Human research on genetics began with the pea in your bowl

If you ask me which name I am most familiar with in biology textbooks, Mendel must be on the list! Whenever we mention Mendel, the father of genetics, the first thing that comes to mind is his pea experiments.

Mendel's main job was a priest in a monastery in Brno (now the second largest city in the Czech Republic). He showed interest in animal and plant genetics when he was a young student. After becoming a priest, he still paid close attention to research related to horticulture and agronomy.

Mendel

(Image source: Wikipedia)

What secrets of biology did he discover? What inspiration did Mendel's discovery bring to the development of science in later generations? What is the current progress of gene exploration?

1. Mendel and the pea experiment

From 1856 to 1863, Mendel personally planted and tested about 5,000 pea plants (22 varieties). By artificially cultivating these peas, he meticulously observed, counted and analyzed the characteristics and numbers of different generations of peas, such as tall or short stems, round or wrinkled grains, gray or white seed coats, etc., and found that certain characteristics of peas can be stably and regularly inherited to the next generation.

In his experiments, Mendel discovered the basic laws of biological inheritance and obtained the corresponding mathematical expressions. His discoveries are now known as " Mendel's First Law " (i.e. Mendel's Law of Segregation) and "Mendel's Second Law" (i.e. the Law of Independent Assortment of Genes), which are the basic laws that reveal the mysteries of biological inheritance. In 1865, Mendel summarized his observations over the years and wrote a paper titled "Experiments on Plant Hybridization".

The characteristics of peas used by Mendel in his study include the characteristics of seeds, flowers, pods, stems, etc. This experiment is also the starting point for the knowledge about genes that we learn in our junior and senior high school biology textbooks.

(Image source: Wikipedia)

However, since the scientific community at that time lacked the ideological basis for understanding Mendel's laws, this paper was not taken seriously. It was not until 1900 that de Vries from the Netherlands, Correns from Germany and Czermak from Austria independently "rediscovered" Mendel's laws of inheritance at the same time. This major scientific event in the history of science is called the rediscovery of Mendel's laws. From then on, genetics entered the Mendel era.

2. Deciphering genes and solving the secrets of life

In 1909, Danish biologist Johnson modified the term "hereditary factor" used in Mendel's paper to gene, and proposed the concepts of phenotype and genotype .

In 1952, after the infection experiment of the American bacteriophage team, DNA was determined to be the genetic material of organisms. Since then, DNA and genes have been tightly bound together. In 1958, Francis Crick first proposed the "central dogma" to explain the flow direction or transmission law of genetic information in life , so people have become more aware of the importance of genes.

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In 1990, the Human Genome Project was launched with the aim of determining the nucleotide sequence of the 3 billion base pairs contained in human chromosomes (haploids) to map the human genome and identify the genes and their sequences it contains, in order to achieve the ultimate goal of deciphering human genetic information - decoding life, thereby understanding the origin of life, the laws of growth and development, the reasons for differences between species and individuals, the mechanisms of disease, and life phenomena such as longevity and aging, providing a scientific basis for the diagnosis and treatment of diseases.

The structure of a bacteriophage and the process by which it infects a cell, first injecting DNA into the cell, then replicating the DNA inside the cell, and finally causing the cell to die.

(Image source: Wikipedia)

Seeing this, you may ask, once the human genome project is completed, can we use the gene editing technology that has been very popular in recent years to artificially modify genes? For example, if we change the gene that controls single eyelids into a double eyelid gene, then people who like double eyelids will no longer need double eyelid tape or go through the trouble of plastic surgery? Will this really work?

3. What is gene editing?

Gene editing, as the name suggests, is a technology that edits and modifies target genes. It is a genetic engineering technology that can modify specific target genes in the genome of an organism. Theoretically, we can "modify" the gene that controls single eyelids into a gene that controls double eyelids.

Currently, the most popular gene editing technology in the world is CRISPR/Cas9, which can edit the genome by "cutting and pasting" deoxyribonucleic acid (DNA) sequences. It can edit the genes of animals, plants, and bacteria. It has a wide range of applications. It can not only study the functions of various genes in animals and plants, but can also be used in the field of human gene therapy.

Figuratively speaking, Cas9 is like a pair of scissors/wrench, which can cut DNA at a specified location for gene editing.

(Image source: Wikipedia)

The CRISPR/Cas9 system was first discovered in Escherichia coli. When scientists were studying the genes of the bacterium, they accidentally discovered a repeated palindromic sequence, that is, certain base pairs at both ends of the sequence were repeated. This type of code was later found in the genomes of many bacteria. Some scientists realized that this was definitely not a coincidence. After careful research, they found that this type of code should be a tool for bacteria to resist the invasion of foreign DNA.

Subsequent series of studies have shown that the CRISPR/Cas9 system can integrate fragments of invading phage and plasmid DNA into CRISPR, and use corresponding CRISPR RNAs (crRNAs) to guide the degradation of homologous sequences, thereby providing immunity.

Seeing this, I believe everyone has already figured out that as long as this type of codon is modified in a targeted manner so that it can degrade specific DNA fragments, the target DNA can be edited.

Soon, Jennifer Doudna, a structural biologist from the University of California, Berkeley, and Emmanuelle Charpentier from Umeå University in Sweden confirmed this idea through in vitro experiments. Then, someone used the CRISPR/Cas system to edit the genes of zebrafish, fungi and bacteria, and Zhang Feng's laboratory successfully applied it to mammalian cells.

Genetically modified pigs produced using CRISPR/Cas9 technology

(Image source: Journal of Biomedical Engineering)

Nowadays, CRISPR/Cas9 gene editing technology is one of the most important revolutions in biology and medicine, and has successfully achieved precise genome modification of fruit flies, nematodes, rats, pigs, sheep, rice, wheat, sorghum, etc. It even shows great application prospects in the application field of gene therapy for some diseases, such as blood diseases, tumors and other genetic diseases.

As people learn more about CRISPR/Cas9 gene editing technology, they have gradually discovered its shortcomings, namely the serious off-target effect. Because the CRISPR/Cas9 system only needs to avoid accidentally damaging its own DNA in bacteria, when it is used for gene editing, it may fail to edit the target gene due to inaccurate target recognition, inaccurate cutting, or inability to accurately edit the cutting site. Therefore, people are constantly developing new technologies, and I believe that gene editing will become more mature in the future.

Back to the question of single eyelid genes, can we use gene editing technology to make ourselves more beautiful? Theoretically, yes, but it must be edited when you are still a fertilized egg, so as to ensure that you will have double eyelids when you grow up.

In fact, there is no need to worry about it. It is precisely because of the diversity of genes that people are different, and everyone's beauty is unique. Compared with relying on gene editing to change our appearance, perhaps what we should learn is to appreciate ourselves from the bottom of our hearts and accept our unique beauty.

References:

Gao Mengyu, Yang Guang, Bao Ji. Research progress in the medical field of breeding gene-modified pigs using CRISPR/Cas9 technology. Journal of Biomedical Engineering, 2018, 35(4): 637-642.

[2]Doudna, JA, & Charpentier, E. . (2014). The new frontier of genome engineering with crispr-cas9. Science, 346(6213), 1258096.

[3]Hsu, P., Lander, E., & Zhang, F. (2014). Development and applications of crispr-cas9 for genome engineering. Cell, 157(6), 1262-1278.

[4]Comfort, N. . (2017). A crack in creation: gene editing and the unthinkable power to control evolution. Nature, 546(7656), 30-31.

Produced by: Science Popularization China

Author: Lu Xiaowei (Institute of Microbiology, Chinese Academy of Sciences)

Producer: China Science Expo