According to US media reports, the University of Maryland School of Medicine released a message on its official website on March 9 that the first patient in human history to transplant a gene-edited pig heart died on March 8. The patient underwent a swine heart transplant on 7 January, about two months after he underwent surgery.
Although it is only a short period of two months, it is already very shocking, and for many people, life is not calculated in years, but in minutes or even seconds. In this case, it is simply incredible to give a person who dies immediately 2 months.
So what exactly caused the death? Visual inspection is a problem of immune rejection, which has also been observed in our trials. However, in the end, we still have to wait for the next anatomy and the results of the paper, and there may be new discoveries at that time. Today, I will talk to you about the problem of immune rejection and the knowledge of gene editing.
01, immune rejection problems
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To simply understand immune rejection, the common problem is the problem of histocompatibility antigens, that is, the problem of the body recognizing dissidents.
But for an organ, this recognition is very broad.
In the case of the heart, many people simply think that the heart is only responsible for beating and pumping blood. But in fact, as an organ, it has hundreds of billions to trillions of cells, and it has been metabolizing itself.
We take the common mice in the clinic as an example, and the mouse database MGI (Mouse Genome Informatics) is one of the most comprehensive databases, recording a variety of data.
Just one myocardial system, probably encompassing so many tissues. The tissues inside also have a variety of genes expressed in real time, which are eventually summarized and estimated to be thousands of proteins.
Humans still reject the same kind of protein, not to mention the heterogeneous proteins that enter the bloodstream all the time. As a result, the human body continues to repel. Although we can use immunosuppressants, this thing is not only expensive, the key is that it is not all-powerful.
As a result, over time, immunity continued to kill the pig heart until it was killed. No way, immunity is so mechanical.
02, Gene editing
In fact, the biggest highlight of this pig xenotransplantation is actually: gene editing.
For example, in 2020, a pig gene editing study was published in Nature Biomedical Engineering.
Using a combination of CRISPR-Cas9 and transposon technology, a total of 13 genes were modified, the immune and coagulation incompatibilities between pigs and humans were modified, and the endogenous retrovirus (PERV) of pigs was completely eliminated. The following two issues are explained here
1, the number of genes is a very important word
Although you may think that gene editing has been changing rapidly, in fact, in reality, there are many problems, typical of which are marginal efficiency and cell survival.
And multiple genes editing at the same time, it is even more difficult, such as ABCD editing at the same time, there will be ABCD\ABC\ACD\ABD\BCD\AD... And so on, a series of combinations, screening is difficult.
How many edits? This can cause chromosomes to be very fragile, which is also a common problem in engineering.
2. The question of which genes to edit.
This problem is actually more troublesome, the pig genome and human genome is basically the same, more than 20,000 genes, in the end which to change, everyone is also discussing.
The longest list I've seen so far is in the hundreds. Everyone is also taking stock of their experiences.
At present, it is generally necessary to edit GGTA1, which is responsible for ultra-acute immune rejection.
But on this basis, there is controversy. For example, perv, at least I understand that there is currently a domestic controversy, on the one hand, Yang Luhan and Church they think it is necessary to knock perv, on the other hand, another group of domestic pig organ transplants think that perv is actually not harmful as observed, and excessive knockout may lead to genomic problems.
03, the problem of gene editing
On this basis, there are two major categories.
1. Immunization-related
It is easy for everyone to understand, such as the complement gene CD series, etc., after all, immunity is directly related.
Second, functional genes
We don't want to transplant a pure pig organ that can't express the protein that people need, and it doesn't make sense.
And further down, there is a more troublesome problem: the more genes are edited, the more the organ will face the rejection of the pig itself, which is embarrassing.
Because, we first have to let the organ survive in the pig, and then we can transplant it to the human.
So now everyone is also discussing, in the end, what degree of editing is good.
But either way, I think that's a good direction.