Where to find a parasite that was once ubiquitous?

In 2003, around the time Weinstock was assembling his first volunteers to test Trichuris suis, a twenty-three-year-old young man from New York (let’s call him Rick) was diagnosed with ulcerative colitis after a bout of abdominal pain and loose bloody stools.

Rick’s colitis did not respond to the usual anti-inflammatory drugs — only large doses of the steroid drug hydrocortisone helped. Of course, long-term use of steroids was accompanied by the already mentioned side effects, such as obesity, premature osteoporosis and an increased risk of infectious diseases. A year after his diagnosis, Rick’s gastroenterologist urged him to go to the hospital for a course of intravenous injections of cyclosporine — a powerful immunosuppressor that is also used to prevent rejection of transplanted organs. Rick and his doctor hoped that this would bring the inflammation under control. However, the damage could be such that Rick would have to partially or completely remove the colon.

Of course, Rick wanted to avoid the colectomy and the colostomy bags that would have come with it. Cyclosporine has been associated with risks such as kidney and liver problems, an increased risk of infectious diseases, and an increased chance of developing certain types of cancer.

All of these circumstances would have been acceptable for an incurable disease (a genetically determined disease), but everything Rick had learned about ulcerative colitis suggested that it was caused by environmental factors. None of Rick’s close relatives had the disease. And the prevalence of colitis differed significantly in different regions of the world, with the disease occurring much less frequently in poor countries. Given the fact that many signs point to a certain environmental factor, why not try to cure the disease by changing the environment?

Rick tirelessly searched for an alternative approach. The bloody stools continued with the same intensity. Whatever Rick thought about the failure of Western medicine, he needed to do something, and do it as quickly as possible. Otherwise, he could have a condition known as” toxic megacolon”: an enlarged colon as a result of severe chronic inflammation, and then, possibly, its rupture.

In the end, Rick found information about Wainstock’s research. He immediately found the theoretical basis of these studies reasonable, which is that helminths have co-existed with humans throughout their evolution, and if they are absent, the normal functioning of the immune system can be disrupted. However, Rick reasoned that if the parasite manipulates his immune system, then it must be adapted to the human body. And T. suis was known to be a pig helminth.

Rick decided to get a human whiphead-Trichuris trichiura. His gastroenterologist considered this idea erroneous and refused to follow the course of the experiment. Rick found a new doctor. His wife, who was studying to be a surgeon at the time, thought the plan was crazy and refused to take part in it. They later broke up. Even the scientists Rick turned to for help thought the idea was crazy. However, Rick clearly saw the possible options. “What was I supposed to do — take cyclosporine, which causes blood cancer, or helminth, found in the oldest coprolites? – he says. “I mean, even Ezi had this helminth.” (Ezi is a human mummy, about 5,300 years old, found in an Italian glacier with a whipworm in its intestines.)

The human whiptail reaches approximately 45 millimeters in length and lives, according to various estimates, from one to three years. Today, this helminth is present in the colon of about a billion people. According to the Centers for Disease Control and Prevention, it is the third most common roundworm in the world.

The paradoxical absence of diseases caused by whipworm is often mentioned in the literature on parasitology. This observation has received very grudging recognition and inevitably undermines the views of authoritative experts in this field. One typical textbook lists a number of possible side effects of whipworm infection (thickening of the terminal phalanges of the fingers, mental retardation, and rectal prolapse), and calls whipworm itself “a serious public health problem of global importance.” But then, in the same textbook, it is stated, as if with bewilderment, that ” the studies conducted have demonstrated a striking lack of immunopathology, despite the severity of infection with this parasite.”

Parasitologists are still debating what exactly this helminth, being an obligate parasite, takes from the host. At first, it is embedded in the intestinal wall, which may seem quite aggressive. Females lay between 3,000 and 20,000 eggs per day, and definitely exhausting the resources of the host. However, unlike hookworms, the whipworm does not suck human blood. He can live at the expense of intestinal secretions. So what’s wrong with a parasite that consumes mucus?

For Rick, the only question was how and where to find the human whiphead. In the United States, this parasite lived in different zones scattered throughout rural areas of the southern states, as well as in Puerto Rico. New York hospitals from time to time there are patients with trichuriasis. However, the more Rick studied epidemiology, the more he realized that the main obstacle is not to determine the location of the whipworm, but to make sure that he found only the whipworm.

This parasite usually co-exists with other helminths, such as the giant roundworm “human ascaris” (Ascaris lumbricoides) — the most common helminth that has adapted to humans. However, the ability of the ascaris to protect against inflammatory bowel diseases has not been tested; in addition, this helminth was frighteningly large. Rick was also worried about tapeworms, which created a number of possible complications. If tapeworms, whose life cycle includes intermediate and final hosts (humans and pigs, for example), mistake you for an intermediate host, they can invade important tissues (such as the brain) and kill you. Dangerous viruses (such as the hepatitis C virus and cytomegalovirus) that stay with you for life live in the same environment as helminths. Rick needed to minimize the chance of contact with these pathogens. With all this in mind, in 2003 he went to a country he considered relatively safe — Thailand.

Rick refused to provide too much information (according to him, in order to protect the people who helped him) and said only that he had cooperated with representatives of a non-governmental organization working on the destruction of helminths in rural areas. Ultimately, it was these people who provided Rick with a sample of feces containing whipworm eggs taken from an eleven-year-old girl from southern Thailand. “I hope one day I can thank her,” Rick says.

However, the difficulties were just beginning. At first glance, it may seem that it is not so difficult to grow a parasite that, under natural conditions, without any effort (you can even say, very aggressively) infects about a sixth of humanity. However, Rick failed for several months to make sure that the helminth eggs formed embryos and that they became invasive.

Like chicken eggs, which require the heat of the hen’s body for a certain time, geohelminth eggs must undergo an incubation period in suitable soil at a certain temperature and humidity. The period of embryo formation can last from two weeks to one month. Without proper development of the embryo, the eggs remain incomplete, never turning into larvae.

Rick tried keeping the whipworm eggs in sterile conditions, closed containers, open containers, and also tried washing them with antibiotics and then discoloring them. Nothing seemed to help. The eggs remained non-invasive. “I was very upset,” Rick says. In the end, he simulated conditions similar to those that can be found under a tree in the tropics: saturated with oxygen, non-sterile, moist soil. A year and a half after starting the research (and after numerous trips to Thailand) in 2004, Rick swallowed a dose of larvae that took root. He received the colony of vlasoglav.

After three months, Rick gradually stopped taking all immunosuppressants. In mid-2005, two years after being diagnosed with ulcerative colitis, he went into complete remission without taking medication. “I went back to a lifestyle that I thought was completely normal,” he says. At this point, Rick took the unusual step of finding a scientist who was willing to investigate him.

Rick reasoned that the theory of the co — evolution of humans and helminths was good, but he needed scientific data on what exactly these parasites were doing to his intestines. So in 2007, he (having moved to San Francisco by then) contacted a young Malaysian parasitologist from the University of California, San Francisco named Ping Lok. After some hesitation, Lock agreed to study Rick after hearing his incredible story over lunch.

I met Rick on a November evening at a coffee shop in Torrance, California, south of Los Angeles. Rick speaks firmly and clearly, like someone in a leadership position. He seems tired.

Tomorrow, December 1, a description of his case will be published in the authoritative journal Science Translational Medicine. Rick’s colon and the helminths that live in it are about to become world-famous, at least in certain circles.

A few months earlier, I had seen pictures of Rick’s hairheads. I was shown them by Ping Lok, who recently transferred to New York University. These were photos of four endoscopies performed over five years. At first I was startled, then fascinated, by the dozens of small white worms anchored in bizarre curlicues on the wall of Rick’s intestine.

“He may have more of them than he thinks,” Lock said, pointing to the red damaged area. “You see, they do some damage.”

More significant, however, was the damage that these helminths supposedly prevented. During the entire study period, Rick’s colitis worsened twice, and in both cases this was preceded by a reduction in the number of eggs laid by the whipworm. At the same time, white ulcers appeared. Rick came to the conclusion that, as they age, helminths lose their healing effect. Each time, another dose helped him get his colitis under control. The ulcerative lesions seemed insignificant. But if you remember what excruciating pain even a mild herpes on the lips brings, which these ulcers look like, they will seem simply huge.

Rick’s cases of acute colitis made it possible to assess the difference between illness and health. And although this was the only example studied, it was a great achievement in the framework of the cooperation of Lock and Rick. As expected, the inflamed areas were saturated with pro-inflammatory signaling molecules of the same type that is associated with autoimmune diseases in general, especially interleukin-17 molecules. However, less expected was the conclusion that these helminths increase the production of mucus.

Scientists have drawn attention to the fact that inflammatory bowel diseases in many cases are accompanied by a relative lack of mucus. Mucus strengthens the thin but very important barrier between the intestinal lining and the resident microbiota. Our lives are closely intertwined with the ecosystem of microbes, but this ecosystem remains at some distance from us. There is a view that if the bacteria get too close, the immune system reacts to it in the same way as it does to an invasion — with inflammation. In this regard, it is suggested that inflammatory bowel diseases occur as a result of the loss of this protective layer. Rick’s case showed that helminths can repair the mucus layer; Lock believed that this is a kind of” witness effect ” that occurs when trying to expel helminths.

When I emailed Wainstock about Locke’s research (based largely on his work), his response was both cautious and optimistic. “This data only applies to one patient,” Weinstock warned. However, the conclusion about mucus production is something new and potentially important. In addition, this study demonstrated for the first time that human whipworm can help in the treatment of inflammatory bowel diseases. “This is an excellent clinical case description, once again showing the potential benefits of helminth exposure,” Weinstock said. “Without a doubt, there will be many more such cases.”

Other scientists were less optimistic. A few days later, when Rick’s case was reported several times in the media, a prominent gastroenterologist called the study irresponsible.

“This is ridiculous and completely unacceptable,” Stephen Hanauer, a member of the board of trustees of the American College of Gastroenterology, told CNN, referring to both the study itself and its media coverage. — You encourage people to search the Internet and buy these worms, and they are potentially pathogenic organisms. These eggs can enter the body of people with weakened immune systems and cause infectious diseases”.

Even Rick refuses to give an accurate description of the embryo-forming process he used, for fear of inspiring others to copy these actions. However, it is difficult to ignore one simple fact: if Rick had followed the advice of his first gastroenterologist, there is a high probability that he would have lost at least part of his rectum and would now be wearing a colostomy bag.

“It’s incredibly encouraging that (at least in my experience) this kind of live therapy can actually have a positive impact, “says Rick.” It’s allowed us to find a completely different approach… to treating diseases.”

We’ll need all the help we can get in the future. One of the surprising aspects of Wainstock’s work is that in the two decades he has been thinking about helminths and inflammatory bowel diseases, the epidemiology of these diseases around the world has changed exactly as one would predict if helminths provided protection against them, and populations previously infected with helminths suddenly lost their parasites.

The north-south gradient of inflammatory bowel disease across North America has decreased, although it has not completely disappeared. East Asians, who in most cases were considered immune to inflammatory bowel diseases, also note a slight increase in this gradient, although the absolute indicators are still much lower than in the West. It should be noted that in Japan and South Korea, measures to destroy helminths began to be implemented several decades later than in the United States-only some time after the Second World War and the Korean War, respectively.

The bad news is that when people in developing tropical countries emigrate to cleaner, temperate countries, they seem to develop an even stronger predisposition to inflammatory bowel disease than the indigenous people. People who emigrated from South Asia to the UK are less likely to suffer from intestinal inflammation compared to native Britons, but their children born in this country have a two and a half times higher risk of developing inflammatory bowel disease.

In India, which has been developing rapidly over the past decades, there is also an increase in the prevalence of inflammatory bowel diseases. At first, the rate rose sharply in the very regions (such as Kerala) that experienced the earliest improvements in public hygiene. “A steady improvement in sanitation is certainly just what is needed, but such an improvement can have some detrimental effects,” said a Mumbai-based doctor in 2005. Other Indian scientists have seized on this opportunity (different segments of the population were at different stages of the epidemiological transition) to test Wainstock’s ideas in real life — and so far their findings confirm his initial premise.

People who develop Crohn’s disease usually live in large cities, and judging by their poor response to whipworm proteins, there were relatively few parasites in their lives. Meanwhile, residents of southern India suffering from type 1 diabetes are 14 times less likely to become infected with filariasis, which is carried by mosquitoes, compared to the general population of the country .

In addition, do not forget about allergic diseases. Does the simultaneous occurrence in the past of both inflammatory bowel diseases and hay fever in the same population group, in the same period-among the representatives of the well — to-do strata of society in the XIX century mean anything? Is it possible that the loss of helminths was a driving factor in both phenomena? The complex relationship between allergic diseases and parasites is the topic of the next chapter.

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