Four "Nature" published together!

Today, the top academic journal "Nature" published four blockbuster papers online, depicting a thumbnail of human embryonic development
.

By tracking mutations in somatic cells, we can finally reshape the family tree of these cells and write a family history for them

A review article in the journal Nature pointed out that this discovery not only provides insights into the dynamic development of cells, but also allows us to rethink the genetic mechanism of cancer, which is expected to change our understanding of cancer!

The common point of these four papers is to use the somatic cell mutation as a marker to trace the ancestor of the cell, thereby reconstructing the development history of the cell
.

We know that cells will accumulate mutations randomly during normal growth

Therefore, cells growing in different organs and parts will have different types of mutations.
These mutations are like fingerprints, telling their unique stories
.

By sequencing these cells and sorting out the mutation information, we can sort out the history of the ancestors of these cells dividing and reproducing from generation to generation

In the first two papers, the researchers extracted corresponding cells from different tissues of recently deceased adults, and constructed a family history of the cells based on somatic mutations
.

When tracing back to the original "separation" point, they found that the effects of these two cell branches on human tissues are not equal, but can be quite different

The review article in "Nature" pointed out that this finding is consistent with the results of past research and shows that cell fate has a certain degree of randomness in the early developmental stage
.

▲Schematic diagram of the first two studies (picture source: reference [1]; Credit: "Nature")

These two studies also revealed some interesting findings.
For example, after three rounds of division of a fertilized egg, only about three of the first eight cells formed will be used to produce embryos, and most of the remaining cells will form embryos.
Peripheral tissues, such as the placenta
.

In addition, the researchers also found that in the early embryonic development process, somatic cells accumulate mutations at a rapid rate-in the first few rounds of embryonic cell division, an average of 2.
4 mutations per generation of cell division
.

This mutation rate will not drop until the cell's DNA repair mechanism gradually matures

In the third and fourth papers, the researchers isolated some cells from different organs and analyzed the richness and diversity of mutations
.

One of the studies found that whether an organ renews itself has a great impact on the composition of cells

In addition, these two papers also found that mutations in different organs and tissues may have completely different sources
.

For example, most of the mutations in intestinal cells come from cell division itself, while the mutations in the liver are affected by external toxins

It is worth mentioning that although most of the mutations in these somatic cells are neutral, some mutations can greatly change the behavior of the cells and drive their growth
.

However, how much impact these cells can ultimately cause is additionally limited by other factors

▲Schematic diagram of the last two studies (picture source: reference [1]; Credit: "Nature")

The review article of "Nature" pointed out that these four papers revealed the powerful power of modern genetics in analyzing cell dynamics
.
Similar studies on a larger scale will allow us to understand how organs are formed, and also allow us to understand how different mutations can cause disease
.
Perhaps the root causes of many diseases have already been planted in the embryonic period
.

In addition, these findings also help us better understand cancer
.
In fact, before these few studies, scientists have realized that there are many mutations in healthy tissues, even mutations related to cancer, but these mutations do not always drive the occurrence of cancer
.
The researchers pointed out that this may just be because these mutations are inherited by cancer cells from healthy cells, and it does not mean that they actually cause cancer
.

One of these four studies today also found that in the esophagus and rectum, there are certain tissues with at least three "carcinogenic mutations
.
" Coincidentally, some early studies also found that there are up to three mutations that drive cancer in the healthy respiratory cells of smokers
.
The “Nature” review article mentioned that considering the small number of samples collected in these studies, if it is easy to find cells with three mutations, it is not difficult to find cells with four or five "driver mutations".
, And this is the average number of key mutations that ordinary cancer cells carry
.

If this is the case, does it mean that many healthy cells already have a genetic basis for cancer, but they have not really caused cancer? If so many cancer-causing mutations did not cause cancer, what caused the cancer? Or, cancer not only depends on whether there are mutations, but also on the environment in which these mutant cells are located?

Obviously, without a clear comparison, it is difficult to get accurate answers to these questions
.
Only by combining factors such as different ages, medical history, and living habits to obtain more genomic information of healthy tissues can we better understand the key to cancer
.
Hope that this day is no longer far away from us
.

Reference materials:

[1] Mutation fingerprints encode cellular histories, Retrieved August 25, 2021, from https:// Coorens, THH, Moore, L.
, Robinson, PS et al.
Extensive phylogenies of human development inferred from somatic mutations.
Nature (2021).
https://doi.
org/10.
1038/s41586-021-03790-y

[3] Park, S.
, Mali, NM, Kim, R.
et al.
Clonal dynamics in early human embryogenesis inferred from somatic mutation.
Nature (2021).
https://doi.
org/10.
1038/s41586-021-03786 -8

[4] Li, R.
, Di, L.
, Li, J.
et al.
A body map of somatic mutagenesis in morphologically normal human tissues.
Nature (2021).
https://doi.
org/10.
1038/s41586-021 -03836-1

[5] Moore, L.
, Cagan, A.
, Coorens, THH et al.
The mutational landscape of human somatic and germline cells.
Nature (2021).
https://doi.
org/10.
1038/s41586-021-03822- 7