However, in the theory put forward by Professor Stanley B Prusiner, he thinks that those abnormal prion proteins can "affect" other normal prion proteins and lead to structural changes. The accumulation of these abnormal prion proteins in the brain will cause cavernous cavities in brain tissue and affect the normal central nervous system function. In other words, prion is different from bacteria, molds, viruses and other microorganisms, and it has strong resistance to ultraviolet rays and disinfectants. It has no genetic material (such as DNA and RNA), but it can cause diseases in the host. It is a kind of protein, but high temperature can't destroy it. This mysterious pathogen has greatly subverted traditional thinking. However, more and more evidence shows that this terrible pathogen does exist.
Some diseases that may be caused by prions are usually called spongiform encephalopathy, because these pathological brain tissues are often seriously damaged, a large number of nerve cells die and are spongy, and many small cavities are scattered in the brain tissues. In fact, this mysterious disease with an incubation period of several years is quite common in the animal kingdom, and the most famous example is scrapie. As early as 1732, a neurodegenerative disease occurred in sheep. These sick sheep will only be unstable because of severe itching, unable to stand, trembling all over, itching to fall off the trunk, and eventually lead to the death of the sheep. As for bovine spongiform encephalopathy (BSE) caused by prions, it is a familiar and worrying mad cow disease.
Mad cow disease once caused panic in Europe, especially in Britain, so even now, compared with other meats, beef is still less popular in British supermarkets, and it seems that the British people still have a lingering haze about mad cow disease. However, why does the itch that originally only happened in sheep also appear in cattle? John W. Wilesmith of the Central Veterinary Laboratory in Britain and others found that there was something wrong with the feed for cattle! Because of the use of dead mutton products (especially bone meal, spinal cord, internal organs and so on. When feeding cattle, prion protein crossed the racial barrier from sheep and infected cattle.
Historically, scientists have discovered a mysterious and terrible disease in the cannibal colony of Papua New Guinea, which is called "Kuru disease" by local people. This terrible disease caused many women and children in the tribe to have motor dysfunction, giggle, dementia and other symptoms, and then died tragically. At that time, some scientists thought it was a family hereditary disease. Until 1957, Dr. Vincent Zigas and Dr. Carleton Gajdusek found that the brain tissue of the deceased was seriously damaged and showed spongy cavities. They also noticed the strange habit of women and children in this settlement to eat the brain of the deceased (men only eat the muscle part), so they highly suspected that the virus in the brain of the deceased might be spread through diet. When the tribal cannibalism ceremony was banned, Kuru disease no longer occurred. Now, scientists already know that the chief culprit of Kuru disease is prion.
As for Creutzfeldt-Jakob disease (CJD), it is also considered to be a disease that occurs in humans and is closely related to the pathogen of prion. Its symptoms are similar to those of Kuru disease, but there is no geographical limitation of Kuru disease. Kuru disease occasionally occurs all over the world, mostly in patients over 60 years old, with an incidence rate of only about one in a million. Except for a few cases caused by genetic variation, unfortunately, most cases are caused by improper medical operation, such as corneal transplantation and brain surgery pollution.
In fact, what worries everyone most is/kloc-0, a new variant of Creutzfeldt-Jakob disease (vCJD) that appeared in Britain in 1996. Although the symptoms of brain diseases caused by vCJD and CJD are similar, CJD mostly occurs in the elderly, while vCJD mostly occurs in young people in their twenties, and the mortality rate is high. Eating mad cow disease is the most likely cause of vCJD infection, especially the brain, spinal cord, lymph nodes and other parts of the sick cow contain a lot of pathogenic prion proteins, so it is considered to be the most dangerous part. Unfortunately, scientists know very little about this disease, not only the early diagnosis technology is very scarce, let alone the development of drugs to deal with mad cow disease. The British government once burned and destroyed sick cows on a large scale, but even after the sick cows died, traces of prions could still be found, showing how difficult this mutant protein is!
In the field of research on mad cow disease, two Nobel Prize winners in medicine and physiology have been produced (1976, 1997). The first one is Dr. Carleton Gajdusek, who discovered kuru disease in a cannibal tribe in Papua New Guinea and speculated that the source of the disease might be a chronic virus. Professor stanley prusiner is the second scientist to win an award for his research in this field. He found that the pathogen causing sheep itch was not a virus, but a substance without DNA or RNA. In fact, it's just a variation of protein. Professor Prusiner named this infectious pathogen prion (protective infectious particle).
At the early stage of research in this field, Dr. Carleton Gajdusek speculated that the pathogen was a virus with chronic effects, but at that time, a research report from hammersmith Hospital in London, England, deeply attracted Professor Prusiner. In that article, Tikvan Alper and others treated the brain tissue of sick sheep with scrapie by ultraviolet rays or ion rays. However, it is strange to find that these tissues are still infectious ... because nucleic acids will be destroyed after being treated with ultraviolet rays or ion rays, it is necessary to eliminate all infectious pathogens. Unless the infectious agent is not a familiar bacterium or virus at all, unless the infectious agent has no DNA or RNA…… ... Not at all ... Because of this report, Professor Prusiner is determined to purify this mysterious pathogen that causes sheep itch.
From 65438 to 0974, Professor Prusiner began his research at the University of California, San Francisco (UCSF). At the beginning of the study, they hoped to extract infectious pathogens from the brain tissue of sheep with scrapie, which was an arduous and dangerous task. Many researchers in Professor Prusiner's laboratory were deeply frustrated with this work, but with his repeated insistence, the work of purifying infectious pathogens was finally completed.
1982, professor Prusiner published an article entitled "scrapie of sheep caused by a new infectious protein" (science.216:136 (1982)). As for the most important pathogenic protein in this pathogen, it is also called prion protein, abbreviated as PRP. Important questions have arisen. Protein translated through gene transcription. Where is the PrP gene?
Professor Prusiner cooperated with Leroy E. Hood of California Institute of Technology. They determined the fifteen amino acid sequences at one end of PrP, and then used this sequence to deduce the nucleic acid sequence and make molecular probes. With this probe, they can further explore whether PrP gene exists in mammalian cells. Soon after, Swiss scientist Charles weismann discovered that hamster cells contained PrP gene. Almost at the same time, American scientist Bruce Cheseboro also found PrP gene in mice, and then many mammalian cells were detected. Surprisingly, many mammalian cells contain PrP gene, and humans are no exception! ! Then why don't these animals with PrP gene get diseases? This problem once put the Prusiner research team in trouble at that time, and even suspected that PrP had nothing to do with the disease.
Professor Prusiner boldly speculated that there may be two different kinds of PrP in cells, one is pathogenic and the other is normal. This hypothesis made him like winning the lottery, because he found the key factor of whether PrP was pathogenic or not. Originally, protein was easily decomposed by an enzyme called protease in cells, but Prusiner's research team observed that PrP extracted from infected brain tissue was quite difficult to decompose and destroy, and this peculiar property was very different from that of normal protein, so he further named PrPSC (scrapie PRP) and PRPC which was normal and easy to decompose.
The most important evidence that PrP is a pathogenic factor is that it can induce diseases in the brain of mice. Prusiner's research team has not been very smooth in this field, so they shifted their research focus to analyzing the PrP gene sequence of patients with familial prion diseases. The results showed that there was a mutation in one position in the PrP gene sequence of the patient! These findings also suggest that it is dangerous to produce mutant PrP. Then, they went back to mice for experiments, using transgenic technology to change the genes of mice, so that mice had mutated PrP genes, which would be translated into many mutated PrP proteins. If the mutant PrP is related to pathogenicity, these transgenic mice should get sick, and the experimental results are as they expected-the mice are sick, which is a great progress in their initial research.
Because PrPsc is pathogenic, it is not easy to be destroyed. PrPc (cellular PrP) is normal and easy to decompose. What is the difference between PrPsc and PrPc in protein structure? After molecular simulation analysis, Prusiner's team found that PrPc (normal protein) is composed of α helix, while PrPsc (pathogenic protein) is a completely different β -sheet structure. The structural differences of protein also lead to their completely different chemical properties. Compared with PrPc, PrPsc with β -sheet structure is more stable and less easily decomposed by enzymes. In addition, they also believe that PrPsc can induce normal α-helix PrPc to be transformed into β-folded PrPsc, but the related research on the induction mechanism is still quite vague.
Back to the original findings, scrapie is a neurodegenerative disease that occurs in sheep. In Britain, due to the problem of cattle feeding, prion protein crossed the fence from sheep and infected cattle. Humans ate sick cows, so prions crossed the classification barrier between humans and cows and infected humans. In fact, as early as A.D. 1960, British scientist Pattsion had found it difficult to transmit scrapie from sheep to rodents. However, after Professor Prusiner's research team used transgenic technology to make mice carry hamster PrP gene, they found that racial barriers could be broken. Because hamster-infected prion pathogens do not infect normal mice, mice with hamster PrP genes (both mice and hamster PrP genes) will be infected by hamster prion pathogens.
Prusiner's team further found that the emergence of racial barriers is related to the amino acid sequence of PrP. That is to say, the closer the protein sequence of PrP molecule of sheep pruritus is to the PrP sequence of the host itself, the easier it is for the host to be infected. For example, the PrP sequences of sheep and cattle are very similar, so PrPsc that causes itching in sheep can easily infect cattle through food. As for the PrP sequence of cattle, it is very different from that of humans. Excluding some special mutation PrP genes, the probability of PrPsc spreading from cattle to humans across the racial barrier is relatively low.
The mechanism of PrPsc destroying cells is still a mystery. Of course, it is even more difficult to develop drugs. Charles weismann and others once knocked out PrP in mice. Fortunately, all physiological functions of mice are normal, and PrPsc can't infect mice from now on. If PrP gene is so unimportant in human body, antisense or RNAi may be used in the future, but this is the most ideal situation, and there should be a long way to go in the future.
For AIDS, cancer and other diseases, people have planned to carry out preventive work step by step, and developed drugs and even vaccines, but in the face of strange and dangerous diseases such as prions and cujd, scientists suddenly become ignorant. Perhaps it should be said that they are powerless! Common sterilization methods such as high temperature, high pressure, ultraviolet rays and disinfectants can't eliminate pathogens, which are contagious and have high mortality. Without DNA or RNA, it can replicate and attack nerve cells. What is this molecule that transcends the traditional concept of genetics? I'm starting to get confused, too.