godfather of surgery

Chapter 1091: Liberating Thoughts
This experimental pig not only needs to undergo PET-CT, but also various blood tests. Various indicators are dynamically monitored. Although the time intervals between each test are different, they all need to be checked at intervals. Collecting experimental data is a boring job, and researchers must be able to endure looking for valuable clues from boring data.

Judging from the results of several subsequent examinations, the experimental results are not optimistic. NK cells still cannot avoid the fatal weakness of cell therapy, even if the K factor is embedded. After all, no matter what is embedded, it does not change its nature as an immune cell, and it still cannot penetrate into solid tumors in large quantities.

In response to this unoptimistic interim result, everyone gathered together to discuss, accumulate experience and learn lessons for the next experiment, and then make some modifications. The experimental route gradually became correct through such modifications.

Instead of being discouraged, everyone was full of passion. This is the basic quality that a researcher should possess. Real scientific researchers need to spend decades or even a lifetime immersed in the laboratory. Sometimes they spend their entire lives doing nothing without any valuable breakthroughs, or they may only publish a few meaningless papers.

“Our NK cells encounter the same limitations as CAR-T cells. Although they can express receptors for recognizing specific tumor markers and thus treat blood tumors, it is difficult for them to penetrate tumor tissue through the blood system. In addition, due to the lack of expression of chemokines involved in the infiltration of T cells into tumor tissue and the presence of dense fibrotic matrix in solid tumors, their ability to migrate and invade tumor cells is very low, so the therapeutic effect is destined to be not very good.” Tang Shun leaned over to start the discussion. He had to admit that this experiment did not make any breakthroughs.

Lu Xiaolu held the experimental data in his hand. These pages had been wrinkled by his repeated reading. "Yes, this is a difficult point. We must overcome this difficulty before we can move forward. There is a method of injecting CAR-T cells directly into the tumor, but I think this method is meaningless. Local injection of cells may also reduce the risk of off-target effects. However, many solid tumors are metastatic, and local injection faces the same difficulties as surgery. It is impossible to accurately and thoroughly remove the tumor. In other words, local injection cannot be expected to use immune cells as a scalpel, and it is doomed to be difficult to succeed. There are also chemokines that mediate the transport of CAR-T cells and enhance the localization of tumors. For example, the expression of CSF-1R factor in CAR-T cells makes these cells respond to CSF-1, which enhances the signal transduction of CAR-T cell proliferation without affecting the cell's killing toxicity. However, in experiments, this method is also far from arbitrary."

Yang Ping thought what he said made sense. He pondered his thoughts and said, "While promoting tumor growth and proliferation, the tumor microenvironment of solid tumors can cause immunosuppression on immune cells, including immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, growth factors produced in solid tumors, local cytokines, immune checkpoint molecules such as CTLA-4 and PD-1, etc. The tumor microenvironment under these complex environments will greatly limit the efficacy of immune cells. Both genetically recombinant T cells and NK cells face this problem. There are two ways to solve this problem. Either jump out of the framework of cells and use running viruses to solve the problem, or improve immune cells so that they can break through the blockade of the tumor microenvironment. This brings us back to our starting point - the fatal flaws of both carrier viruses and immune cells."

"Some researchers in the United States use Gr-1 antibodies produced by genetic engineering to deplete myeloid-derived suppressor cells, thereby improving the tumor-killing effect; some researchers also construct secreted ECM degrading enzymes, which can dissolve barriers and help immune cells break down the physical barriers in solid tumors. However, these technologies have been developed for so many years, and I have not seen any substantial breakthroughs." Li Yingtong was very familiar with these cutting-edge technologies in the United States when she worked in the Whitehead Laboratory at MIT.

This is indeed a difficult problem. If it weren't a difficult problem, there would not be a need for so many laboratories and so many top talents working together to solve it, and Yang Ping would not have spent so much money. Yang Ping has never thought of solving this problem easily, as that is unrealistic.

The results of the first experiment were not ideal, but this was just a beginning. Through this experiment, we mastered the entire technology of NK cell therapy and also knew how to improve it later. Originally, we did not have high expectations for the first experiment. It was definitely rough, with wrong meanings, and sometimes even completely wrong, but this did not affect our continued exploration.

"In fact, we should be more open-minded and not be limited by the existing technology. If we are restricted by the so-called cutting-edge technology in Europe and the United States, it will be difficult for us to make a breakthrough. NK cells don't work, but we can use macrophages. Macrophages have good penetrating power. If all else fails, we can use them to recombinant cells and create a new type of cell. Remember, we have now entered the real positional realm and there is no reference, so solving all problems depends on our methods." Yang Ping listened to their discussion. It was obvious that everyone was still constrained by the cutting-edge technology in Europe and the United States.

"Macrophages?" Tang Shun asked, because there is very little research in this area.

Yang Ping nodded: "Yes, macrophages also have their inherent shortcomings, but we can genetically recombine them with NK cells."

Professor Yang's ideas were always so innovative, and they always jumped out of the inherent thinking. Tang Shun, Lu Xiaolu and Li Yingtong thought about it for a long time. Indeed, this idea was very novel. "Should we follow this idea next?" Tang Shun could no longer grasp the strategic direction of this experiment.

Yang Ping said confidently: "Try more and don't be afraid of failure. We are blazing a trail in a wasteland. We can only take the first step and change the route if it doesn't work. We learn advanced technologies from Europe and the United States in order to surpass them, not to always follow and worship them. So we must have confidence. Now that we have come to this point, we are at the forefront. All problems can only be solved by ourselves."

Yang Ping's speech freed everyone's thoughts, broke the invisible authority of Europe and the United States, and established strong self-confidence, which is indispensable in independent scientific research.
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Lin Lan, who works in the genetics experiment at Nandu Medical University, is also very busy now. She has to conduct genetic sequencing on immune cells and related cytokines. To complete the sequencing work, Lin Lan needs to use single-cell sequencing technology.

As a breakthrough biotechnology, single-cell sequencing has been favored by the medical field in recent years. Through this technology, researchers can conduct life science research at the level of single cells, perform high-throughput sequencing analysis on genomes, transcriptomes, and epigenomes, and classify and annotate cell populations according to cell characteristics to draw cell maps.

The Human Cell Atlas Project was initiated by Aviv, Sarah and others in 2016. It is a large-scale international collaborative project comparable to the Human Genome Project. Its purpose is to classify and define all cell types of human individuals based on unique molecular information, and to correlate this information with traditional cytological characterizations, and to determine the unique gene expression patterns, physiological states, developmental trajectories and location information in all types of cells of an individual, thereby providing more in-depth and complex information at the cellular genetic level for the health of the entire human race.

For Lin Lan, this task is not difficult, and it is exactly what she is good at. With the support of digital human technology, Lin Lan's gene sequencing work is much simpler, because Professor He has accumulated a wealth of data on cells in this regard during the process of building digital humans. It is precisely because of this data that he can build digital cells, and then use digital cells to build digital human bodies, pushing digital humans to the level of functional digital humans. Lin Lan can use this ready-made data, so the amount of work she needs to do can be reduced by almost half.

In addition, Nandu Medical University has established close cooperation with the supercomputing center of Nandu Province. With the help of supercomputers, Lin Lan's sequencing work went very smoothly. Her first sequencing comparison work showed that there is indeed overlap between the K factor and the gene fragments of various immune cells. This result is very encouraging to everyone. It seems that Professor Yang's hypothesis seems to be correct. Of course, whether it is really correct requires completing all the sequencing and comparison work.

The current situation of Professor Zhang Zhiwei of the Department of Virology at Nandu Medical University is not optimistic either, because he has now reached a deserted place with no reference and has to rely entirely on himself to move forward.

All existing carrier viruses, no matter how advanced, cannot escape the fate of being attacked by the immune system. It is very difficult to select safe viruses as carriers that can infect all cell types and evade the immune system.

Moreover, this operating virus needs to be completely recombined and some functional fragments of immune cells need to be incorporated into it. How to recombinant it and how to control the characteristics of the recombinant virus are all difficult problems.

Professor Zhang searched all the relevant papers in the world and found that no one had done this. Even the most advanced research team was stuck on the idea of ​​oncolytic virus therapy. Now their topic is completely different from oncolytic virus therapy.