Humans Altered by Infectious Diseases

　　Readers must have heard the saying that “red meat causes cancer”. Although the actual situation is not as serious as the legend, the fact that red meat can increase the risk of cancer has been confirmed by many studies, but the increase is not much. Not as strong carcinogens as tobacco and ultraviolet rays.
　　The red meat mentioned here refers to the meat of mammals such as pork, beef and lamb, and the color is not so red. It stands to reason that red meat is closest to the human body in terms of nutrients. Why does eating red meat increase the risk of cancer?
　　The reason for this has not been gradually clarified until recent years. The mechanism behind it has something to do with a malaria epidemic that broke out 3 million years ago.
　　In terms of time, 3 million years ago happened to be the transition stage from ape to Homo erectus. Our ancestors descended from the trees and gradually learned to walk upright. Perhaps it is precisely because of this major change in lifestyle that more frequent contact between people has created conditions for the large-scale transmission of malaria.
　　Malaria is a serious infectious disease that infects 241 million people and kills 627,000 people worldwide in 2020 alone. In order to deal with malaria, humans have tried various methods, and even evolved a genetic disease called sickle cell anemia, sacrificing part of their health in exchange for resistance to malaria.
　　Sickle-cell anemia is a well-known example of an infectious disease altering the human genome and is mentioned in every genetics textbook. In addition, humans can also reduce the infection rate of malaria by changing the structure of sialic acid, which is why red meat causes cancer.
　　Sialic acid is probably the most underrated organic macromolecule. It is an important component of cell membranes and is found on the surface of all animal cells.
　　Because of its ubiquity, many pathogens use sialic acid as the key to successfully invade human cells, such as the familiar influenza virus and coronavirus.
　　There are two main types of sialic acid in mammals, called Neu5Ac and Neu5Gc, the latter being the “key” for malaria parasites to invade human cells.
　　So during the malaria pandemic 3 million years ago, some people’s genomes mutated and no longer produced Neu5Gc. This mutant quickly spread among the population and became the standard for humans today. But other mammals have not experienced such severe malaria outbreaks, so Neu5Gc can still be found in their bodies.
　　The two sialic acids differ slightly in structure, but the immunogenicity of the two is not the same. Therefore, when humans eat the meat (red meat) of other mammals, the Neu5Gc contained in it will be absorbed by the body and become a part of their own cell membrane. However, because of the subtle structural differences between the two, the Neu5Gc molecule will be regarded as an enemy by the human immune system, thereby inducing a persistent inflammatory response. Chronic inflammation is known to be a very common carcinogen, which is why eating red meat increases the risk of cancer.
　　In contrast, the sialic acid contained in the “white meat” of poultry and fish is too different in structure from that of mammals to be directly used by the human body, so eating white meat will not cause an inflammatory response, so It won’t cause cancer.
　　This case tells us that the impact of infectious diseases on humans is sometimes very subtle, and we need to turn several corners to figure it out. There is a more tortuous case in this regard, also involving sialic acid, but this time it is not sialic acid that is mutated, but its receptor.
　　As mentioned earlier, sialic acid exists on the surface of all animal cells without exception, which provides a way for the mammalian immune system to recognize friend and foe. All mammalian immune cells are known to have a receptor called CD33 on their surface, which is responsible for recognizing sialic acid on the surface of other cells and using it to decide whether to attack immediately or ignore it.
　　Mammalian brains also have immune cells called microglia. In addition to being responsible for killing bacteria, microglia also have an important function, that is, they are responsible for clearing damaged brain neurons and amyloid plaques, which are the most likely culprits of Alzheimer’s disease. The problem is that brain neurons happen to be the cells with the highest abundance of sialic acid, which marks brain neurons as “self,” which severely interferes with the cleaning tasks of microglia, causing waste to accumulate in brain tissue More and more, the result is various degenerative brain neuropathies, such as Alzheimer’s disease.
　　Of all mammals, only humans have evolved a mutant form of CD33 that no longer binds sialic acid. Microglia with this mutant form of CD33 can better play the role of cleaners and keep the brain healthy for a long time, which is why a considerable number of elderly people still have clear thinking.
　　The importance of this cannot be overemphasized, because of all land mammals, only humans have had three generations living together. Although human grandparents have lost their fertility, they are still physically and mentally healthy and can help their children raise the next generation. Anthropologists believe that it is precisely because of the existence of grandparents that human women can raise more children and accelerate the intergenerational transmission of knowledge.
　　Why don’t other mammals have grandparents? Because they were eliminated by natural selection. According to classical Darwinian evolution, natural selection will only act on genes related to reproduction. When an animal loses its ability to reproduce, natural selection fails, and the result is a rapid decline in bodily functions, and the animal dies quickly. Even if you are lucky enough to live to old age, you will lose your mobility due to the degeneration of the brain nervous system. Although humans are no exception, they are the best performers in this regard. A large number of elderly people can still live with a clear mind for a long time, and other mammals cannot do this.
　　It is worth mentioning that neither the Neanderthals nor the Denisovans, the two most famous relatives of humans, did not have this mutant type, so they are both a species without grandparents, and perhaps this is what they were tragically eliminated reason.
　　So, how did humans evolve this mutant type? That’s the question Professor Ajit Varki of the UC San Diego School of Medicine wants to answer. He and his colleagues studied the evolution of CD33 mutants and found that this human-only mutant arose along with the gonorrhea pandemic, because people with this mutant would not be infected with gonorrhea and thus have an evolutionary advantage.
　　Specifically, the culprit in gonorrhea is a Gram-negative coccus called Neisseria gonorrhoeae. This bacterium secretes sialic acid exactly the same as that of humans, in order to deceive the human immune system, so as to achieve the purpose of invading the human body. But the mutant CD33 receptor doesn’t bind to sialic acid, so it can’t be tricked, so people with this mutant don’t get gonorrhea. As a result, this mutant type quickly became popular among the population and became the standard configuration for modern people.
　　Professor Waki ​​wrote the research results into a paper, which was published in the journal “Molecular Biology and Evolution” on July 9, 2022. The paper draws the seemingly inconceivable conclusion that the gonorrhea epidemic gave humans an evolutionary leap by giving humans long-lived grandparents.