Author: Scientific Sound Knowledge Writing Training Camp Wang Ning
<h1 class="pgc-h-arrow-right" > citation</h1>
At 11 a.m. on June 12, 1984,[1] Barry Marshall, 32, in a laboratory at Fremantle Hospital in Australia, took a glass test tube from colleague Neil Knox. He raised the tube to the height of his eyes and looked at a little peptone at the bottom of the test tube in the Australian winter sun.
"Volume?" Marshall asked.
Knox replied, "10 ml."
"pH?" Marshall asked again.
Knox replied, "8.0."
Marshall said, "Well, make a good record, and when the experiment is successful, we will issue a paper." Again, the number of colonies? ”
Knox replied, "It has been measured repeatedly, 10 to the 9th power[2]. “
Marshall said: "10 to the 9th power, that is... 1 billion. 1 billion colonies, it must be enough. ”
Knox looked at Marshall worriedly: "Do you have to do this?" ”
Marshall squeezed out a smile: "Don't worry. If the experiment is successful, these bacteria will only make me suffer from peptic ulcers, and they will not kill me. Besides, other doctors can't cure it, we can cure it well. We know what the root cause of the disease is, and isn't this experiment just to prove it? ”
Knox was still worried: "Does Madame know? ”
Marshall smiled and replied, "I didn't tell Adrian, I didn't want her to worry." If she knew, she would have stopped me. I should have only very mild symptoms, or even no symptoms at all, without having to tell her. ”
But Knox couldn't laugh, he knew in his heart that things weren't as easy and simple as Marshall said. What kind of consequences these bacteria will have, no one can be sure. The most severe may have resulted in Marshall having to have gastrectomy.
But Marshall didn't hesitate to take a sip of the peptone containing 1 billion Helicobacter pylori colonies. Knox took the empty test tube and sighed, "Mr. Marshall, you are crazy! Marshall said quietly, "This is the only way." ”
Why would Marshall drink these Helicobacter pyloris, which sound a little scary to the name? It's a long story, and I have to tell you from the beginning.
<h1 class = "pgc-h-arrow-right" > Marshall's indissoluble relationship with Helicobacter pylori</h1>
Marshall graduated in medicine from the University of Western Australia and joined the Royal Pass Hospital after graduation. In July 1981, the rotation system brought Marshall to the Gastroenterology Department. The mentor told Marshall that Dr. Warren had discovered a new bacterium when he biopsed some of the patients' stomachs and needed someone to follow up on them to see what clinical conditions they had. Marshall felt he could handle the task, but when he got the list of patients, he immediately became intrigued, because there was a patient on the list that Marshall knew. It was a lady in her forties and fifties, and she was suffering from severe stomach pain, but on examination, apart from some redness in her stomach and the bacteria that Dr. Warren had found, nothing unusual was found. According to the general understanding of the medical community at that time, peptic ulcer was caused by excessive secretion of gastric acid, and excessive secretion of gastric acid was caused by excessive mental stress, so the woman was transferred to the psychiatric department. The doctor prescribed antidepressants to her while chanting the industry's famous proverb "no acid, no ulcers"[3] while prescribing her antidepressants. However, these drugs did not work much, and stomach pain still tormented her.
Marshall sympathized with the woman's plight. So, on a normal afternoon, he found Dr. Robin Warren, who liked to drink strong black coffee and smoke cigars, and began to study the curved bacteria found in the patient's stomach.
Photo: Robin Warren (left) and Barry Marshall
Marshall's hobbies played a big role. He established a network of networks from the hospital library to the National Medical Library of the National Institutes of Health, allowing him to retrieve a large body of medical literature. Today, this is almost standard for scientific work, but at the time Marshall was probably the only doctor with this condition. Over the next six months or so, Marshall read extensively all the relevant papers she could find, the references to the papers, and then to the references to the references. Gradually, he found that papers related to peptic ulcers repeatedly mentioned this bacterium with a curved shape living in the stomach, but did not attract enough attention. Acutely aware that there might be some intrinsic link between the bacteria and peptic ulcers, Marshall thought to himself, "Maybe an interesting paper is being born." ”
In 1982, Marshall and Warren formally began studying the relationship between the bacterium and peptic ulcers. Just as everything is difficult at the beginning, Marshall suffered setbacks at the beginning. He needed to culture the bacteria in vitro in the medium, but failed one after another. After one gastric biopsy specimen after another, none of them were found to have bacterial growth. Flipping through the experimental records, it has failed 30 times in a row. Obviously using standard Campylobacter medium, Ming ming cultured for 48 hours, why not? Marshall was so confused that he almost gave up.
Discouraged, he decided to spend the Easter holidays with his wife and children, leaving his work aside beforehand. After five days of vacation, Marshall returned to the lab to find that the medium of the 31st sample he had forgotten to throw away was full of colonies.
After many more experiments, Marshall finally confirmed that the bacterium was not a normal Campylobacter, that it grew slower, and that the optimal incubation time was 3 to 5 days instead of 48 hours. At this time, Marshall did not know that many years later, ribosome RNA sequencing showed that the bacteria were only similar in appearance to Campylobacter, and did not belong to the genus Campylobacter, but to helicobacter.
The next work was relatively smooth, Marshall and Warren successively performed stomach biopsies on many patients, most of whom found this bacterium in their stomachs, and there were many successful cases of in vitro culture. Marshall excitedly presented his and Warren's findings at the local medical college meeting in October, but unexpectedly touched a nose of ash. Some people say that these are harmless bacteria, others say that it is precisely because of ulcers that this bacterium takes advantage of the void and multiplies in large quantities, and even some people say that it is impossible for bacteria to live in such an acidic stomach, and the culture medium must be contaminated. Undeterred by the criticism, Marshall felt that the level of local physicians was limited and submitted their findings to the Australian Gastrointestinal Society.
By this time, Marshall had completed her doctor training at the Royal Perth Hospital, could not renew the contract for the next year, and had to stop working with Warren and leave the Royal Perth Hospital. He was invited to join another hospital in Western Australia, Fremantle Hospital, to continue his research in gastroenterology and microbiology.
In his new workplace, Marshall received a response from the Australian Gastroenterological Society, which not only rejected Marshall and Warren's paper, but also rated it as the worst 10% of papers received in 1983.
Pictured: Original rejection letter
Faced with such an outcome, Marshall was devastated. In fact, it is not unreasonable for peers not to accept his thesis. Because Marshall was not able to prove the causal relationship between this bacterium and stomach ulcers as required by the famous Koch Law. There are four Koch's laws, the first of which is that the bacteria must be present in every case. This Marshall had long since confirmed. The second rule is that the bacteria must be able to be isolated from the patient and can be cultured purely in vitro. He also achieved this. The third rule is that when a pure culture of the bacterium is inoculated into a healthy susceptible host, the disease must be reproducible. This, Marshall has not been able to do yet. The fourth rule is that the bacteria must recover from the host of the experimental infection.
So, if Marshall wants to prove himself right, he must infect an animal with this bacterium and make it suffer from peptic ulcer. Marshall first tried the mice most commonly used in medical experiments, but without success. Then he began to experiment with piglets for 6 months, but he still did not succeed. Not only did the piglets not get peptic ulcers, but they grew fast. This frustrated Marshall, who I suspected was probably not suitable for scientific research, more suitable for pig raising.
In 1984, the Lancet published Marshall and Warren's paper" "Unknown Campylobacter in the Stomach of Patients with Gastritis and Peptic Ulcers". The paper is based on their previous research, which observed the presence of unidentified Campylobacter in the stomachs of many patients with gastritis and peptic ulcer. Although it has not been proven that Campylobacter is the cause, Marshall is very happy to publish papers in top medical journals. He has passed the age of establishment, and his peers have achieved success in their careers, and he has finally made some achievements. Marshall and Warren's family went out to celebrate together. Warren's wife said they might win a Nobel Prize, and Marshall joked that the Nobel Prize would be awarded to Warren and himself in a few years. [7]
However, things did not go as smoothly as he had imagined, and animal experiments were still impossible. At the same time, he saw that doctors were still prescribing antacid and antidepressants to patients with peptic ulcers. One patient nearly died of ulcer bleeding, and Marshall decided that only a little antibiotic was needed to cure him. But Marshall couldn't do anything about it, because it wasn't his patients, and he had no right to interfere. He also shouted to the attending doctor: "This is the wrong treatment!" But the attending physician replied, "I am responsible for the patient." I can't change medication guidelines just because I don't have a definitive paper. Marshall knew that the doctor was right to do so, and that the only thing he could do was try to find evidence.
The next day, when Marshall visited the patient again, he found the bed empty. He asked the nurse, "Where did he go?" The nurse replied, "I'm going to have surgery to remove my stomach." [8] This result further stimulated Marshall.
Marshall didn't know how he got back to the lab, and along the way he thought about what the problems of the experiment were and why they didn't always succeed. He meditated on Koch's law over and over again: "The disease must be reproducible when inoculated into a healthy susceptible host", "Inoculated to a healthy susceptible host..." Suddenly, there was a flash of inspiration, the susceptible host, yes, the susceptible host! The only known susceptible host now is a human, a human! So the most likely to succeed is to experiment directly with people. But who wants to experiment with their health? In addition, it is also required that the person has no gastrointestinal diseases and no family history of peptic ulcers. Marshall thought of a man who met all the conditions and was willing to experiment on himself, and that person was himself.
Marshall hesitated, did he really want to do this? He didn't think about it. "Let's make sure you're really eligible." With this in mind, he asked his gastroenterologist[9] to help him with a gastroscopy to confirm that he did not have this bacterium in his stomach. The mentor asked Marshall, "Barry, are you unwell?" Marshall felt a little embarrassed and replied in a panic, "No, no." "He suddenly regretted that he was such a fool!" Why do you want to find a tutor to help you do a check, and you must not tell the tutor about the experiments you want to do. The mentor knows that it is inevitable to conduct an ethical review, even if it is voluntary, it must not pass. The mentor seemed to see Marshall's intentions, sighed softly, and said, "Don't tell me, I don't want to know." [10] "Is this acquiescence?" Marshall thought to himself, "Since the mentors have acquiesced, it is better to do so." ”
<h1 class="pgc-h-arrow-right" > the story after a mouthful</h1>
The results showed that Marshall was healthy and suitable for experimentation. So, on June 12, 1984, at 11 a.m., Marshall swallowed 1 billion bacteria.
During the first 24 hours, he felt a noticeable increase in abdominal squirming, and at night he could hear his stomach grunting as he lay in bed. But for nearly a week, there were no other symptoms. Marshall was so sad that he was so healthy, how could he not get sick! It wasn't until the seventh day, after dinner, that Marshall finally felt a little strange again, he felt very full, but he ate no more than ever. On the eighth morning, Marshall woke up less than 6 o'clock, and he couldn't tell whether he was awakened by hunger or by nausea, and he was very uncomfortable anyway. Suddenly, a wave of nausea struck, and Marshall hurried to the bathroom and spat out some mucus. Looking at the vomit, Marshall was very happy and smelled it. For the next few days, Marshall often felt headaches. When his colleague euphemistically reminded him that the exhaled gas had a rotten smell, Marshall not only did not feel embarrassed, but laughed and smoked away from his colleague.
Marshall knew that he had finally succeeded in developing a peptic ulcer, and the third rule of Koch's law had been confirmed. On the tenth day, Marshall was confident and underwent another gastroscopy. The examination was not smooth, a large amount of mucus flowed down the gastroscopic hose, making a mess, and the specimens taken out were small and fragmented. But all these dissimilarities only added to Marshall's confidence. Sure enough, many helicobacteria were found in the specimens, and article 4 of Koch's law confirmed it. His experiment was a success!
Fig.: Gastric mucosa and glands on day 10 after swallowing Helicobacter pylori, Fig. 3 Chromogenic bacteria
After completing the experiment, Marshall began taking tinidazole, which kills bacteria. Just 24 hours after the first dose, all symptoms disappear completely. This can be said to be a real recognition of the root cause of stomach disease.
He wrote a paper on the experiment and published it in the Australian Medical Journal. The paper later became one of the most cited papers in the journal.
Although conventional wisdom did not change in an instant because of Marshall's experiments, it slowly changed. People began to pay attention to Marshall's theory. Australia's National Health and Medical Research Council has also begun funding Marshall for further research. Marshall's theory was accepted in Europe and welcomed in the United States.
In 1989, the bacterium was officially named Helicobacter pylori. The so-called pylorus is the lower opening of the stomach, the door connected to the duodenum. The pylorus, like the anus, has a sphincter, which can be controlled by opening and closing, so that the speed at which food that passes through the stomach and becomes a semi-fluid substance enters the duodenum from the stomach. Therefore, the name Helicobacter pylori means a rod-shaped bacterium that lives on both sides of the pylorus and has a spiral shape.
Marshall's theory has gradually gained the recognition of peer experts around the world, and more and more scholars have devoted themselves to the study of Helicobacter pylori. To this day, there are tens of thousands of scientific publications about the bacterium, and a medical journal called Helicobacter has emerged. Humans gradually have more understanding of Helicobacter pylori. For example, the susceptible host of Helicobacter pylori is primates, which is why Marshall always failed to do animal experiments, he chose animals such as mice and piglets, if he chooses to experiment with orangutans or monkeys, he may not have to test poison with his body.
But there are still some things that have not been studied to this day. For example, Helicobacter pylori is undoubtedly contagious, but how does it run from one person's stomach to another? That is, what is the route of transmission, which is currently unclear.
Three possible routes of transmission are generally considered. The first is transmission caused by treatment by a doctor, such as an endoscope that has been in contact with one patient's gastric mucosa without sterilization and is used in another patient, although this rarely happens. The second route is fecal-oral transmission, where Helicobacter pylori may be excreted with feces, contaminating food and water, and then entering the human digestive tract to infect people. The third possible route is oral transmission, which is possible if the mother and child use the same spoon. [14] It can be seen that washing hands before eating and after going to the toilet, dividing spoons and chopsticks, and eating separate meals are all good hygiene habits.
In addition, statistics show that Helicobacter pylori infection in different regions is closely related to the level of economic development. The country with the lowest infection rate is Switzerland, which also has 18.9%, and the country with the highest infection rate is Nigeria, with a high of 87.7%. The infection rate in our country is about 50%, [16] which is comparable to the global average.
You may ask, with such a terrible infection rate, why do many people never hear of this bacterium? This is because more than 85% of infected people do not develop any symptoms [17], and less than 15% of infected people develop gastritis or peptic ulcer. However, prolonged gastritis or peptic ulcers can lead to stomach cancer, and Helicobacter pylori was classified as a class of carcinogens by the International Institute for Cancer as early as 1994 [18]. Studies have shown that people infected with Helicobacter pylori have a 65% higher risk of stomach cancer than those who receive eradication treatment, compared with 1.7% in absolute terms and 1.1% in the latter. [19] Sounds a bit scary, so does infection with Helicobacter pylori definitely have to be treated? In China, it is generally believed that if an infected person does not develop symptoms, he does not need treatment. [20]
On October 3, 2005, the Nobel Prize jury announced that the Nobel Prize in Physiology or Medicine for that year had been awarded to Australian scientists Barry Marshall and Robin Warren in recognition of their "discovery of Helicobacter pylori and the role this bacterium plays in diseases such as gastritis and stomach ulcers." [21] This was a reward for Marshall, who was more than half a hundred years old, and a well-deserved reward.
< h1 class="pgc-h-arrow-right" > the end</h1>
After listening to this story, do you have the same respect for the spirit of exploration in the community of scientists as I do? Human knowledge is really hard-won. Some people believe that human knowledge comes from God. God is omniscient and omnipotent about the world he has created, and human beings are fortunate to have gained some knowledge from God. Others believe that knowledge comes from mysterious ancestors, who have wisdom that is unattainable to future generations. However, the truth is that the tower of human knowledge has been gradually built by human beings themselves through the efforts of generations. Behind any brick that builds this tower of knowledge, I don't know what kind of hardships and twists and turns have been experienced. The story told today is only the tip of the iceberg, and every brick is a legend.
< h1 class="pgc-h-arrow-right" > source</h1>
Marshall, Barry (2002). "The discovery that Helicobacter pylori, a spiral bacterium, caused peptic ulcer disease". In Barry J. Marshall (ed.). Helicobacter pioneers: firsthand accounts from the scientists who discovered helicobacters, 1892–1982. Oxford: Blackwell. pp. 165–202. ISBN 978-0-86793-035-1.
Marshall B J , Armstrong J A , Mcgechie D B , et al. Attempt to fulfil Koch's postulates for pyloric Campylobacter[J]. The Medical journal of Australia, 1985, 142(8):436-439.
Unge, Peter (2002). "Helicobacter pylori treatment in the past and in the 21st century". In Barry Marshall (ed.). Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia. pp. 203–213. ISBN 978-0-86793-035-1.
Pamela Weintraub. The Doctor Who Drank Infectious Broth, Gave Himself an Ulcer, and Solved a Medical Mystery.2010-4-8
Seeing What Others Don't, chapter 4, by Gary Klein
Marshall B , Warren J R . UNIDENTIFIED CURVED BACILLI IN THE STOMACH OF PATIENTS WITH GASTRITIS AND PEPTIC ULCERATION. 1984.
Q&A: Barry Marshall < https://www.nature.com/articles/514S6a> When did you realize your work might be worthy of a Nobel prize?
The Doctor Who Drank Infectious Broth, Gave Himself an Ulcer, and Solved a Medical Mystery
Professor Barry Marshall, gastroenterologist
Q&A: Barry Marshall < https://www.nature.com/articles/514S6a> You swallowed a culture of H. pylori to prove your hypothesis. What led you to do this, and what did your family and colleagues think?
Van Der Weyden, Martin B; Armstrong, Ruth M; Gregory, Ann T (2005). "The 2005 Nobel Prize in Physiology or Medicine". Medical Journal of Australia. 183 (11/12): 612–4.
Ahmed N . 23 years of the discovery of Helicobacter pylori: Is the debate over? [M]. 2008.
Duynhoven Y , Jonge R D . Transmission of Helicobacter pylori: a role for food? [J]. Bulletin of the World Health Organization, 2001, 79(5):455-60.
ames K.Y. Hooi et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-analysis. Gastroenterology.April 26,2017
XIE Chuan, LV Nonghua. Current status of Helicobacter pylori infection in China[J]. Disease Surveillance, 2018, 33(4): 272-275.
Bytzer P, Dahlerup JF, Eriksen JR, Jarbøl DE, Rosenstock S, Wildt S. Diagnosis and treatment of Helicobacter pylori infection. Dan Med Bull. April 2011, 58 (4): C4271 [7 August 2013]. PMID 21466771.
List of Classifications
Fuccio L, Zagari RM, Eusebi LH, Laterza L, Cennamo V, Ceroni L, Grilli D, Bazzoli F. Meta-analysis: can Helicobacter pylori eradication treatment reduce the risk for gastric cancer?. Ann Intern Med. 2009, 151 (2): 121–8.
WEI Chengyao. LU Junwen. LIU Yirong. Those things you need to know about Helicobacter pylori. Xinhuanet.2020.03.30
The Nobel Prize in Physiology or Medicine 2005. NobelPrize.org. Nobel Prize Outreach AB 2021. Wed. 21 Jul 2021.