoukhratMitalipov) would have been the most high-profile stem cell research scientist during this period.

On November 14, the scientist at the National Primate Research Center in Oregon published a paper in the journal Nature, announcing that he had successfully obtained a cloned embryo of a rhesus monkey. this is the first time scientists have cloned viable embryos from primates. Of course, in 2004, Hwang Woo-suk of South Korea announced that his research team had obtained the first cloned human embryo, but as was later known, the result was bogus. The study of primate embryo cloning is still a big problem, which is different from cattle and sheep cloning, according to many scientists.

Mitalipov's work is outstanding. He used traditional somatic nuclear transfer techniques to transplant skin cells from rhesus monkeys into eggs and grow them into embryos from which embryonic stem cells were extracted. This is not much different from the technique used by the British to create Dolly Sheep in 1996, but Mitalipov improved some steps to make it possible in monkeys (although the success rate is still not high).

After 11 years, stem cell research scientists have finally struggled to make the leap from sheep to monkeys, making people realize that human embryo cloning technology may be on the horizon. It is of great significance to extract totipotent embryonic stem cells from cloned embryos for the treatment of some major diseases such as Alzheimer's disease. But inevitably, a new round of ethical debate about human cloning has begun.

Landmark progress

Only a week later, however, the arguments shrunk to one side like poked balloons. On November 20th, ShinyaYamanaka of Kyoto University in Japan and James JamesThomson of the University of Wisconsin in the United States published heavyweight papers in Cell and Science, respectively, announcing that they had genetically modified human somatic cells into embryonic stem cells, which are almost comparable to embryonic stem cells in function.

This similar result is obtained in both laboratories at the same time, and the possibility of fraud is of course extremely small. It can be said that the field of stem cell research suddenly has a new way to obtain embryonic stem cells: there is no need to use human eggs, no need to grow human embryos and destroy them, let alone to make mixed human and animal cells. All previous ethical debates can go down, which is undoubtedly a landmark development.

After hearing the news, Ian Wilmot, a professor at the University of Edinburgh in Scotland and the father of Dolly Sheep, immediately announced that he would give up using somatic nuclear transfer technology to study embryonic stem cells. He believes that the new method is the key to the treatment of difficult diseases in the future.

Robert Lanza (RobertLanza), chief scientist at Advanced Cell Technology, praised the work as "biologically equivalent to the Wright brothers' maiden flight".

Face multiple obstacles

Perhaps the happiest person to this breakthrough is US President Bush. For more than six years, although he has been criticized, Bush has consistently opposed human embryonic stem cell research, arguing that the process of obtaining embryonic stem cells will involve "creating" and "killing" life. Bush used his veto to ban federal funding for embryonic stem cell research, and then made a slight concession in 2001, agreeing that scientists could use federal funding to study pre-existing human embryonic stem cell lines. Bush firmly believes that one day scientists will find a way to obtain embryonic stem cells without destroying embryos, and now this sentence has finally come true.

However, it is because of multiple obstacles that embryonic stem cell research has been slow. On the one hand, it is difficult for scientists to apply for a large number of funds to study human embryonic stem cells, and on the other hand, because the success rate of this research is not high, it requires a large number of human eggs, so the research cost is huge. While these difficulties hinder the progress of stem cell research, they also force scientists to start thinking differently.

One way is to let animals replace humans as "cloned Trojans".

Esmael Zagani, a professor at the University of Nevada, has worked for years to grow human cells in sheep embryos. He injected human bone marrow stem cells into sheep embryos and obtained sheep with up to 15 per cent of human cells. Through this method, it is possible to use sheep to cultivate human organs and overcome the problem of organ transplant rejection. However, opponents are strongly skeptical, and the prospect of mixing people with sheep is also frightening. In addition, many researchers transplant human somatic cells into the eggs of animals (such as rabbits and sheep), and use some factors in animal eggs to reprogram human somatic nuclei and cultivate embryos. However, human-animal mixed cells are also difficult to be accepted by people, and there are also a lot of technical problems.

Open up the second battlefield

Shinya Yamanaka and Thomson's method can be said to be another way.

Somatic cells are a kind of cells that have differentiated into mature cells, which is equivalent to a fixed fate. However, Shinya Yamanaka and Thomson used retrovirus as a vector to transfer four key genes with different functions into somatic cells, recombining them with the original genes, and unexpectedly allowed somatic cells to return to the "origin of life." become a multi-functional stem cell with the characteristics of embryonic stem cells. These cells, known as inducible pluripotent stem cells (iPS), are like amnesia, forgetting their previous identity and starting from scratch.

This method seems amazingly simple, but even a year ago no one dared to say it would be successful.

The dawn first appeared in August 2006. At that time, Shinya Yamanaka first reported that his team introduced four transcription factor genes into mouse tail tip fibroblasts using a modified retrovirus as a "transport vehicle". The new "skin cells" thus obtained have the characteristics of stem cells-they can differentiate into other types of cells. However, they are still quite different from embryonic stem cells and cannot be cultured into mouse embryos. However, this is a very important first step to break the "superstition" of embryonic stem cells. Many people think this is the maiden flight of Stem Cell Wright.

The publication of this paper directly spawned an "arms race" in the field of stem cell research. The first reaction of many scientists was "how is this possible?" and some large laboratories immediately began to work on it.

In June 2007, Shinya Yamanaka's laboratory and Harvard Stem Cell Institute, Whitehead Biomedical Research Institute and other institutions have published further research work. This time, the scientists still used these four genes, but they obtained truly pluripotent stem cells and were able to enter the germline-- these skin cells were implanted into early fetal mice, and they could develop like real embryonic stem cells. participate in the formation of various parts of the body of fetal mice. It can be said that the conditions have come naturally.

Then there are these two new papers more than four months later. Shinya Yamanaka extracted cells from the facial skin of a 36-year-old woman and the connective tissue of a 69-year-old man, while Thomson chose fetal skin cells and a newborn foreskin cell. However, in this "research rush", Thomson's team has the upper hand, because Shinya Yamanaka's group still uses the first four genes (Oct3/4,Sox2,c-Myc and Klf4), while Thomson chooses two different genes (Oct4,Sox2,Nanog and Lin28). These genes start the cell's "rejuvenation" like a switch, but c-Myc is a shoddy switch. Its introduction may bring side effects such as cancer.

Yu Junying's contribution

The fierce research crash has strained the scientists involved in the competition. Yu Junying says she has worked in the laboratory for more than ten hours a day for the last two years, often giving up holidays. Yu, from Zhuji, Zhejiang, China, graduated from the Department of Biology of Peking University in 1997 and went to the University of Pennsylvania to study for his doctorate in the same year. She joined Thomson's lab in 2003 and is currently working as an assistant researcher in the lab.

Yu Junying is the first author and co-correspondent of the paper published by Thomson's team in Science, which also shows that she is responsible for the main work of the experiment. At the time, she wrote in an email, "I independently came up with the idea of an experiment, which is a very heavy workload project, and I think it is the only way to study the problem of reprogramming." I didn't expect anyone to do the same work on mice. Because the experimental research cycle of mice is shorter and the method is relatively simple, the Japanese research team was able to take the lead, but fortunately we did not lag behind in the study of human cells.

Yu Junying finally finished this part of the work in July this year. She was very excited, but the first celebration she thought of was to go home and get a good night's sleep. Yu Junying hopes to have time to read books, watch TV and go to nearby Milwaukee to watch Yi Jianlian's game. But biological research is so competitive and time-consuming that she will immediately devote herself to the next stage of research.

A new starting point

But the new findings are not perfect. The success rate of stem cell transformation is very low, and due to the use of retrovirus as a gene vector, it will cause the activity of oncogenes. Twenty percent of the mice bred at Kyoto University developed tumors, which could also cause cancer if applied to humans.

Yu Junying also told Southern Weekly that improving the method of gene transfer is the focus of the next step, and further proof of the similarity between induced pluripotent stem cells and embryonic stem cells is needed. However, she believes that there is "little difference in clinical application" between the two. "induced pluripotent stem cells should be able to completely replace embryonic stem cells."

Yu Junying believes that "the application of this technology in the medical field is still in its infancy". For organ transplantation, "the current methods only solve the problem of immune rejection". The remaining problems are the same as those faced by embryonic stem cell research, so it is too early to discuss the use of these stem cells to grow human organs and carry out transplantation. The first step will be applied in the drug testing of some disease models.

But this achievement will be a new starting point in the field of stem cell research. Next, many laboratories will use this as a basis to carry out more breakthrough research. Once the related technical problems are solved, the traditional human embryo cloning technology will be "no longer necessary" because of its ethical problems and its high cost.