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Dr. Manuel Varela: Stomach Ulcers—and Barry Marshall

Jul 13, 2018 by

An Interview with Dr. Manuel Varela: Stomach Ulcers—and Barry Marshall

Michael F. Shaughnessy –

1) Professor Varela- I can remember back in the 1950’s- hearing about stomach ulcers and heartburn and their treatments. And what foods should be avoided. Today, we believe that something is called Helicobacter pylori.  Who developed this concept or discovered this?

Indeed, heartburn, gastritis, and especially ulcers of the stomach have historically been very unpleasant medical diseases, perhaps for millennia.  Until the early 1980s, these afflictions had been attributed largely to factors pertaining to diet, stress, and lifestyle.

At the time, treatment had been limited to largely unsuccessful regimens of antacids, stress-reduction, avoidance of certain spicy foods, etc. Improvements in the medical conditions were mild and temporary.

However, a wrench was thrown into these long-lasting historical attributions with the relatively shorter-lasting scientific works of Barry Marshall and his collaborator J.  Robin Warren. With the exception of the heartburn, Drs. Marshall and Warren earned the Nobel for having discovered that a bacterial microbe, called Helicobacter pylori was the infamous culprit that had very likely been causing these other maladies all along.

In fact, it has now been established that infection with the H. pylori  is correlated with the onset of the more serious disease of cancer, as well.  Such stomach cancers were relatively rarer but had definitely included gastric adenocarcinoma and the so-called mucosa-associated lymphoma.

Sadly, their scientific evidence for an H. pylori-stomach ulcer connection had been strongly opposed, and their scientific peers had treated both Marshall and Warren quite harshly. They had even been publically ridiculed with name-calling.

With their eventual acceptance of an ulcer-microbe association, however, treatment of these maladies was altered to include anti-bacterial agents.  These antimicrobial agents showed good promise in the medical treatment of ulcers and other diseases caused by H. pylori.

2) Back in the day, doctors would indicate (perhaps correctly) that individuals should avoid caffeine, nicotine, and “spicy foods”.  Does this have any validity?

While it is now firmly established that certain medical conditions such as gastritis and peptic ulcers have a causation with the Helicobacter pylori bacteria, other conditions, like the heartburn that you mentioned above, may in fact be attributed to certain elements like the “caffeine, nicotine, and spicy foods” in some individuals. These items may in certain individuals be considered as triggers of heartburn, also called by the technical medical term pyrosis, a condition which is manifested by a pain or a burning sensation in the trunk of the body, often caused by the bringing up of acidic-peptic or gastric juices from the stomach into the lumen of the esophagus.

If one considers the H. pylori bacteria, however, along with the peptic ulcers and their cancers, then the avoidance of caffeine, nicotine, and spicy foods would reflect indirect associations, which may instead serve to worsen the heartburn symptoms.

Heartburn in other individuals may also be caused other factors such as alcohol, non-steroidal anti-inflammatory medications (NSAIDS), acidic foods, obesity, hiatal hernias, pregnancy, and unfortunately, chocolate. Additionally, heartburn may be a symptom observed in a medical condition called gastroesophageal reflux disease (GERD).

3) I have actually undergone the treatment for Helicobacter pylori– it took about 30 days- what is the actual treatment?  And has it changed recently?

Prior to the discovery that the peptic ulcers, such as gastric ulcer (stomach) or duodenal ulcer, and gastritis (stomach inflammation) could be brought about by a bacterial infection, traditional treatments were largely ineffective.  These historical treatments involved changes in lifestyle, such as stress reducing regimens, cessation of alcohol intake and of smoking, changes in diet, and lots of antacids.

Modern treatment for H. pylori infection involves a combination of two or more medicines. For the onset of the gastric ulcers or gastritis, treatment currently involves a so-called combination therapy regimen.  This therapy may include antibiotics such as clarithromycin (inhibits bacterial protein synthesis and is a member of the macrolide class of antimicrobials), amoxicillin (inhibits bacterial cell wall synthesis and is a member of the beta-lactam class of antimicrobials), and a proton pump inhibitor, such as omeprazole or pantoprazole.

Usually, this treatment is indicated for about a week to 10 days, but may last longer if the bacteria are resistant to the macrolide antimicrobial. When the antimicrobial agent metronidazole has been used in combination therapy, treatment failures occasionally occurred, likely due to bacterial resistance having arisen against the agent. In cases were clarithromycin resistance is encountered, an alternative antibiotic has been used. The substitute includes levofloxacin (DNA synthesis inhibitor and member of the fluoroquinolone class of drugs).

At first, combination therapy involving only one antibiotic plus bismuth was met with limited success for treatment against peptic ulcers and gastritis. Thus, this particular therapy may no longer be indicated for these ailments.

Early antibiotics that were first used to treat the H. pylori bacterial infection included tetracycline (bacterial protein synthesis inhibitor) and metronidazole (inhibitor of bacterial DNA synthesis), but bacterial resistances to these agents have compromised the clinical utilities of these medicines, as well.

The gastric carcinoma disease (e.g., stomach cancer) caused by H. pylori presents a serious public health problem, as it is a common cause of death by cancer; it ranks in the top-third of common causes in human mortalities by cancer on a worldwide scale.

Anti-cancer treatments of the H. pylori may involve not only anti-bacterial agents, called eradication therapy that is meant to eliminate the bacteria, but also may involve surgical removal of gastric cancer lesions (in the stomach) that are observed by endoscopic means.

4) Tell us about “Helicobacter pylori” and what does it look like and how does it cause stomach ulcers?

The H. pylori organism is a bacterial microbe. Dr. Giulio Bizzozero had described the bacterium originally, in 1892.

Although it is presently not clear how a patient acquires the H. pylori bacteria, one potential idea includes the so-called fecal-oral route of transmission, as the bacteria have been detected in both human feces and in dental plaque of the teeth.

The microorganism’s Gram-negative cellular shape is reminiscent of a twisted rod with a helical type of bacillus configuration. It has evolved an ingenious set of characteristics that allow it to survive and grow in the midst of the body’s well-honed defenses.

The H. pylori bacteria are most excellent swimmers, due primarily to the corkscrew type rotational behavior of the bacterial spiral within fluid and of their powerful propeller-like filaments called flagella.  This motility behavior, thus, allows the H. pylori bacteria to swim in the stomach and avoid the deleterious effects of the powerfully corrosive stomach acid.

The acid of the stomach is a corrosive body fluid and the mucous that surrounds the stomach wall is a thick and viscous layer.  These conditions are inhibitory to the pathology of H. pylori.  The bacterium, however, has found several ingenious ways to circumvent the acid and the mucous.

First, the bacterium in the stomach acid will secrete an enzyme called urease, which digests urea to carbon dioxide, water, and ammonia, the latter chemical of which reduces the acidity of the stomach, thereby allowing the bacteria to avoid the acid.  Next, the bacteria produce and secrete two additional enzymes, one called collagenase and the other called mucinase, both proteins of which function to digest the mucous layer that normally covers and protects the stomach lining from the corrosive gastric acid. These enzymes further allow the bacteria to swim through the acid and the mucous, gaining access to the stomach lining.

Next, upon reaching the stomach wall, the H. pylori bacteria secrete variety of adherence factors, which are proteins that permit bacterial binding to the lining of the stomach. Then, the bacterium secretes a set of virulence factors, such as one called VacA (vacuolating cytoxin), and another called NAP (neutrophil activation protein), both factors of which damage host stomach cells, inducing inflammation.  The inflammatory process is key to the gastritis and gastric lesions observed in the stomach linings. Then, in a coup de grâce, the H. pylori bacteria, on relatively rare occasions, make and emit CagA, a protein that elicits a cellular growth mechanism to produce the gastric carcinoma—stomach cancer.

5) Stress and worry—does it exacerbate the condition? Or it is irrelevant?

In general, stress and worry are known to affect the immune system in a detrimental way, allowing bacteria to circumvent various elements of the immune response and grow further.  Often, if a person is healthy, their immune system is healthy, too.  Conversely, if a person is unhealthy or stressed, then their immune system may be somewhat unhealthy, as well.

Sometimes, when one falls into the difficulty of excessive worry and of being stressed out, the resulting compromised immune system may permit the microbe to gain a foothold, making illness worse and the patient more stressed and worried as a result. It can then become, unfortunately, a vicious cycle, making matters only worse.  It is strongly recommended, therefore, that the patient maintain a healthy positive attitude, partake in stress reduction avenues, eat properly, exercise regularly, sleep sufficiently, etc., if one desires to acquire and maintain a generally healthy state.

6) Now, tell us about Barry Marshall and his search for a cure for stomach ulcers.

The story of Dr. Barry James Marshall is one of both adversity and triumph in the face of universal skepticism and hardship. The scientific and medical communities considered the very notion that stomach ulcers could be caused by a mere bacterium to be ridiculous if not outright nonsense. In fact, for ages it had been widely thought by biologists, physiologists, microbiologists and many other scientists that the stomach acid was so powerful that microbes simply could not survive in such harsh conditions for very long, and it was considered much less that such bacteria could actually grow and cause disease within the harsh acidic environment of the stomach.

Marshall was born on the 30th day of September in 1951in a small Western Australian town, called Kalgoorlie, devoted mainly to mining activities. His family was of modest means.  In 1972, he married Adrienne Feldman. Marshall earned his medical degree in 1974 from the School of Medicine at the University of Western Australia, housed in Perth.  Starting work in 1977 as a physician intern at the Royal Perth Hospital, he became interested in bacteriological pathology.

Dr. Marshall’s interest in the microbe-stomach axis at Royal Perth Hospital was inspired by the work of his mentor Dr. Robin Warren in 1981.

Marshall’s colleague and longtime collaborator John Robin Warren was born on the 11th day of June in 1937 in the city of Adelaide, located in South Australia. Warren was educated in the field of medicine at St. Peter’s College, University of Adelaide earning his medical degree in 1961. After residency, Dr. Warren began work at the Royal Perth Hospital in 1968.

Marshall and Warren were to receive the Nobel in the field of Physiology or Medicine in 2005. A brief description of their work follows below.

Starting in 1979, Dr. Warren had observed the H. pylori bacteria in tissue sections from clinical biopsies of patients suffering from gastritis and in both types of gastric ulcers, those involving the stomach or the duodenum. Interestingly, these bacteria were absent within 20 samples of tissues from patients who did not have any of these gastric ulcer problems. These results by Warren had inspired Dr. Marshall to begin work in the field.

Together, Marshall and Warren started a more detailed investigative study involving about a hundred patients, collecting patient histories, endoscopic data, and tissue specimens from clinical biopsies of patients with and without gastric ulcers. The results of these studies showed that the bacteria were present in pathological specimens of gastric ulcer tissues but were absent from tissues of normal patient controls. These data were published in a series of papers to scientific journals, including e.g., The Lancet, a prestigious medical journal, in the early- to mid-1980s.

These published works were met with immense skepticism. Firstly, there was the almost universal belief, held for over a hundred years, that microbes could simply not be able to live within the confines of an extreme acid (pH of 2 to 3) environment, like that to be found in the stomach. Secondly, it was also widely believed that gastric ulcers were already caused by certain lifestyle attributes like diet and stress, etc., all converging to confer a hyperacidity condition in the patient and that this extreme acidic condition was responsible for inducing the ulcer lesions of the stomach and the duodenum. Thirdly, there was also the criticism that perhaps the microbes had simply contaminated the gastric ulcer tissue after retrieval from the diseased patients. Lastly, there was the criticism that perhaps bacteria were indeed present in the living gastric tissue, but that the microbes were nonetheless merely non-pathological in nature, being harmless commensal bacteria instead.

In a second set of research studies, Marshall and Warren then performed a series of experiments aimed at satisfying the famous Koch’s postulates, devised in the late 1880s, and which were considered the gold standard for providing acceptable evidence that a microbe (the H. pylori bacterium) would be responsible for a clinical disease (an ulcer).  These postulates of Koch held that (1) the causative microbe should be present in all clinical cases of the disease; (2) the microbe must be isolated and grown pure in a cultured state; (3) when the microbial isolate is introduced to a new healthy host, the same clinical disease should be observed in these new hosts; and (4) the same microbe should be observed and retrieved from these newly inoculated diseased hosts—the same microbe as that found in the first and second postulates.

The first published papers by Marshall and Warren had already established Koch’s first postulate (the microbe is found in all cases), but in satisfying the second postulate (culture the microbe) Marshall and Warren encountered problems.  They simply could not grow the H. pylori bacteria in the laboratory setting—it just failed to grow, even after a year of trying various culture media types in the laboratory.

A solution to the problem with postulate number two was found rather serendipitously because of a mistake. Petri dish plates harboring putative ulcer tissue bacteria were left languishing in the laboratory incubator for over a week, as the laboratory personnel had vacated the lab for Easter vacation. Returning to the lab after their vacation, microbes were found growing as visible colonies on the Petri plates!

These newly cultured bacteria that satisfied the second postulate were at first named as Campylobacter pylori, but later renamed Helicobacter pylori. The specific epithet pylori was derived after the pyloric valve, an anatomical gate that controls the food conduit between the stomach and the duodenum. Unfortunately, more problems were encountered with their attempts to experimentally satisfy the third postulate (pure microbe causes disease in the healthy host).

Injection of the purified cultured H. pylori bacteria into healthy laboratory animal hosts (primarily mice) failed to result in clinical disease, such as, namely, the gastric ulcers and the gastritis. Thus, postulate no. 3 could not be fulfilled. It was a terrible blow to Drs. Marshal and Warren and to the notion that the H. pylori bacterium was a causative agent of gastric ulcers.  It especially emboldened their skeptical detractors within the biomedical sciences field of infectious diseases and with many other scientists. The disparagers had even taken to public ridicule at scientific conferences in the mid-1980s, calling Marshall and Warren “madmen” and “crazy people saying crazy things” like microbes causing ulcers!  Others had falsely claimed to have repeated the published experiments of Warren and Marshall, but being unable to replicate any of their original results. The editors of medical journals were readily rejecting Marshall’s manuscripts for publication. Remarkably, even some of large pharmaceutical companies (big pharma) got into the fray, mounting a blistering critical campaign against the findings of Warren and Marshall, while publically lamenting perceived potential economic damage to the industry.

Then, Dr. Marshall, in the midst of the “ulcer wars” and driven by these desperate times, called for desperate measures to be taken, on his own behalf. He conducted a largely unprecedented and non-traditional experiment. He drank a solution of the H. pylori bacteria!

Within a day, Dr. Marshall became violently ill, exhibiting virtually all of the clinical symptoms of the dreaded gastritis. In so doing, he provided the first experimental evidence that the H. pylori bacterium caused a disease, gastritis. In essence, he obtained experimental evidence in favor of the last two postulates of Koch, albeit with a sample size of one, himself. Fortuitously for Marshall, he did not develop the classical signs or symptoms of the gastric ulcers. The incident, however, made quite a sensation in the national and world news outlets. I remember reading about the episode in a local newspaper when I was an undergraduate student.

Meanwhile, physicians with patients suffering from ulcers, upon hearing of the self-experimentation incident of Dr. Marshall, began anti-bacterial treatments on their ulcer patients, garnering successes in clinical improvements in their symptomatic conditions.  Furthermore, in 1984, a small number of research groups from various parts of the world were actually obtaining data that were supportive of the H. pylori bacterium-gastric ulcer causation. Some of these investigators had taken on their own H. pylori experiments with the express purpose of disproving the hypothesis of Marshall and Warren that the bacteria cause gastric ulcers. However, with these new data showing support of the hypothesis, instead, these investigators then became prime proponents of the “crazy” idea, having been, thus, suitably converted.

Today, the “outrageous idea” that a microbe causes ulcers has been definitively confirmed, firmly established, and widely accepted amongst the scientific and medical communities.  The H. pylori work is now routinely discussed in the scientific literature and included in the medical textbooks.

7) What have I neglected to ask?

It may be somewhat surprising, if not shocking, for our readers to learn that Dr. Marshall was not actually the first scientist to conduct such dramatic types of experimentation on themselves.  You’ll recall above that, in the face of unrelenting skepticism, Marshall drank a glassful of an H. pylori bacteria solution in order to show that the microbe caused a disease and to complete the two remaining conditions of Koch’s postulates: observe disease in a healthy host with the pure microbe and show that it was identical to the original microbe.

Well, it just so happens that others before Marshall have similarly conducted the same sort of these self-experiments, making themselves their own “guinea pigs” or “laboratory test rats.”  For example, in 1868 Dr. Otto Oberheimer actually died from the cholera, a serious disease, after drinking a solution laden with the fluids that had been taken from cholera patients.  It was reported that Dr. Oberheimer, while literally in his own death bed, insisted in examining his blood under the microscope.

In another example, Dr. Max Joseph von Pettenkofer, was a non-believer in 1892 of the experimental evidence published by Robert Koch of Louis Pasteur’s germ theory of disease.  Dr. von Pettenkofer instead felt that germs, albeit possible causers of infectious disease, weren’t the only factors that needed consideration—he thought that many other environmental factors were at play, as well, in causing disease. Therefore, to substantiate his point, he consumed another glassful of the purified bacteria, called Vibrio cholerae, provided by non-other than Dr. Koch himself.  Unfortunately, for Dr. von Pettenkofer, he acquired a serve case of the cholera!  He almost died from the self-induced ailment. To his further chagrin, and to add insult to his self-injury, he had learned that he had been quite inaccurate about his view of the germ theory of disease.

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