Did you ever wonder why one in six children has a mental health disorder? One in every six seems to be a few too many, I would think. Did you ever wonder why 20 per cent of women, in the United States at least, have been diagnosed with depression after menopause, and why ‘chronic fatigue syndrome’ has mysteriously emerged? Why should almost half of us be allergic to something? Why should more than four in every 10 children be on medication for a chronic condition? Why do more than one in 10 women have an autoimmune condition? When asking why we get sick, we take the first step in understanding the origins of disease. If we find the answer to that question, we become empowered to prevent disease.
Modern medicine does not often bother to ask why. We don’t talk very much about it in medical school or during our internships or in residency. We don’t discuss it with our patients very much either. In line with this attitude, our biomedical research focuses on elucidating detailed mechanisms aimed at developing the next drug, but not on why we need a new drug in the first place. Modern medicine asks what and how: what conditions do you have, and how do we treat them? But we should be asking why – this is the first critical step toward prevention. If we don’t know why something happens, we can’t hope to stop it. We might or might not be able to pull drowning people out of the river, but we really should ask how these people got in the river in the first place. Where are the sinking boats that left these people stranded in the water?
I started out in biomedical research asking what and how, but after stumbling into some inexplicable questions that cannot be addressed by the what and the how, I started asking why. Our Western diet is certainly a factor. And our stressful lifestyle. But we and others are coming to a fascinating conclusion: intestinal worms are almost certainly involved. But it’s not the presence of the worms that is hurting us. To the contrary, the almost complete loss of intestinal worms in modern society is, surprisingly, a very significant problem. Intestinal worms, called ‘helminths’, have caused untold human suffering, killing the weak and disabling the strong. Labelled uniformly as disease-causing parasites by biologists, they have inspired fear and hate, leading to major campaigns aimed at their eradication. The Rockefeller Foundation, for example, was originally formed to eliminate hookworm from the southern US. Their genocidal campaign was very successful, and similar campaigns are now underway in developing countries. This fearsome menace has been virtually eradicated in the US and in western Europe, and we hope to accomplish the same in developing countries. Good riddance.
But what if we erred? What if our bias against a handful of helminths led us to slaughter billions of innocent and even helpful worms? Indeed, my research and the research of many others tell us that helminths are necessary for our health. A barrage of scientific evidence points toward helminths as being important regulators of immune function. Because of this, our genocidal campaign against intestinal worms apparently has a very nasty backlash that nobody saw coming. But science moves very slowly. All helminths are still labelled as parasites in textbooks, despite the fact that we now know this to be incorrect.
I saw bias override observation earlier in my career, while working in the field of transplantation therapy. Some 25 years ago, we all accepted the thinking of the day: that the immune system was strictly antibacterial. Given that the field of immunology was founded to combat infectious disease, a view that embraced bacteria as the ever-present enemy made sense. But following this accepted dogma, my research team got bogged down in inexplicable observations. The results in the lab didn’t make sense. Why were bacteria carrying ‘tags’ on them, alerting the immune system to their presence and helping the microbes survive? And why hadn’t bacteria simply mutated, evading antagonistic immune systems and killing off our ancestors millions of years ago, long before we ever had a chance to develop antibiotics?
Then one day 20 years ago, standing in front of the fume hood in my lab that is still there today, something clicked in my brain, and everything fell into place. The organisation of bacteria for gut health was immediately obvious, and numerous puzzling observations we had long struggled to grasp fell quickly into perfect order like brawling soldiers suddenly hearing the voice of a fearsome drill sergeant. The immune system was actually supporting rather than fighting off most of the bacteria in our body! This paradigm-shifting idea had far-reaching implications for the field of immunity. For example, the function of the vermiform (worm-like) appendix, that troublesome little structure in our gut, could now be seen clearly as a type of safe house for beneficial bacteria.
The vermiform appendix had long puzzled scientific legends, from Leonardo da Vinci to Charles Darwin, and it was an honour to be at the leading edge of science when the answer presented itself. The thrill of discovery was initially great, and lab experiments designed to test the new paradigm worked beautifully. But repeated rejections by scientific journals and funding agencies along with sarcastic critiques from anonymous reviewers were the norm for the lab during those early years. Fortunately, the paradigm shift made perfect sense to scientists working on the microbial ecology of the gut, and support from that field eventually overcame bias in the field of immunology. We’ll never know how long the paradigm shift in immunology would have taken if it weren’t for the microbial ecologists researching the microbiome.
Now I’m seeing history repeat itself as we attempt to overcome bias against intestinal worms with scientific experiments and observation. With the function of the vermiform appendix, there honestly wasn’t much at stake other than a battle for intellectual territory. Unfortunately, this new battle has more at stake, with tens of millions suffering from diseases that appear to be related to our loss of helminths. But there is hope. Once again, biologists with expertise in the organisation of ecosystems are on our side.
One of the first to light the way was Peter J Preston, a medical doctor with the Royal Navy. In 1970, Preston reported that 12 naval officers who ‘had suffered from hayfever for some years’ were free of hayfever after acquiring the human roundworm. Preston reported that other individuals ‘amongst a large series of patients’ continued to suffer from allergy. Then, six years later, a young British scientist, John Turton, found that intentionally inoculating himself with hookworms eliminated his seasonal allergies.
These early observations led to numerous additional studies, summarised in 2004 by Rick Maizels at the University of Edinburgh, showing inverse relationships between helminths and allergies in various human populations. At the same time, Maizels also compiled an impressive list of studies using laboratory mice, showing that helminths attenuate a multiple sclerosis (MS)-like syndrome, a Type 1 diabetes-like condition, inflammatory bowel disease, gastric ulcers and allergic reactions, including allergic reactions to peanuts.
Mice experiments were quickly followed by studies in humans: in 2005, Joel Weinstock and colleagues at the University of Iowa used porcine whipworms to treat patients with inflammatory bowel disease. Most of the patients had proven unresponsive to pharmaceutical intervention, but 2,500 porcine whipworms administered orally every three weeks for 24 weeks effectively treated more than half of their patients.
Then, in 2007, shortly after Weinstock’s work came to light, the neurologists Jorge Correale and Mauricio Farez at the Institute for Neurological Research in Buenos Aires published results looking at the effects of intestinal worms in humans with MS. At that time, the disease was essentially untreatable and deadly, and, as Maizels had pointed out, work in laboratory animals had suggested that intestinal worms might help.
A complete loss of intestinal worms has something to do with the high rates of mental-health disorders in children
But Correale and Farez took a different approach than Weinstock. They had hundreds of patients with MS, and decided to see if any who accidentally got an intestinal worm might get relief from their disease. Eventually, Correale found a dozen patients who had accidentally contracted an intestinal worm. During the study period, there were three clinical relapses of MS in the infected group compared with 56 relapses in the uninfected group, showing that, in general, the presence of worms offers protection against the symptoms of MS. Correale followed his patients for more than 10 years, and found that, as long as patients kept their worms, their autoimmune disease did not progress. But if they lost their worms, their disease returned. Importantly, it did not seem to matter which intestinal worm the patients had. Some patients had flatworms, while others had roundworms, two very different types of worms, both apparently having the same benefits.
My own research has shown that thousands of humans are now using intestinal worms, from a variety of sources, to effectively treat a wide range of allergic, autoimmune and digestive diseases. Based on previous studies, we were not surprised that people were having success. But we did find one puzzler: people and their doctors were reporting that helminths were helping to treat neuropsychiatric problems such as anxiety disorders and migraine headaches.
Ultimately, we began back-translating the results we were finding in people to see if we could recapitulate the effect in laboratory animals. In collaboration with Staci Bilbo, a renowned neuroscientist at Duke University in North Carolina, we gave benign (harmless) helminths to female rats before the rats became pregnant. Surprising to some but anticipated by us, we found that the brains of baby rats (pups) are protected from inflammation if their mother has an intestinal worm. Thus, it seems likely that a complete loss of intestinal worms has something to do with the high rates of mental-health disorders in our children. Of course, most studies tapping these finds are aimed at using something the helminths make, the molecules produced by the worms, to design a new anti-inflammatory drug. The thought of actually using a helminth as a cure doesn’t seem to be under consideration, perhaps because we are locked into the view that only a drug can help us.
But based on available evidence, we and others conclude that we don’t need to take the risky and potentially very long route of trying to make a worm-inspired drug. In fact, trying to recapitulate a complex biological relationship using a single molecule in a pill might be a lost cause. In contrast, the naturally occurring worm will apparently work just fine.
If we could treat or even prevent many of our modern inflammatory diseases with harmless intestinal worms, why don’t we?
Some of the problem appears to be a lack of trying, and we don’t need to look far for a well-known example where a lack of effort has profoundly hurt the public health: why do public schools in the US feed our children high-fat, processed food known to have dire health consequences after decades of consumption? In a school I’m very familiar with, the hallmark problem with nutrition as defined by the Centers for Disease Control and Prevention is that many children do not have breakfast. Our government ‘solves’ this problem by providing free breakfasts in the public schools. The children have a choice of waffles or cinnamon rolls made from highly processed grains and topped with high-fructose corn syrup, or a colourful round-shaped cereal, again made of highly processed grains and added sugar. In this particular school, my colleague observed that about 70 per cent of the children attending a required health class recognise unhealthy food when they see it. But they generally don’t worry about it very much because they feel that their diet could be worse than it is. In other words, they know that what they are eating is not good, but they don’t worry because they could find even unhealthier food if they really tried. I doubt that their lack of concern is valid. And I wonder why we don’t seem to be trying to fix the problem.
Sometimes, the answer just doesn’t get distributed to the people who need it. The ‘poop transplant’ – officially called the faecal microbiota transplantation – now widely appreciated by medical researchers, is a truly tragic example of this problem. The transfer of faecal material from a healthy donor to an unhealthy one was shown, as long ago as 1958, to cure Clostridium difficile colitis. This recurrent C diff colitis is initiated by the destruction of the friendly microbes in the gut by prescription-antibiotic use. Without the friendly microbes to protect the system, the naturally occurring C diff bacteria overgrows and essentially converts the human gut into a toxic, inflamed wasteland that cannot digest food.
The poop transplant technique was validated by several hospitals in California during the early 1960s, shortly after its discovery. But, sadly, recurrent C diff colitis has continued to take the lives of thousands of Americans each year. Estimates vary, but in terms of American casualties, the death toll was equivalent to repeating the entire Vietnam War every three to five years. Now emerging as a first-line therapy, but still not universally in place, the poop transplant will probably soon become the standard of care. The question is, why did it take 60 years to become popular, despite more than 10,000 Americans dying each year from a disease that could have been prevented? The answer is that the life-saving solution just didn’t get out to the doctors who were treating the dying patients.
It remains to be seen whether anybody can successfully patent a worm that occurs in nature
Reintroduction of helminths to the human body and poop transplants share several things in common. First, they involve naturally occurring organisms that are difficult to patent. With no patent, or ‘intellectual property’, the financial incentive for developing the associated therapy vanishes. The prospect of striking it rich with a new drug under these conditions is nonexistent. One might think that the incentive to heal people and save lives would be sufficient, but the fact is that the current drug pipeline costs more than $100 million. That cost leaves the drug business in the hands of large corporations, and large corporations, regardless of the propaganda they serve in their advertisements, are not interested in making people healthy. If it doesn’t make money, large corporations are not interested. Worse, if the new therapy would undermine millions or maybe even billions of dollars in profit from pharmaceutical sales, corporations are obliged to shy away. It is not their business to put themselves out of business. In the assessment I published with several colleagues, we boiled down the problem to one factor: our government assumes that anything that will treat disease will make enough money to drive the drug past the current cost barriers. This is not true for ‘orphan drugs’ that treat rare diseases and conditions, and it is certainly not true of naturally occurring organisms that are difficult to patent.
The German immunologist Klaus Erb and colleagues at Boehringer Ingelheim – a 130-year-old pharmaceutical company that is one of the world’s 20 most profitable – summarised the problem well: ‘Patent protection is a mandatory prerequisite.’ Erb has a good point. How can any company stay in business if it invests more than $100 million and then can’t protect its investment? It remains to be seen whether anybody can successfully patent a worm that occurs in nature, and that possibly hundreds or even thousands of people are already buying from a local supplier and using without approval from regulatory agencies. Rather than wait and hope for a miracle, our view is that the problem needs to be acknowledged, and that the policy needs to change. Rather than being classified as a drug, helminths need to be classified as something new: as something that we need for maintenance of health, and that’s available to all, rather than a drug owned by corporations and available to those with adequate health insurance.
A second thing that helminths and poop transplants share in common is that they don’t require any of the panoply of modern molecular, genetic tools to sort out what’s going on. What was lost has been found, and now the biological system is restored. It’s easy to comprehend, akin to a vitamin, with no PhD required to grasp the picture. This might seem to be an advantage. Indeed, I believe that it should be an advantage. But, oddly enough, it doesn’t work that way in reality. The reason is that most research on inflammatory disease focuses on the mechanisms and genetics underlying those diseases, and any work not digging deep into mechanistic underpinnings is simply considered to be unscientific. If engineers were in charge of biomedical research, this would not be a problem. I suspect that we might have other problems imposed by engineers (I have a family full of them), but straightforward solutions that make sense would move forward rapidly if engineers were in charge. That’s not true in the current science-driven environment. Anything that doesn’t involve a few molecular-signalling pathways and up to four unrecognisable acronyms just isn’t science these days. Fifty unrecognisable acronyms might be overkill, but at least a few are required to get federal funding.
I am not anti-science. I am a scientist and I love running a fun experiment now and then to see if my guess is any good. In science, biophysics and biology are my passions. I remember the day an experiment confirmed my hypothesis on why we have an appendix attached to our caecum. We knew that, if our hypothesis was correct, intact films of bacteria, called biofilms, should be present in high quantities in a healthy human appendix. It took two years to run that experiment, but I remember the moment when the predicted bacteria showed up on the imaging screen. I found the only other human I could at that time of night, and showed the bewildered fellow the exciting result! I remember a few missed calls as well, and I still have ideas that I would love to test one day. I love science, but science can wait. First we need to implement commonsense therapies to alleviate suffering to the extent possible, and then it would be interesting to dissect out many of the fine points of how those therapies work using modern scientific approaches. Those reductionist details could possibly help us refine the therapies. And it would be fun for scientists such as me to dig up the details. But to wait indefinitely on science when the therapy is available and ready for testing is much worse than unreasonable. It is inhumane.
Most of our science dollars go toward biomedical research, looking for treatments to diseases that, for the most part, are associated with dangerous levels of inflammation. But what if worms offer a cure for many of our modern inflammatory conditions? We don’t expect them to be a magic bullet, but in combination with a healthy lifestyle, increasing evidence suggests that the reintroduction of worms will effectively prevent or even treat many of our modern inflammatory diseases. What if allergy, autoimmunity, digestive disorders and neuropsychiatric disorders were a thing of the past? Our research dollars could be spent on fun things, such as space exploration, particle physics or even the biology of the life on this planet. Understandably, we do not spend our research dollars studying scurvy or rickets. We have a cure for those conditions (vitamin C and D supplementation, respectively), and there is no point in studying a disease that is easily prevented. But just maybe we are in fact spending most of our energy studying readily preventable diseases. That’s akin to studying a fish out of water. That fish is going to be sick, and the sickness will be complicated. But if the goal is to make the fish well, we should stop studying the sickness and put the fish back in the tank. For better or worse, the water tank for humans contained a few intestinal worms.
Why did we do those successful experiments with helminths if nobody is going to translate them to the clinic?
Every one of us, regardless of our training in science and medicine, should be asking not so much what a disease does to our body, but rather why we got the disease in the first place. Most of the work we do in science is geared toward understanding exactly what components of our body are affected by disease and precisely how those components are affected. That’s important if we want to develop the next generation of drugs. But I believe we deserve more. With the vast resources we have dedicated to our health, our society could be very close to disease-free. If we don’t start asking why, however, the trend toward sickness and dependence on medicine will only continue to spiral out of control. As that happens, the struggle for access to costly but limited medical resources will intensify, and that struggle will continue to blind us to the central question: why do so many of us need medicine?
The toxic food served to our children by our government is an obvious indication that something is horribly wrong with public-health policy in the US. The lack of acceptance of proven and commonsense therapies such as faecal transplants is yet another. Failure to fund work aimed at the reintroduction of intestinal worms to alleviate inflammatory disease, despite compelling evidence from the laboratory, is another indication still. Why did we do all of those successful experiments with therapeutic helminths if nobody is going to translate them to the clinic? Why the great sacrifice of laboratory animals and human effort?
I’m often asked if some nefarious pharmaceutical corporation might be flying the plane of public health in this country. I don’t think so. I have come to understand that this plane is on autopilot, and is built of certain assumptions that look reasonable at first glance. Sadly, those assumptions are false, and the infrastructure of that plane is fatally flawed. We need to withdraw our faith and our focus away from creating an ever-increasing litany of drugs for treating an increasingly sick population, and design a new plane that asks why we get sick – and aggressively address the answers to that question.