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An Interview with Professor Manuel Varela: From an autopsy comes Science

Nov 28, 2018 by

Michael F. Shaughnessy –

1) Professor Varela – we have all seen these things on various television shows. There is some death or murder and the body is brought in for an autopsy- and miraculously – the cause of death is determined…and clues are given to some detective, and they find the killer. But with William Welch, M.D. he was doing autopsies during World War I at Johns Hopkins and made some very interesting discoveries.  Just briefly- what did he find?

It is quite true that Dr. William Henry Welch, an American born in Norfolk, CT, on April 8, 1850, made an astute discovery, in 1892, regarding the disease gas gangrene and its bacterial causative agent. It is this discovery for which Dr. Welch is most well-known.The finding revolutionized medicine and especially surgery pertaining to battle wounds and tissue trauma.

Dr. Welch is known also for having studied several other scientific topics. For instance, he demonstrated the tissue damaging property of the diphtheria toxin, in 1891. Dr. Welch also studied a microbial cause of lobar pneumonia, a bacterium called Micrococcus lanccolatus, in 1892. He was also a noted advocate of the practice of Listerism, a form of antiseptic-based surgery. 

Interestingly, Dr. Welch also studied medical education, in 1894, developing relevant curricula that has been described as having revolutionized the practice of medicine. As the first dean of medicine at Johns Hopkins, his influence in medicine are still present in modern times. He introduced the latest developments pertaining to tissue pathology. He is also credited with influencing the teaching of medical bacteriology. He published on these topics well into his later years.

When he traveled to Europe, in1884, to study with the famous Dr. Robert Koch in Germany, Dr. Welch learned basic bacteriological laboratory methods and took Prof. Koch’s bacteriology course.

Many of his contributions to science and education are indirect. For instance, he routinely published review articles dealing with various topics related to his research interests,providing an educational influence in these areas. In his writings, Dr. Welch dealt with matters relating to surgical techniques, infection modes, pneumonia pathology, immunology of serum therapy, and general themes pertaining to bacteriology.

As an aside, Dr. Welch published a seminal review, in 1893, dealing frankly with the issue of sanitation and its relationship to those living in poverty. He provided views meant to improve the living conditions of the poor.

2) Apparently, he discovered a new bacterium–Bacillus aerogenes capsulatus- what exactly is this? And his writings came to link his name with the bacteria—Bacillus  welchii. Why is this so important?

As you mentioned in your question above, in 1892, Dr. Welch collaborated with Dr. George Henry Falkiner Nuttall in performing an autopsy on an individual who had died from a ruptured blood vessel aneurysm. Together, Drs. Welch and Nuttall determined that the blood vessels were necrotic and bubbled a foul-smelling gas. They then determined that the gas was emitted from a bacterium that they had isolated in culture from the cadaver. They called the cadaver isolate Bacillus aerogenes capsulatus, the causative agent of the gas gangrene. It was sometimes called amongst the investigators as the “gas bacillus.”

In 1898, Drs. A. Zuber and A.Veillon changed the name of the gas gangrene agent to Bacillus perfringens.  Apparently, Dr. A. Fraenkel had also isolated the same microbe, and he had called it Bacillus phlegmones emphysematosae. Yet,the microbe became known as Bacillus welchii but was widely referred to colloquially as “Welch’s bacillus.” 

Then, in 1920, the gasgangrene-causing microbe was renamed Clostridium welchii. The modern name for this pathogenic organism is Clostridium perfringens. The genus term Clostridiumarises from Greek meaning spindle, referring to the cell arrangement.  The specific epithet perfringens refers to the “breaking through” of the microbe into deep layers of tissue to causenecrosis, a characteristic of the gas gangrene microbe.

3) Gas bubbles were found in many of the cadavers’ blood vessels–a Clue!  What did this clue tell Dr.Welch?

At first, it was believed that the bubbling observed in the blood vessels of the cadaver was due merely to the presence of trapped atmospheric air within the cadaveric tissues. Then, Dr.Welch attributed the origin of the bubbling gas from the infected cadaver tissue to a microbial agent. Correctly believing that the bacillus-shaped bacterium was the source of the gas, they tacked onto its Bacillus name the specific epithet aerogenes, meaning “generator of air.”

The capsulatus term refers to the fact that the bacteria produced a visible endospore, reminiscent of a protective capsule. However, the bacteria are not known to produce capsules, aswe know them in modern times. The endospore structures typically form under conditions that are unfavorable for vegetative growth.

The gas bubbles harbor nitrogen,hydrogen sulfide, and carbon dioxide gases, likely due to metabolic fermentation of the sugars by the Clostridium perfringens bacteria that have invaded deep into tissue layers where oxygen is limiting. Incidentally, along with these gases, the bacterial fermentation of sugars, namely glucose,produces odorous organic molecules, such as butyrate, acetate, and lactate,plus a small amount of ethanol.

4) Gas gangrene – what is the link -what is the association? And what does this explain?

Thanks to the work of Dr. Welch,the gas bubbling observed in necrotic and cadaveric tissue is indicative of the gas gangrene condition. An association was established by Dr. Welch between the bacterium and the production of the foul-smelling exudate within the necrotic tissue of the cadaver. In modern times, the odor of the exudate is the chief symptom that points directly to gas gangrene. It is a unique property of the gangrenous condition and of the bacterium.

The bacterium itself, Clostridiumper fringens, is a large rod-shaped prokaryotic microbe that is Gram-positive in its cell wall composition with an ability to form an endospore structure. The microbe resides in soil in large numbers. Often, when traumas result in skin breakage, the opening of the wounds permit contamination with dirt that is laden with an endospore form of the microbe. Frequently, the bacteria exist in such an environmentally protective structure when present in soil.

The newly invasive Clostridiumper fringens endospore will now vegetate to undergo germination in order to grow within the deep tissue. The anaerobic conditions of the deep host tissue are prime conditions for the Clostridium perfringens bacteria to colonize and secrete its toxins, resulting in the death of the surrounding tissue. Mean whilethe vegetative bacteria are metabolizing the nutrients, like sugars, of the host cells to produce the organics and the characteristic gases.

5) His later work apparently was based on case studies and second-hand anecdotes- but in a sense- these case studies are also critically important in science. Tell us why.

Dr. Welch’s published case studies were important for advancing the field of medical bacteriology. His works in the areas of gangrenous wound treatments, plus pneumonia, and tissue damage by the Clostridium diphtheriae toxin were all important contributions. It is from his various case study work that Dr. Welch made his historic discoveries having to do with diphtheria toxin pathology and gas gangrene bacteriology.

Indeed, case studies are relevant to the publication of many newly emerging diseases.  The first time an emerged infectious disease is made known to the rest of the world it is often disclosed in terms of the experience with its first few patients, if not the first patient, as discovered by astute medical practitioners.

However, it has been reported by his students, especially Dr. Simon Flexner, who wrote a biographical review article about Dr. Welch, that he often conferred with many of his colleagues at scientific meetings informing them of many new ideas that he never published.

In a sense, one might envisage that if an important finding is not published for the scientific world to pass judgement on the validity of the work, it can be considered that the novel finding, no matter how important, never existed. Thus, the flow of second-hand anecdotal information is not necessarily how an investigative scientist should like their work disseminated to the rest of the world.

 touted seemingly uncanny hypotheses, of which he never published. We have Dr. Flexner’s discourse in hand to shed light on Dr. Welch’s unusual ideas.  For instance, it is dutifully recorded by Dr. Flexner that Dr. Welch intoned the idea that bacterial immunity could involve the production by the bacteria of antibodies, a property known only to higher organisms.  Dr. Welch never published theidea.

6) Any last ideas or clues to tell about those poor cadavers, those soldiers who fought so bravely and died in World War I? And why is this gas bubbles and gangrene association so important?

By the time of the Great War, World War I, in 1916, Dr. Welch was well into his 60s. He joined the military and served slightly more than a year as a brigadier general. During his military service Dr. Welch was a medical staff officer and key advisor to the Army’s Surgeon Major General Dr. William Gorgas. Some of the key advice was in the form of medical treatment of battle wounds, especially of the gangrenous type.Any battle wound was considered contaminated. Thus, treatment involved thorough tissue cleaning and debridement to remove any contaminated and possibly gangrenous tissue as quickly as possible. Damaged tissue was resected until the surgeons came across undamaged tissue.

Another function accomplished by Dr. Welch was that of a medical inspector general. In his capacity he travelled to various military training camps. He conducted epidemiological studies and provided important advice to military medical personnel prior to deployment abroad. 

Prior to the Great War, it was well known that mortality due to post-wounding infections was significantly higher in all previously recorded wars in history. The First World War was also first to see important improvements in the prevention of the notorious gas gangrene.Dr. Welch’s discovery of the causative agent of the foul-smelling post-wound infections was a profoundly important discovery in ultimately reducing mortality associated with wound necrosis. In modern times, gas gangrene is are latively rare occurrence. 

 It has been reported that Dr. Welchdid not totally conform to the proper military dress and decorum. Moreover, he apparently never properly mastered the correct form of the salute. Nonetheless,he continued to serve active duty for three years after the end of the war.

7) To wrap up the case- Clostridiumperfringens–why is this important and what role does it play in the big scheme of things?

This microbe is important for the various diseases it causes. There are three main diseases associated with this bacterium, and they are discussed briefly here.

First, the gas gangrene infection starts by inoculation of a deep wound with endospores of the bacterium. The wound may be caused by surgical incisions, or traumatic wounds due to violence,or breakage of bones and subsequent piercing of the skin.  The microbes then gain entry into the wounds.

The gas gangrene caused by be Clostridium perfringens is characterized by extreme pain around the wound, plus swelling, fever, a discoloration of the skin around the wound, and then formation of a foul-smelling exudate emerging from the infected tissues. The tissue necrosis often is the end result.Importantly, the prime symptom indicative of the gas gangrene is the bubbling gas surrounding the infected tissue. If left untreated, the condition can lead to shock, coma, and death of the patient. When a patient is experiencing the gas gangrene ailment, it is considered a major medical emergency.

Treatment must be prompt and vigorous. Often the treatment is in the form of surgical removal accompanied by antitoxin-containing antisera, plusantibiotics. Frequently, penicillin and clindamycin are the antibiotics of choice, when available. In order to prevent the occurrence of the gas gangrenein any wound, the wounds must be cleaned properly. Sometimes high-pressure hyperbaric chambers are used to expose the organisms to oxygen, a condition in which the bacteria fail to grow. The Clostridium perfringens bacterium is known to be an anaerobic-based microbe, and oxygen would certainly inhibit its growth.

Another disease caused by the Clostridium perfringens microbe is that of the so-called clostridium-based food poisoning. The major mode of transmission in this case is food- and water-borne.  The symptoms may include watery diarrhea and abdominal cramps, but are lacking in fever,nausea and vomiting. Often the implicated foods include beef and poultry that are contaminated with the organisms. Treatment often involves replacement off fluids and electrolytes. The food poisoning bout typically occurs for about a day and should resolve itself by the end of that time-frame. Antibiotics are usually not indicated, as the food poisoning cases by this microbe are frequently self-limiting.

A third rare ailment caused by the Clostridium perfringens is called necrotizing enteritis. It typically occurs in the gastrointestinal tract, in a location named the jejunum. This condition involves also food- and water-borne modes of transmission. Though rare, the mortality rate for this infection can be as high as 50% in certain situations. 

In short, Clostridium perfringens will no doubt continue to be taught to all medical students, as Dr. Welch had first started.

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