Exploring chronic disease
Patients with diabetic neuropathy may not notice minor injuries due to loss of feeling in their lower extremities. Since the Vitamin D Receptor is inactivated by bacterial ligands, a small cut or sore can become infected, and flare into a limb- or life-threatening condition in as little as three days. These wounds are so difficult to heal that most of medicine considers them a lost cause and treats them with amputation. Amputations are often considered to be the beginning of the end for patients with diabetes.
70% of diabetics who undergo an amputation die within five years due to the stress placed on their hearts from their altered circulatory system. During those five years they are likely to have more amputations and to rate their quality of life worse than cancer patients, according to some studies.
Nationally, an estimated 82,000 people with diabetes had lower-limb amputations in 2002, according to the Centers for Disease Control. But thanks to a doctor at the Southwest Regional Wound Care Center in Lubbock, Texas, who has teamed up with researchers from Montana State University’s Center for Biofilm Engineering, this situation is changing. After sending samples of the sludge on his patient’s wounds to the Center, Dr. Randall Wolcott was informed that his samples were largely composed of bacterial biofilms.
This discovery eventually led to a paper on the findings published in the October issue of Wound Repair and Regeneration, an important step in convincing the medical community of biofilms’ importance in chronic wounds.
In the meantime, with the help of other scientists, Wolcott created a series of treatments that allow him to successfully kill the biofilm bacteria that have taken over his patients’ wounds, saving most of them from the horrors of amputation.
Before treating the biofilms on his patients’ wounds, Wolcott admitted patients for an estimated 10 to 15 amputations a month. Now, he’s gone months without one of his patients receiving an amputation. He can confidently look patients in the eye and say he’s 80% certain that their wound is going to heal.
Since patients with diabetes and a host of inflammatory diseases are also killing biofilm bacteria thanks to the Marshall Protocol, Dr. Wolcott’s work is yet another wake-up call as to the massive role these communities of bacteria play in causing all stages of chronic disease. I was lucky enough to speak with Dr. Wolcott and his laboratory research coordinator, Dan Rhoads. We spoke about their work, the importance of biofilm research, and the characteristics of biofilms in general.
Well, that’s a big question but I’ll do my best! Biofilms have been around for at least 3 million years. They are essentially how organisms protect themselves from environmental attack – from chemicals, phages (viruses that infect bacteria), UV light, or other challenges. We now understand that early on, bacteria learned to act as a community. By doing so, they allowed their existence to become much more secure. When bacteria first started to be studied about 150 years ago, the idea of a bacterial biofilm was simply too complex for scientists at the time to grasp. Consequently, early microbiologists were only able to study single bacterial organisms, one at a time.
However, today we have an array of new molecular tools that have opened up a whole new world when it comes to understanding how bacteria survive. We now realize that bacteria are hardly ever found individually (in what is referred to as a planktonic state), but instead frequently join communities. These communities are then able to secrete substances that allow them to grab substances from the surrounding environment in order to create a matrix that protects all the bacteria inside.
Planktonic bacteria produce certain proteins, but once they join a biofilm, the biofilm community expresses vastly different proteins and genes. For example, studies have shown that when a single bacterium becomes part of a biofilm the expression of over 800 genes can change.
When a bacterium is in its planktonic state (on its own), it’s generally able to be cultured in a laboratory. It can also usually be killed by antibiotics. But since biofilms are entities that form under specific conditions in the human body, it is often difficult or impossible to grow them in a laboratory setting. They can no longer be killed by the standard high-dose antibiotics that easily target most single, planktonic bacteria because the community works to protect its members.
So planktonic bacteria and biofilms are as different as caterpillars and butterflies. The organisms have the same genotype, but totally different phenotypes.
I believe that they could be. Once bacteria have joined into biofilm communities, they can no longer be effectively targeted by the immune system. This means that after a biofilm is created, it persists as a chronic infection. Like patients who suffer from chronic inflammatory disease, people with biofilm infections find that high-dose antibiotics or steroids may offer them temporary relief, yet their infection never actually goes away.
Dan and I have been reading several review articles that link autoimmune disease to chronic inflammation, and the more we’ve read, the clearer it’s become that chronic inflammation is a result of bacterial infection. So we think there is a clear link between chronic inflammatory diseases and bacteria, and when we think, “chronic inflammation” we believe we are typically dealing with biofilm infections.
I attended a lecture about biofilms in 2002 which piqued my interest in the subject. Then I used Google to search for further information on biofilms and came upon the Montana State University’s Center for Biofilm Engineering – the place that is, in my opinion, the keeper of all knowledge about biofilms. I called them and told them about what I was observing on the wounds of my diabetic patients. I highly suspected that much of the sludge that I was removing from the wounds was biofilm. The center agreed to work with our office, and we proceeded to send them 50 samples of material scraped off our patients’ chronic wounds. Their molecular techniques confirmed that the majority of the samples did contain bacterial biofilms.
At this point, let me pause to say that diabetic foot ulcers kill tens of thousands of people. Over 100,000 limb amputations happen every year because of infected wounds. The suffering is tremendous and, if the infection from a wound spreads or if the limb is amputated, the patient has a high risk of death. So finding a way to quell the bacterial infections and to heal diabetic wounds is a matter of life or death. So when we realized that we had discovered a previously unrecognized bacterial cause that explains the chronicity of diabetic wounds – wounds that cause patients to lose their limbs – we went after the whole hog.
First we use diagnostic tools to determine that biofilms are indeed present on the wound. The techniques also help us identify the species of bacteria in a particular biofilm.
Well, now that you’ve brought that up, let me address the question now. The agar cultures that most scientists still use today in order to grow bacteria in the lab are 150 years old. A century ago, Robert Koch first discovered that planktonic bacteria could grow on a plate of agar. He used agar because you can manipulate the plate, scrape out the contents, thin out the contents enough, and finally end up with just one single bacterial species growing on the plate. Koch is the founding father of medical microbiology, and we are now standing on his shoulders. However, our understanding of science and medicine has changed a lot in the last century. Based on his pure-culture techniques, he created a series of postulates which state that only one single species of bacteria can cause any one disease. His postulates also state that a disease pathogenesis can only be considered legitimate if the single bacterium connected to the disease can again be isolated alone on an agar plate.
Of course, Koch did not isolate bacteria and try to grow them on a medium that wasn’t agar. This is because if he did – let’s say he had tried to grow a bacterial species on a potato or an egg – the single bacterium would have surely congregated with other bacteria in the environment to form a biofilm – a biofilm that Koch could not isolate and study. So growing bacteria on anything besides an agar plate meant dealing with a situation that was too difficult for Koch to understand. So it seems he chose not to deal with such matters.
Unfortunately, Koch’s postulates caught on among other scientists and eventually became the rule of thumb for growing bacteria and accepting organisms as disease-causing agents. Agar was, and still is seen by many, as the only appropriate bacterial growth medium. Even today, doctors still rigorously adhere to Koch’s postulates, which I believe has significantly impeded their ability to study and understand how bacteria actually survive and cause disease in the body where they are seldom found as single entities.
Of course, growing some strains on agar has helped us better understand diseases such as strep throat, but we’ve pretty much knocked such diseases out. What we are only starting to realize today is that at least 80% of all the infections we treat are caused by biofilm bacteria, not planktonic bacteria. Now the playing field has changed. We’ve taken care of the planktonic bacteria that cause infections. Now we need to start treating polymicrobial diseases – those caused by combinations of bacteria. Continuing to culture on agar and adhering to Koch’s postulates is going to hinder that line of research because it impedes us from looking at the real thing, or what actually happens in the body. In the body, bacteria group together in communities. Changing the way we look at infection will require a paradigm shift in the way doctors think about bacterial populations and the potential of biofilm bacteria to cause disease.
Happily, PCR [polymerase chain reaction] has allowed us to detect many of the bacteria in the biofilms we have studied. There are also many other molecular tools that exist or are being created that will allow for better detection of biofilm bacteria and bacteria in general. Once our team started using some of these sensitive, DNA-based technologies to identify the composition of bacteria in wound biofilms, we detected hundreds of different species, most of which would never grow on an agar plate. And every time we run the tests over again, it seems like we come across even more sequences of DNA that indicate the existence of new pathogens. So, the more we use these molecular diagnostic tools, the more we are realizing what highly diverse populations are inside wound biofilms.
Consider this. In one of our latest studies, we found that it is common for at least 10 bacterial species to comprise at least 1% of each wound’s microbiota. And there were over 40 different species of bacteria that comprised at least 1% of the population in one sample or another. When you look deeper at that 1%, you see that there can be 40, 50, 60 species of bacteria on every wound – an incredible amount of diversity.
Our next step is to determine which of the bacteria we have identified are important and which are not? Perhaps it will turn out that all species detected are important contributors to the virulence of each biofilm, or maybe we will discover that some are key species that cause more harm than others. By continuing to identify the bacterial species in the biofilms of as many of our patients’ wounds as possible, we also hope to determine possible correlations between the component bacterial species in the biofilm population and wounds’ severity. For example, the existence of some species may be found on wounds that are more difficult to treat. Based on this information we may decide to treat different wounds in different ways.
There are a lot of people in the biofilm community who argue about the importance of particular species of biofilm bacteria, and many different research groups, each of which usually has its own opinion on which bacteria in a biofilm may be causing more harm than others. But our stance is that all the bacteria in a biofilm are important because they may act synergistically. Biofilms represent entire ecosystems, just like a forest. A forest isn’t made up of just squirrels, or just trees. Rather, all the entities that make up a forest work together and all are important to the survival of the community.
This brings me to the concept of functional equivalence – a phenomenon that explains why biofilms are able to resist so many sources of stress. Let’s say a single bacterial species such as Staphylococcus aureus is floating around as a single entity. It can be easily identified and attacked by the immune system. Similarly, if it attaches to a surface and starts to form a protective protein matrix around itself – a biofilm – the biofilm is still relatively easy to break down because Staphylococcus aureus has limited defense mechanisms on its own.
But lets say that when Staphylococcus aureus starts to form a biofilm, 10 other nearby bacteria develop the ability to attach to the biofilm as well. Now, if the biofilm is attacked again (by the immune system or other chemicals) it will be much harder to break down. That’s because each different species of bacteria in the biofilm possesses its own characteristics and its own strengths to combat the attack. If one species goes down, four others may still be able to fight and remain functional. A different form of challenge may take down those four species, but then some of the species that were not as effective against the first challenge may rise up and have the capability to deal with the new attack. I think this phenomenon – functional equivalence – is a very, very, important concept in chronic inflammatory infection.
Functional equivalence has been documented in vaginal biofilms. Most vaginal biofilms seem to be composed of only one species of bacteria called Lactobacillus. These biofilms adjust the vaginal environment so that it has a pH of around 4.5, a pH that is most conducive to their survival and the woman’s good health. But it has been found that functionally equivalent biofilms develop that mimic these Lactobacillus biofilms. In the functionally equivalent biofilms, subgroups of different bacterial species come together and interact in order to allow the environment to create the same acidic environment. The difference is that the functionally equivalent biofilms, composed of many different species of bacteria, can perform similarly to the lactobacillus biofilm. These two genotypically different biofilms are phenotypically equivalent. They are functional equivalents.
The same thing happens in wound biofilms. We see some that are predominantly colonized by single, well-known pathogens. But then we also see clinically similar biofilms made up of many different species of bacteria, and it is usually these diverse biofilms that display interesting growth patterns, interesting characteristics, and probably the best survival mechanisms.
We don’t know, although Dan and I have had several conversations about it. It’s mostly conjecture at the moment. We do know that a delayed immune response is what allows wound biofilms to become established. When wound biofilms start to form, they do so very quickly. Sometimes, they can even be detected after 20 minutes of growth. In other words, bacteria begin to form biofilms as soon as possible. If the immune system of people with diabetes were working up to par, they would be able to delay or retard such quick establishment of the biofilm, which is what a healthly individual can do.
Yes, most of our patients’ wounds heal by using various treatments to wear away at the biofilms that cover them. These treatments include putting lactoferrin and xylitol on the wound. Lactoferrin occurs naturally in tears, mucus and breast milk and appears to attack the bacteria from multiple angles. It is used commercially in meat packing plants to prevent biofilms from growing on carcasses. Xylitol occurs in fruits, vegetables and other plants. It is also produced as part of normal human metabolism. It is used in toothpaste and chewing gum because of its anti-biofilm properties.
An invaluable first step to treating a wound is debridement, or scraping the biofilm — a yellow-greenish sludge — along with dead tissue off the top of the wound with a curette. For some patients, this can be painful even with an anesthetic. Others feel nothing as diabetes has destroyed the nerve endings in their feet and legs. We also use five hyperbaric chambers where patients spend hours in a super-oxygenated environment that’s good for healthy tissue and bad for biofilms. We also use an arsenal of antibiotics and a new lipid-based gel. We recently finished a study in which we used a bacteriophage (viruses that infect bacteria) cocktail to fight the biofilms.
I don’t mean to sound arrogant, but we know we’re right. We know that diabetic wounds are covered in biofilms and that it is biofilm growth that causes them to deteriorate to the point where most other doctors usually just cut them off. Once we realized that our patients’ wounds were covered with biofilm bacteria, we just knew, “This is it!” So we intend to spread the word about our discoveries ASAP. There are just a drastic number of medical issues that stem from biofilm infection. 500,000 people suffer from sinus infections caused by biofilms ever year. There are dozens and dozens of chronic infections that are biofilm related – infections that are now left uncured and thus force people to have heart valves put in, or lead to the removal of entire colons, or lead to tubes in the ears – all kinds of things. It’s bad, and we need a different answer to the way we treat so many conditions.
Yet we are still often met with skepticism. I try to take the approach that nothing is fun if it isn’t controversial. Once the presence of biofilms on diabetic wounds is accepted as truth, the excitement and ambition of working in the area will dwindle. What we want now is confrontation. We want to push our ideas. It’s up to us to prove this is the real thing. It’s a vetting process, but we can win.
What we do need is for researchers and doctors to be open minded. Instead of brushing us off, they need to look at the evidence we are presenting, absorb it, and at least argue with it if they think it’s wrong. When it comes to chronic biofilm infections, we are dealing with life and death situations, so it’s important that others take note of the facts and reasonable arguments that are currently on the table.
Well, when diabetic patients develop an infected wound that causes a limb to turn black, the trauma serves as a major wake-up call. Many of our patients start taking their illness much more seriously. Some buy insulin pumps. Others are careful to buy special diabetic shoes that offer better foot care, or finally make regular visits to their podiatrist to have difficult-to-cut nails sawed off. All these measures reduce the likelihood that they will develop another wound.
We do realize that even when we effectively save a patient’s wound, our patients are still at risk for new wounds because they are immunocompromised. However, when a patient comes in with a wound on one limb we can demonstrate that the same comorbidities are present in the other limb as well, but it does not have a wound. The other limb appears to be intact and generally healthy. If we can work to heal the wounded limb, it should be just as healthy as the patient’s unwounded limb.
But yes, we do have patients that we have treated once for a wound who come back two or three years later with another wound. The good thing is that, based on their first experience, these patients know to come see us as quickly as possible. The sooner we can treat the wound the less likely it is that the infection will spread to the bone where it is much harder to manage.
Oh, don’t get me started! Here’s my favorite example. I went to a biofilm conference in 2005. The first speech I heard was given by researchers from Proctor and Gamble. They had developed Compound 227 that works to prevent biofilm growth in the mouth and thus prevent the accumulation of dental plaque. They had literally spent millions and million of dollars on this research, just tremendous amounts of money so that they could use any discoveries to create a more effective toothpaste. Others spend millions to identify chemicals that can better remove and prevent biofilms that often accumulate on toilets—you know, those ugly rings.
The presentation that followed the dental and industrial presentations was about biofilms and medicine. There was next to nothing to report and practically no spending whatsoever in the area. I came away understanding that right now we are spending way more money on preventing biofilm growth on teeth and toilets than on finding ways to effectively treat the dozens of different serious (many life or death) medical conditions that result from biofilm infection.
Well, as we’ve moved forward with our work, we’ve taken our share of hits from all different types of regulatory agencies as well as funding agencies. So for some doctors, it may seem like this kind of scrutiny is not worth the extra hassle.
But I feel many other doctors care. They are tired of telling their patients, “That’s just the way it is. I can’t make you better,” but often they don’t know how to get started. For example, a physician from England recently came to visit the clinic. She is interested in starting to treat the biofilms that she encounters most often: chronic and recurring bladder infections. However, in order to take this new approach, she is required to begin to work more independently from the National Health Service.
I take it you are familiar with evidence-based medicine? It’s the increasingly accepted approach for making clinical decisions about how to treat a patient. Basically, doctors are trained to make a decision based on the most current evidence derived from research. But what such thinking boils down to is that I am supposed to do the same thing that has always been done – to treat my patient in the conventional manner – just because it’s become the most popular approach. However, when it comes to chronic wound biofilms, we are in the midst of a crisis – what has been done and is accepted as the standard treatment doesn’t work and doesn’t meet the needs of the patient.
Thus, evidence-based medicine totally regulates against innovation. Essentially doctors suffer if they step away from mainstream thinking. Sure, there are charlatans out there who are trying to sell us treatments that don’t work, but there are many good therapies that are not used because they are unconventional. It is only by considering new treatment options that we can progress.
We know without a doubt that chronic diabetic wounds can be saved if the biofilm bacteria that cover them are eliminated. So we are simply unwilling to use a control group as guinea pigs when we know we’ve got the methods to save most of their limbs as well. Granted, we are using some medications for off-label purposes, but they are all approved by the FDA. This is not just experimental stuff. We know that what we are doing is right for the patient. So we simply refuse to do a study where the control group is not treated. The only double-blinded trial we’ve done tested the effect of bacteriophages on wound biofilms, but in that case, the control group still got treated with everything else in our arsenal except the bacteriophages.
We hope we can come to a compromise. We have plenty of data, and even though it’s retrospective, it’s still very valuable. So we hope that the medical community will take this evidence as proof that we are doing the right thing, in lieu of a blinded trial. Right now, rather than focusing on a blinded trial, we are simply focusing on what is best for the patient. We are trying to heal as many patients’ wounds as possible. That’s our main priority – treating patients right here and right now. If you take time to look at the retrospective evidence, it is solid. Our patients do very well.
Only from what you’ve just told us, but we plan to investigate it further. The idea of pulsed antibiotics makes a lot of sense – essentially it may allow the antibiotics to target the growing or regenerating cells in the biofilm, which were previously persister cells. Please send us more information.
Me: Great! I think that the Marshall pathogenesis will help you better understand why the diabetic patients you treat are so immunocompromised. As you know, we believe that the entire pathogenesis of diabetes is caused by L-form and biofilm bacteria, and that these bacteria are able to create substances that slow the Vitamin D Receptor and subsequently the activity of the innate immune system. Thus, we believe that restoring the competence of the Vitamin D Receptor is key to recovery to inflammatory disease. Activating the VDR, or putting your patients on the full Marshall Protocol, could help restore their innate immune function, which may go a long way in preventing them from developing new infected wounds. At least that’s my take!
The following is an excerpt taken directly from an article on the Montana State University’s Center for Biofilm Engineering website. It describes the experience of just one of Dr. Wolcott’s patients.
The fruits of this science can be seen in the story of Jerry Montemayor, a 38-year-old school administrator in Lubbock, who stubbed his toe on the corner of his bed one morning in December 2005 and nearly lost his foot.Initially, Montemayor ignored the bruise. A diabetic, Montemayor has poor blood circulation in his lower legs and feet. Three days later, his toe was discolored and he limped with discomfort. He went to an emergency room.Emergency room physicians told Montemayor his foot was severely infected and he must be admitted. He spent the next 12 days in the hospital. When his infection didn’t respond to treatment, Montemayor’s physicians told him his foot should be amputated, or he risked losing his entire leg, and possibly his life.
“First they said it would be the top of my foot, then half of my foot, then my whole foot,” Montemayor said. “They kept telling me I needed to set a date and time for my amputation. Believe me, if it wasn’t for the power of prayer I don’t think I’d have gotten through this.”
Montemayor sought a second opinion. The next day, two staff members from Wolcott’s center visited.
“I’ll never forget that visit,” Montemayor said. “One of the girls said ‘We’ve seen worse. We suggest you do not get this amputated. We can treat this.’”
It was Christmas Eve.
Montemayor took their advice and began nearly a year’s worth of treatments at Wolcott’s clinic on Christmas Day. Today, he walks on both feet.
“The clinic staff said they were going to do their best and they did,” Montemayor said. “I’m blessed to be walking.”
“It’s hard to relive that experience in the hospital,” he said. “At the time I was thinking about my personal life. I was thinking how this would affect me meeting someone, or having a relationship with someone. Is she going to accept and support me? Is she going to be able to walk next to me and accept that I have a prosthetic limb?
“I was thinking ‘If I have kids will I be able to run and play with them?’” Montemayor said. “I was thinking ‘Am I going to be a whole man?’”
Since the time of this interview, Dr. Wolcott has continued to successfully treat his patients’ wounds. At around the time of this interview, Dr. Wolcott authored a paper, the abstract of which appears in PubMed: A study of biofilm-based wound management in subjects with critical limb ischaemia. Here is the money quote:
When comparing the healing frequency in this study with a previously published study, [Biofilm-based wound care management] strategies significantly improved healing frequency. These findings demonstrate that effectively managing the biofilm in chronic wounds is an important component of consistently transforming ‘non-healable’ wounds into healable wounds.
I am also including images Dr. Wolcott put online. Anyone who is interested can view the large PDF file which contains images of the patients Dr. Wolcott has treated according to his biofilm-based wound management strategy. Here’s a sample.
Although it may not seem like a topic immediately related to the Marshall Protocol, I believe that it’s difficult to truly envision the new bacterial pathogenesis of inflammatory disease without taking horizontal gene transfer, or the ability of bacteria to swap DNA, into account. In other articles on this site, I’ve described how people with inflammatory disease gradually accumulate a “pea soup” of pathogens. I like the term because it hints at the fact that everybody’s bacterial load is unique and also brings to mind the image of something stirred or mixed. Everyone with Th1 disease acquires a large mix of different pathogens, but even the image of a great number of different but isolated pathogens does not do justice to the variety of different bacteria that each patient harbors. This is because, if bacteria can trade DNA, they are constantly trading genetic material which allows for the constant creation of new species, with new characteristics and new survival abilities. So the bacterial loads we harbor are probably much more complex than we envision and certainly more complex than what conventional medicine envisions. After all, conventional medicine is still trying to tie one pathogen to one disease, and that’s only if they even decide to factor bacteria into the picture at all.
In order to better understand horizontal gene transfer, I spoke with Dr. Peter Gogarten at the University of Connecticut and Dr. James Lake at UCLA, both of whom are leaders in the field of gene transfer. Both of them were extremely friendly and seemed excited to speak with me about the phenomenon. I asked them the same questions. Here is how they responded:
Lake: Well, without taking horizontal gene transfer into account, how do we explain the fact that prokaryotes (bacterial organisms) continue to trade genes even though they have no means of sexual reproduction? The only way that new bacterial species can form, and populations of bacteria can adapt and conform to new circumstances, is if they exchange DNA or genes during their lifetimes.
We now realize that organisms with similar characteristics find it much easier to swap DNA. But on occasion, a group of organisms, such as a species of bacteria, can trade DNA with a class of organisms that have very different characteristics. If this does happen, it means that through the process of horizontal gene transfer, a bacterial species can acquire a host of new characteristics, even from organisms that are quite different from them. These new acquired characteristics may or may not offer them a survival advantage, but if the acquired traits do endow them with an advantage, they may be able to survive in a new environment or infect a new species – anything along those lines.
So, in my opinion, it turns out that the exchange of genes among prokaryotes is more fundamental than we’ve ever thought it to be in the past. Because of horizontal gene transfer, the evolution of many species, many different types of bacteria, and also multi-celled organisms are all entangled. Our genetic histories are definitely the result of our DNA mixing with the DNA of other species, including bacteria. Clearly this phenomenon plays a significant role in the body.
Gogarten: Horizontal gene transfer allows us to understand how organisms such as bacteria, that don’t have sex, are able to exchange genetic material and create genetic diversity amongst their populations. Human beings and most mammals reproduce via sex in what is called vertical gene transfer. In the case of vertical gene transfer, two sets of different chromosomes (that contain different genes), one from each parent, combine, so that the offspring has a combination of genes from both mother and father. So horizontal gene transfer, the type of gene transfer that occurs between bacteria, viruses etc, is another mode of sharing DNA that still fosters diversity. If bacteria and other organisms couldn’t trade genes via horizontal gene transfer, then there would be no recombination at all, bacteria would not be able to change or acquire new characteristics from generation to generation. Species that have more in common are likely to trade genes more often. However even species that are not of the same lineage can trade genetic material. For example, research has shown that over the past million years, species of bacteria picked up DNA from the domain Archea, prokaryotes that are very different than bacteria. These exchanges may be rare, but still occur.
Lake: I am open to the idea that bacteria may be behind diseases of unknown cause. Lately, I have been fascinated by many of the studies which have found that certain species of bacteria in the gut affect an individual’s tendency to gain weight. Even before these studies came out, I’d been thinking about such a possibility for years. I thought a connection would be found. I started to think about the possibility after taking a trip to Japan about four years ago. I was helping advise a steel plant which had just built two refineries for their waste (waste can easily be infected by bacteria). They were identical – they had the exact same design, were the exact same size, and had the exact same content inside (remnants of waste). Yet one of the refineries worked perfectly well and the second refinery simply didn’t work. We ended up taking the bacteria from the refinery that didn’t work and transferring the populations over to the refinery that did work – much like the researchers in these obesity studies take bacteria from obese mice and implant them into thin mice. In the case of the refineries, once we did the bacterial transfer, the second refinery stopped working in the exact same manner as the first. So clearly, certain species of bacteria determined whether each refinery was able to function. I went away thinking, “If this can happen in a reactor mill, it’s got to be able to happen in the body!”
Gogarten: I do believe that in the future we will discover that many more diseases of unknown cause have a microbial component. I believe the fact that we have not implicated bacteria in more diseases is related to our inability to correctly culture so many different forms of pathogens. Current culturing mechanisms are obviously very poor at identifying the presence of bacteria. Once molecular technology becomes used more frequently, we will probably be able to detect more pathogens and recognize their association with disease. I also suspect that we will be hearing more about how an imbalance of bacteria in the body can cause disease.
Lake: Right now we are only able to estimate and guess about the exact rate of horizontal gene transfer that occurs between organisms. As I mentioned before, it is much easier for similar organisms to trade genes, so HGT happens more frequently between such organisms rather than in organisms with different characteristics. I can’t tell you an exact rate, but I do believe that gene transfer occurs very frequently among similar organisms because of the fact that such transfer happens relatively easily and there are several different ways for DNA transfer to occur. Among all these options, it’s probable that transfer happens quite often. There are three fundamental ways that organisms exchange DNA:
The first is called conjugation. This process simply involves introducing new genetic material into a different organism. Whether the genetic material is actually incorporated by the new organism is something that’s harder to track. It used to be thought that conjugation was a way to explain how bacteria like E. coli might have “sex” or foster new organisms with different genetic characteristics. But researchers soon realized that E.coli can also exchange genetic material with organisms with very different characteristics (like cyanobacteria) through conjugation. So it’s not technically sex if it can happen between very different organisms. Still, this is one of the easiest ways to exchange DNA and can be performed in the lab.
The second way that organisms exchange DNA is through a process known as transformation. I’m really interested in transformation. Several decades ago it was mistakenly thought that organisms actually feared strange DNA, or DNA from organisms not like themselves. However, we now realize that this is definitely not the case. Now we know that, in the lab, it’s possible to take organisms with very different DNA, put them in solution, and electrically shock the plate. During the shock, the organisms in the plate trade much of their DNA. This suggests that under stressful situations in particular, organisms are more likely to engage in gene transfer. So, in the body, gene transfer may be particularly common under situations of stress or starvation. If an organism finds itself in a cell that isn’t getting adequate nutrients, it’s logical that it would try to swap DNA with another nearby organism in the chance that the DNA swap might offer it some sort of survival advantage. It’s quite possible that the DNA swap would have no effect, but then again, maybe the swap could give the bacterial species an enzyme that would allow it to use an alternate energy source still available in the cell. This may be how bacteria remain alive when they are forced to go into “survival mode.”
Last, but not least, gene transfer can occur through transduction – a process in which virus infect bacteria or humans and in the process integrate their DNA into the organism they have infected. So it’s perfectly likely that if a person is infected with both bacteria and viruses, the two forms of organisms can swap DNA.
Gogarten: This is a difficult question. It’s very hard to estimate the rate of HGT. But several studies have been eye-openers to me, suggesting that horizontal gene transfer happens quite frequently. I remember a study in which researchers looked at three different E. coli genomes. Basically, they just took the three genomes and sequenced their DNA. Without taking HGT into consideration one would expect the genes of each E. coli in each genome to be identical because they are all the same species. But, after using a molecular technique, the researchers found that only 40% of the genes that each E. coli harbored were identical. 60% of the genes differed between each E.coli genome sequenced. This suggests that among E. coli, and other similar bacteria, an enormous amount of horizontal gene transfer is taking place during just a short period of time. A really amazing amount of transfer.
One must understand that when bacteria and other organisms swap DNA through HGT, most of the changes that occur when the DNA is swapped are not important or fail to give an organism that acquires new DNA a survival advantage. But in some cases the swap results in a situation that endows another bacterium with a plasmid, or a protein that does provide an advantage, allowing the organism to live in a new ecological niche or survive new environmental conditions. This is how bacteria end up adapting to new challenging circumstances. But for the most part, it is hit or miss. I’d say the occasions on which organisms are actually conferred a serious survival advantage thanks to HGT are rare. They are, for the most part, the exceptions. But when they do occur, the organism involved in the transfer can really benefit.
Also take, for example, the amount of HGT that probably goes on inside bacterial biofilms. Biofilms are definitely environments that foster HGT. I remember a study where researchers took several plasmids and stained them with a fluorescent dye. They did this so that if they were taken up by another organism, you could see them glowing inside and know the plasmid DNA had indeed been incorporated. In this particular case, the researchers started with two bacterial biofilms and introduced several of these plasmids. Soon, both biofilms were glowing with light. So it was obviously quite easy for the organisms in the biofilms to pick up new genes.
Right now, I am very interested in studying xenobacteria, single-celled organisms that live in oceans. There are many strains of these bacteria, and all of them differ because, over time, each acquired different genes. Some of the genes that all xenobacteria picked up allowed them to change from normal bacteria to organisms that are able to perform photosynthesis under the water. Even now, the different strains of xenobacteria still shuttle genes back and forth. It’s almost like trying to study and classify Darwin’s finches. Each bird acquired (through vertical gene transfer) genes that allowed it to adapt to its own niche and find unique sources of food. In the same sense, HGT has allowed xenobacteria to do the same thing, and tracking their diversity is just as interesting as looking at the differences among Darwin’s finches. Studying xenobacteria has convinced me of the tremendous amount of horizontal gene transfer that takes place in the ocean.
Lake: It’s hard to tell because the phenomenon is so complex. For the most part, it seems that researchers are making an effort to account for horizontal gene transfer but some of the genetic changes that occur due to the phenomenon may definitely be too subtle for us to pick up. The whole process is likely too complex to be fully accounted for in the average study.
Gogarten: I think the pendulum swings back and forth. In the 1940s, scientists had largely given up on the idea that we could create a tree of life – a chart that would show us the lineage of organisms on Earth. Researchers figured because so much HGT was going on, it would be impossible to separate species into distinct lineages. Then, over the past decades, researchers like myself have given thought to the possibility that we may indeed be able to classify organisms, at least to some extent, despite the fact that they so frequently trade DNA. Yet rather than a tree of life, I think what we have to envision when we think of connections between species is more like a web, a network – where there are main lines of ancestry, yet some species that don’t fall strictly into any category between them. In this area, I think we are just scratching the surface of what we will find when we really start to learn more about how HGT has affected the evolution of organisms over the course of history.
Lake: These are very exciting times. I feel that in the next five years our whole view of the evolution of life may change as we continue to take this phenomenon into account. I’m glad you’re taking a close look at the characteristics of bacteria on your site.
Gogarten: My work has showed me that HGT is capable of endowing organisms with dramatically new traits and completely change the capabilities of microorganisms.
Paul W. Ewald is an evolutionary biologist, specializing in the evolution of infectious disease. He received his Ph.D. from the University of Washington, in Zoology, with specialization in Ecology and Evolution. He is currently director of the program in Evolutionary Medicine at the Biology Department of the University of Louisville.
The first recipient of the George R. Burch Fellowship in Theoretic Medicine and Affiliated Sciences, Ewald’s publication of Evolution of Infectious Disease is widely acknowledged by doctors and scientists as a watershed in the emergence of the new discipline of evolutionary medicine. He has been featured in The Atlantic, Newsweek, Discover, and Forbes.
Professor Ewald is also the author of a groundbreaking book, Plague Time; How Stealth Infections Cause Cancers, Heart Disease and other Deadly Ailments.
When we consider the possible causes of disease, it’s important to make sure that at our starting point, we put all categories on the table. I believe the most useful way to do this is to think in terms of three main categories:
Once we have this spectrum of categories in mind we ask, “Have all three areas been investigated?
At this point scientists tend to make an error. They decide that if they have found enough evidence for categories 1 or 3, that category 2 is not playing a role. This is a fundamental problem that has led the medical community to misunderstand the cause of most debilitating chronic diseases.
So, which of the three categories is overlooked? Category 1 certainly isn’t – once scientists figured out the structure of DNA and the nature of mutations they were extremely eager to show their relationship to disease. Category 3 hasn’t been overlooked, largely because of the fact that we can sense environmental causes of disease. We suffer from a stomach ache after eating contaminated food or feel the pain from a sunburn.
But, if we look back at every decade, there has been a lack of research on category 2 relative to its actual importance in causing disease. Our track record shows that we have consistently failed to fully understand the role that pathogens play in causing disease and this trend has continued up until 2008.
There are many examples of how we have continually overlooked the category of infectious disease. I’m not talking about acute infection – researchers were essentially able to work out the mechanisms of acute infection from 1880 to about 1920. I’m talking about chronic infection, and thus the role of pathogens in causing chronic disease.
Take the case of peptic ulcers. The idea that bacteria cause peptic ulcers was first solidified in the 1940s, then independently investigated and solidified again by Marshall and Warren in the 1970s. It took over 20 more years before the relationship was finally accepted by mainstream medicine. Now, when people look back on previous theories about the cause of peptic ulcers they think, “Oh, isn’t it surprising that we didn’t understand the cause for so long!” or “We should have known better!” But when they proceed to hypothesize about the cause of other diseases, they go right back to the dogma. They haven’t learned the lessons from the peptic ulcer story.
Instead, they should think in an opposite fashion. If we find that one disease has an infectious cause, we should learn from that information and seriously consider the same possibility in other diseases.
Think about syphilis. In 1913, it was discovered that the disease resulted from infection with the bacterium Treponema pallidum. Soon, the disease was dubbed the “Great Imitator” because its symptoms often resembled those of other diseases, particularly in the later stages. I think syphilis should be called the “Great Illustrator,” because it’s a disease that imitates a whole spectrum of other diseases. This suggests that we should be actively looking for a pathogenic cause in these other diseases as well – especially since so many illnesses are still considered to be of unknown cause. Back in the day, the psychoses associated with syphilis and schizophrenia were grouped together into a single category of illness. But as soon as syphilis was found to have a bacterial cause, we separated syphilitic insanity from what is now called schizophrenia, and assumed that schizophrenia was not caused by infection. Rather than just separating the two diseases we should have actively pursued the hypothesis that schizophrenia also has an infectious cause. The information we can gain from these kinds of relationships is far more enlightening than any genetic data.
That’s one of the realities of medicine – researchers tend to deny associations. Denial plays a major role as scientists love to hold on to the current dogmatic explanation. This suggests that in order for pathogens to be fully tied to chronic disease we will have to wait until the current powerful people pass away and a sufficient number of young people entering the arena without these vested interests mature into positions of influence, to tip the balance of expert opinion. This is something that Charles Darwin, Max Planck, and Thomas Kuhn all agreed with.
That’s because powerful people tend to hang on to the opinions that made them powerful even if there is no longer sufficient evidence to support their views. It’s a social problem that relates to the weakness of the mind. Human beings didn’t evolve to be scientists. Instead they evolved to be competitive – to grab and hold onto what is theirs. Hence the name calling often observed among the medical community and the resistance among scientists to fund or support ideas other than their own, ideas that question the validity of current dogma.
No. Take schizophrenia again. Evolutionary biologists understand that if an allele (a sequence that codes for a gene) were to code for a disease it would slowly get weeded out of the population, particularly since people who are sick are much less likely to reproduce (especially people with a severe disease like schizophrenia). Yet a person’s chances of getting schizophrenia are 1 in 100. The reality is that faulty genes cannot maintain this frequency. If schizophrenia was a genetic disease, then according to the rules of mathematics, it would only occur in about 1 in every 10,000 people. The current frequency of the disease is just far too high.
Some might try to rationalize the 1 in 100 number by saying that schizophrenia is influenced by environmental factors, but if this were the case the environmental factors would have to be widespread and consistent across much of the world which is highly unlikely. Yes, some populations do have a higher incidence of schizophrenia than others, but that variability is much better explained by the idea that some populations harbor more of the pathogens that cause schizophrenia then others.
This highlights another issue. The fact that illnesses tend to run in families does not mean that only faulty genes are at work. Family members could just be passing each other pathogens. If one member of a twin pair has schizophrenia, there is a 35-60% chance that the other member of the twin pair will have it. However, this may be just a reflection of the fact that both twins were exposed to the same pathogens in the womb.
Pathogens also possess the ability to evolve and adapt at rapid rates, meaning that even if the host acquires a defense against them they can often find away around it. As previously mentioned, genetic disease would gradually be weeded out of the population. But as soon as you hypothesize that a disease has an infectious origin, and that the pathogens causing it can adapt and evolve, it is possible to explain how diseases can be perpetuated indefinitely in quite severe forms.
Yes, it’s possible. We know that some viruses and bacteria mutate and damage DNA. Similarly, the compounds created by the body in order to continually combat pathogens are often potent molecules that can also cause genetic mutations.
Cancer is really a special case of the problems we have discussed. The same dogma has been driving how the disease is viewed for so long. But if people are able to recognize the dogma for what it is, they can take a better look at definitive evidence about the disease. Taking a look at the track record of cancer researchers is a good way to decide whether the consensus view is right or wrong.
Back in 1975, mainstream medicine agreed that about 0.1% of human cancer cases were caused by pathogens. When it came to the rest of cases, their view was that they were probably caused by a combination of inherited predispositions and mutagens. Then in 1985, the percentage of cancer cases they tied to pathogens was 3%, and they continued to make the same argument about the remaining cases. In 1995 the percent of pathogen-induced cancer cases was accepted to be around 10%. Now, we’re at 20%. Still, mainstream medicine contends that the other 80% of cases do not have an infectious cause, but the questions is – do you believe them anymore? In this sense, the clarity of hindsight can help a lot. Between evolutionary instinct and plain common sense we can view the issues of pathogens and cancer much more effectively.
Or, take a disease like atherosclerosis in which noting patterns of infection is unavoidable. There are bacteria in the lesions of people with the disease and all kinds of inflammatory markers. What we need to do is take a step back, divorce ourselves from our predispositions, and look at these ideas together.
Modern medicine has done a poor job looking for clues of continued infection. This may be partly explained by the fact that in many cases, it’s hard to link a pathogen to a disease because the pathogen grows and spreads so gradually. So the time at which a person becomes symptomatic may be years after the onset of infection.
Recognizing these patterns requires thinking broadly and deeply, but medical professionals and researchers have been trained to think narrowly. They’ve tried to follow a model that resembles a NASA undertaking for a great moon mission in which every person brings his or her own particular specialty to the table. But that model doesn’t work for medicine. Instead medical professionals need to work together with a unified theory in mind. But at the moment, they don’t have a unified theory, and without a conceptual model to guide them, researchers are only able to determine risk factors for disease rather than come to an understanding of the overall cause.
Evolutionary biology is the most synthetic area of biology. It asks why things are the way they are, and integrates knowledge of how things work mechanistically. Evolutionary biology promises to be the most synthetic area of medicine for the same reason.
Yes. And the immediate questions researchers should be asking is “What causes inflammation?” One thing that we clearly know causes inflammation is the presence of an infection. So, as soon as I hear the word inflammation I think, “What infectious agents are at play?”
That brings us to the concept of autoimmune disease – the idea that the immune system just “goes crazy.” I think the fact that the concept of autoimmunity was developed in the first place is largely related to the fact that our brains have not evolved to think scientifically. People who have studied disease from their own point of view have recognized that the immune system is extremely important. But as we’ve learned more about the immune system, we’ve realized that it is an extremely complicated system – as complicated as the brain. Just like we can’t look at one type of neuron and infer information about the entire brain, we can’t try to understand the characteristics of only some immune cells and think we understand immune function.
So, over the years, as researchers have been daunted by the complexity of the immune system, it has seemed logical that such a complex entity has the potential to go wrong. Because they are limited by the power of their brains, they tend to simplify the issue and view the immune system in the same way they would view a truck that could break down. There are two problems with this type of thinking. For starters, we can’t trust our intuition that something complex is likely to malfunction. The fact is, the immune system functions just fine in a large proportion of the population. The only logical way to explain the immune activation seen in patients with “autoimmune disease” is to suggest that there is some sort of agent pushing the immune system off balance. This argument is only strengthened by the fact that the same evolutionary forces that would cause a serious disease to be weeded from the population would also cause those people whose immune systems are prone to self-destruction to be eliminated from the population.
The concept of autoimmune disease has progressed to the point that now even researchers who previously dismissed the possibility of infection are accepting the possibility that “autoimmune” disease could be triggered by infection. This is some progress, but it’s not enough. Especially since the concept of autoimmunity encourages doctors to prescribe immunosuppressive steroids to patients. But if persistent infection is involved these steroids may exacerbate the fire by allowing pathogens to spread.
Aging is a super-category. We’ve gradually lumped together more and more symptoms under the category of natural aging. Many of these symptoms are the same as those caused by diseases that surely have an infectious cause. In that sense, you could view much of what we now call aging as an incapacitating illness that leads to a decrease in function. We know that inflammation and the interaction of the immune system with pathogens can destroy tissue. So it’s not surprising that the tissues of a person who harbors a lot of pathogens would age earlier and alter their biological structure earlier in life. I do believe it is inevitable that people will eventually die of old age, but I suspect that this should generally happen when they are 80-100 years old. But we are increasingly seeing signs of aging-related diseases in people who are much younger.
Personally, I believe that we label an illness as psychosomatic when we don’t really know what’s going on with the patient. It’s a last resort diagnosis – a black box. If we knew more about what was causing their symptoms we could address the issue more clearly.
Looking at psychosomatic illness from an evolutionary viewpoint, you could say that those people who might exaggerate how sick they feel in order to gain attention and resources could have an evolutionary advantage. But if that’s the truth, it only accounts for an extremely small percentage of cases. It’s also true that often an illness will have both a psychological and physical component. But just because a psychological component is identified doesn’t mean the physical component should be overlooked. Plus, most mental illnesses are probably the result of infection too. Chronic Fatigue Syndrome is a good example of a disease that up until recently has been dismissed as psychosomatic just because researchers couldn’t figure out the cause. On the contrary, it’s quite a serious illness.
I think the Internet plays an incredibly beneficial role as it can provide information to anybody who is willing to put in the time to learn terminology and information presented in the literature available on the Internet. I believe it will, and already is, changing the patient/doctor relationship and also the relationship of the general public with the government mainly because we can now check up on things and check up on them quickly. I can find information in half an hour rather than spending an entire day at the library – and think about the fact that this is happening all around the country.
Of course, now there is so much information on the Internet that it’s too much for an individual mind to keep up with. Sometimes you have to read quite a bit of literature in order to extract the relevant information. That’s why we need people to team up and share information. What we need is small groups of people poring over information together. In this way they can develop a more thoughtful, broad outlook. This is in contrast to the current medical model in which doctors and researchers are trained to specialize in such a narrow area of knowledge. They know very little about issues outside their area of expertise and have trouble seeing the big picture. Thus, what we need is for the NIH to put money into grants that foster interdisciplinary insights.
I think the peer review system is becoming less important because there are so many other outlets where people can put up information. So I don’t see it as too big of a barrier.
When it comes to pharmaceutical companies, it’s important to recognize that they are very good at some things and very bad at others. What they are good at is product promotion and marketing, and working in innovative ways when the resulting product can bring in lots of money. The problem is the products that make the most money are not necessarily the products that actually help people the most.
Basic economic principles first put forth by Adam Smith show that the free enterprise system does not work well under certain situations. Writing over two hundred years ago, he argued that free enterprise cannot be expected to generate an effective national defense. For modern society, pollution control would be another example. If we want to move in that direction there needs to be a profit driven motive, or we have to get the government to do the things that do not generate sufficient profit. Otherwise, it just won’t happen.
If you think about it, there isn’t very much money to be made off a vaccine because a person uses it once or twice in his or her life and that’s it. Instead, think of the amount of money to be made off a statin when a person is going to take it every day of their life. There’s just not much motive for drug companies to invest in products that are cures or very good preventatives. We don’t have to condemn drug companies, just recognize this role that they are playing in drug development. If we want to develop a drug under a high priority situation that may result in a curative solution we can’t count on the pharmaceutical industry. In cases where the free enterprise system doesn’t result in a situation that may benefit the population the government has to step in and provide funding for the possibility at hand.
Most experts in the health sciences advocate a building-block approach to the problem of causation. They try to understand the workings of disease at the cellular and biochemical levels, in hopes that solutions will eventually emerge. Even among infectious diseases, however, the fundamental achievements have occurred more through the testing of deductive leaps than by building-block induction. What it boils down to is that we need both types of development but we can’t have one without the other. Working incrementally can be great as long as scientists understand the big issues and the larger concepts that need to be guiding their research. But right now we have way too many scientists working in building block mode, missing what’s going on outside the box.
Because it’s not in the textbooks. They are trained to look at a patient and try to match them with something in a textbook. These medical texts don’t consider the preponderence of evidence across the entire spectrum of possible causes of most chronic diseases. The evidence implicating infectious causation tends to be a casualty of this restricted perspective, leading to the result that consideration of infectious causation in medical texts is minimal for chronic diseases of uncertain cause.
So until infectious pathogenesis is accepted to the point that it is in the medical texts taught in medical school, they will continue to consult only the standard operating procedure. If they can’t put a label on the patient’s illness it falls into a bin of “unexplained phenomena” which goes back to what I was saying earlier about psychosomatic illness, since they have a tendency to speak dismissively about what’s in the bin.
The problem is that considering a new pathogenesis or a cause that isn’t in a textbook requires thinking hard about unknown problems. They just don’t have the time or training to think logically and deeply about such issues. This is evidenced by the fact that you can go to five different doctors, get five different explanations for your problem and be recommended five different treatment options.
My interest in evolutionary medicine began in grad school around 1977. I came down with a bad case of diarrhea and was thinking about whether I should treat the symptoms or let the illness run its course. At first it seemed like it was most logical to let the illness run its course because that seemed to be my body’s way of eliminating the pathogen. But then I thought about the fact that the pathogens might be manipulating me. If I expelled them, they might be endowed with an evolutionary advantage that would allow them to persist and infect others. I realized that my intuition couldn’t provide me with the answer. That led me on a long web-like series of connections. The more I started to consider medical problems in the light of evolution the more I realized that some diseases simply cannot be caused in a way they are explained by current dogma. So I’ve tried to look at disease in a balanced way, to put all possibilities on the table, and from there to figure out what’s feasible and what’s not.
Greg Blaney, MD, graduated from the University of Ottawa in 1974. Following internship at Edmonton General he joined a Community Health clinic in Ottawa. From 1987 to 1990 he was a teaching assistant in the College of Osteopathy of the CME program at Michigan State University, having trained in both conventional and manual medicine during the first two decades of his career. He went on to also gain competence in Acupuncture and Homotoxicology, was a medical advisor to the LaLeche league, the Childbirth Education Association, the RCMP and the Bank of Canada. He lectured in the University of Ottawa’s Residency program, and its Masters program in nutrition. Dr. Blaney is currently using Autoimmunity Research Foundation’s Marshall Protocol to save the lives of hundreds of patients with a wide variety of chronic inflammatory diseases.
Before learning about the Marshall Protocol my work had evolved into a chronic pain practice, where I focused on osteopathy and trigger point injections. Despite the fact that some people seemed to benefit somewhat from these therapies, I always had a certain group of patients with chronic symptoms that simply did not respond to anything I tried. I had one patient who was actually aggravated by most of these therapies and displayed multiple symptoms in different areas of her body that did not respond to treatment. At the same time, I was also treating a woman who had been diagnosed with Lyme disease ten years before becoming my patient, however her symptoms had gone into temporary remission. Although she had been told by another doctor that she was “cured”, when she was in a car accident, all of her Lyme symptoms returned. After being tested, she was once again positive for Lyme.
I started to investigate Lyme disease and it seemed very feasible that bacteria could be persisting in my patients who had tried everything but were not improving. I decided to attend the International Lyme and Associated Disease Society (ILADs) Conference where Dr. Marshall was scheduled to give a small presentation. Before listening to Dr. Marshall speak, I attended a talk about the standard ILADs treatment for chronic Lyme disease. Their advice was to give patients with chronic Lyme disease high-dose intravenous antibiotics. I wasn’t impressed by the approach because it seemed like administering antibiotics in this manner could have numerous toxic side effects. Now, I also realize that many of the antibiotics used by doctors that follow these recommendations actually foster the growth of L-form bacteria (the beta-lactam antibiotics). Furthermore, I wasn’t impressed with the data they had compiled about high-dose antibiotics and Lyme disease. In the long run, no patients actually seemed to be getting better.
In contrast, Dr. Marshall’s presentation seemed to make a lot more sense. He spoke about L-form bacteria and about how levels of the hormone/secosteroid “vitamin” D become dysregulated in people with inflammatory disease. At the time, I was suffering from quite a few ailments – cardiac arrythmia, low-level psoriasis, restless leg syndrome, general fatigue and some loss of cognitive function. When I came home from Dr. Marshall’s talk I decided to test my own vitamin D levels. My wife was suffering from chronic jaw and sinus problems so I tested her D levels as well.
Sure enough, both of us displayed dysregulated levels of the two vitamin D metabolites, 25-D and 1,25-D. Consequently, I decided that my wife and I should be guinea pigs and start the MP ourselves, which we did. After that point, I also started to check my patients’ D metabolite levels and test them for tick borne pathogens and Chlamydia. Nearly all of them displayed dysregulated levels of vitamin D and tested positive for different species of bacteria. When I looked at their bloodwork they also showed other markers of inflammation. I decided to start many of these patients on the MP.
I’ve had people with numerous inflammatory conditions do very well on the MP. I’ve had patients with arthritis, fibromyalgia, cardiovascular disorders, hypertension, Raynaud’s syndrome, Chronic Obstructive Pulmonary Disorder (COPD), chronic headaches and migraines, and other diseases respond very well. I’ve also had patients with mental afflictions such as obsessive compulsive disorder, anxiety disorders and depression do very well.
I’ve noticed that people with CFS are definitely able to recover as well, but it usually takes them a longer time to note signs of improvement – sometimes well into their second year on the treatment. I find that people with psoriatic arthritis also have severe immunopathology reactions. The people I find most challenging to treat with the MP are those with inflammatory bowel disorders. Not that the MP won’t work for them, but sometimes their immunopathology is hard to manage.
The patients that have the most spectacular initial responses to the MP are often those with severe headaches. I’ve had some patients whose headaches disappeared the moment they started Benicar. I’ve found that many patients with rheumatoid arthritis (RA) also show marked reduction in inflammation after just a few months of MP therapy. It’s easy to see these improvements because they are reflected in the patient’s bloodwork. For example, I can look for drops in C-reactive protein and sedimentation rate. At the moment I have an RA patient who is also being monitored by another rheumatologist. This doctor was initially skeptical of the MP, but I feel that when he sees how this particular patient’s bloodwork has improved, it will be easier for me to cajole him into mentioning this case in some of his papers. Hopefully he may also talk about the treatment with other patients. He just won’t be able to deny the signs of improvement.
Over the long run, what I’m usually most impressed with is the universal improvement in cognitive function that I see in nearly all my patients as they progress to later stages of the MP. The MP is such a safe way to improve mental function.
For one thing, ARB medications have been used in medicine for a long period of time and have not been shown to cause any significant adverse reactions. It is pretty much universally accepted that these medications are safe to use. In fact, at the moment, ARBs are being administered to some cancer patients at doses that are drastically higher than those used by the MP – around 800-1000 mg daily. The standard MP dose is 240 mg a day. Even at these high doses used in cancer, ARBs have not been shown to have any adverse side effects.
The MP antibiotics are taken in very low, pulsed, doses. There is no data showing that antibiotics taken in this manner pose any danger to the patient, and clinically no adverse events have been reported among patients taking antibiotics in this fashion. Some people mistakenly interpret changes in immunopathology as adverse events, without understanding that a rise in symptoms is a necessary part of the healing process.
For more on immunopathology see the Phase 1 Marshall Protocol guidelines.
All of them that are willing to do the treatment. It’s pretty amazing how many people out there are walking around with L-form bacteria and could be helped by the MP. When I tell patients about the Marshall Protocol I say, “This treatment is safe and effective, but you also have to be willing to deal with immunopathology and this is not a short-term process.” This makes some people shy away. Some are intent on searching for a quick fix. For example, I have a patient with back symptoms that I know are the result of inflammation, but he’s not interested in the MP because it requires such a commitment.
But when it comes down to it, I feel that MP will work for anyone who has a chronic condition, unless of course that condition is the result of a catastrophic injury. All chronic symptoms are the result of L-form and biofilm bacteria draining the ability of the immune system to function correctly. These bacteria are always percolating. The science behind the MP is extremely sound. Not that it can’t evolve and improve but I have no doubts about the treatment.
Since Benicar is marketed as a blood pressure lowering medication, many doctors don’t think outside the box and realize that it has other very important effects that allow it to reduce inflammation and stimulate the immune system. They resist the idea that patients can maintain a normal blood pressure while still taking the ARB.
Many doctors are also afraid that long-term use of antibiotics will lead to resistance. In reality this isn’t an issue. When antibiotics are pulsed, the concentration of the antibiotic in the tissues is always changing and there are different levels of antibiotic in the body at any one point in time. Because the level of antibiotic is never constant, it is impossible for bacteria to develop resistance mechanisms. The effectiveness of pulsing a substance in order to eliminate the ability of a pathogen to develop resistance has been demonstrated with pesticides. It has been found that disseminating pesticides in spurts rather than in a continuous fashion keeps the pathogens in crops from becoming resistant to the chemicals in the pesticide. Plus, we continue to find that when patients take minocycline, it continues to generate strong changes in immunopathology even after they have been taking the drug for many years.
I find that general practitioners are generally a little more open to the MP, but most of them feel they are too busy to actually sit down and fully read all the literature pertaining to the treatment. The MP is a very complex treatment so there’s a lot of research to be done if one is to understand it correctly. Specialists are difficult to convince because they tend to be rather narrow-minded. If the MP doesn’t invoke or make reference to something they have heard at a recent conference, they tend to ignore the possibility that it might work. It seems that many doctors are just hardwired to resist innovation and change.
It’s also hard for some doctors to accept the idea that the patient must avoid vitamin D. But I feel these concerns will become less frequent as more doctors realize that we’re telling patients to avoid a hormone/secosteroid, not a vitamin. We need to stop referring to “vitamin D” as a vitamin. I tell my patients, “What would you say if I told you to add testosterone to your food? You would tell me I’m crazy!” Adding “vitamin” D to the food supply is as ridiculous as telling the public to take large amounts of any other hormone. If you ingest massive amounts of any hormone or steroid it’s clearly going to throw off the body’s natural state of homeostasis. I have to say it boggles my mind that when molecular biologists have clearly recognized that vitamin D is not a vitamin doctors are still thinking of it as a nutrient rather than a hormone/secosteroid.
The hardest concept for people to grasp is that of the immunopathology reaction – the fact that a rise in intensity of symptoms is not a sign that the disease process is advancing, but a reflection that the immune system is active and killing bacteria. We have been hardwired to equate symptoms with disease, but what many people do not realize is that all disease symptoms are the result of an immune system response. If a person gets infected with a virus, the rise in symptoms they display is not caused by the virus, but the response of the immune system to the virus. Once on the MP, some patients report intense exacerbation of symptoms, severe lightheadedness, or profound fatigue, and are convinced that they are getting sicker. I have to assure them that what they are feeling is the natural result of their immune systems dealing with toxins, cellular debris and the remains of dead bacteria. Europeans are usually more open to the idea, but North Americans have really been brainwashed to equate symptoms with disease. In cases where people have trouble grasping this concept, the biggest hurdle is to get them through the first phase of the treatment when the immunopathology is often strongest. If I have any dropouts, they come from this group – the people who can’t intellectually grasp the idea that they need to feel worse before they get better.
Well, about 20-25 percent, maybe less, all of them during the first phase of the treatment. People with CFS are often impatient because in most cases even after they’ve done the protocol for over a year they feel just as symptomatic as they did at the start. It isn’t until well into the second year that they begin to note improvement. They do improve, but it takes them longer to get better than patients with other diseases. The CFS people also get a lot of slack from other doctors who don’t understand that they need to hang in for longer periods of time before noting improvement. Some patients also lack family support and find it difficult to push forward with the treatment when those around them don’t understand why they are experiencing temporary rises in symptoms. Those who are supported by family and friends do much better. One of the things I believe we should focus on is how to better educate family members about the treatment so that they can provide a better support network.
Some patients with mental illness also prove to be challenging cases because they need to take quite a few medications in order to manage their symptoms and these medications often interfere with the ability of the immune system to function correctly. Also, many of their family members are not willing to put up with the rise in psychological symptoms that results from the immune system reaction.
I believe that there will finally be recognition of the fact that bacteria do not manifest themselves in the manner in which we are taught in medical school. Doctors will accept that when acute infections are treated, the bacteria causing the disease doesn’t necessary clear, but can mutate into forms that can persist in the body for long periods of time. Then, they will recognize that these persistent bacterial infections are a major medical problem. Perhaps this will lead to further research into how these bacteria will respond to other antibiotics. Maybe new antibiotics will be created to target these pathogens. This reality is already starting to infiltrate mainstream medicine as studies are coming out showing that adult asthma seems to be the result of bacteria that have persisted in the throat since childhood. The same thing can be said for chronic lung infections, chronic bladder infections and well, most chronic conditions.
I also believe there will be an emphasis on further research into the ways that ARBs can be used to regulate the immune system. Finally, I feel there will be recognition of how bacteria can affect the body’s enzyme systems. This will finally move the focus of medical research away from genetics and towards the reality that bacteria are instead able to directly affect the function of the body’s receptors. Rather than looking at how to turn on and off genes, we can look at how the receptors that control and activate the genome are affected by the presence of L-form bacteria and other substances. Dr. Marshall has already shown that the inflammatory process can dysregulate the thyroid receptors, the glucocorticoid receptors and many of the other nuclear receptors. Armed with a better understanding of how the body achieves homeostasis, we can modify the receptor response in order to restore an organism’s ability to go into normal self-regulatory function. Perhaps we can use this information to develop new therapies.
There will also be a revolution in concept that will move doctors away from trying to reduce or suppress the end products of an illness. Instead they will learn how to manage the disease process itself. For example, right now it is believed that high blood pressure can damage blood vessels. But high blood pressure is just the end product of an inflammatory response generated by bacteria in the vessels. Rather than trying to use medications to lower the patient’s blood pressure directly (which is what we do now), we can go after the pathogens that are causing a patient’s blood pressure to rise in the first place and actually cure the illness.
Yes absolutely. My own health has recovered to a point where I see signs of age reversal. My eyesight has improved, my hearing has improved, and my cognitive function is better than ever. After I exercise I feel invigorated – the way I used to feel when I was young, rather than drained. There is no doubt that the MP can have a significant effect on a patient’s longevity. Experts in the field of immunology are increasingly pointing to the fact that the aging of the immune system is a main factor influencing longevity. As people grow older, their immune systems are forced to deal with higher bacterial loads, which in turns means they have to manage a greater inflammatory response. The MP downregulates this inflammatory response, restoring the agility of the immune system, which significantly affects the aging process.
That means that I’m going to be greedy about staying on antibiotics until I’ve reaped every possible benefit of the MP. Come this Christmas I will have been on the MP for three years. All my symptoms are gone and I feel completely healthy. Except for one small issue. I still have occasional tinnitus. Some days it’s completely gone, but other days it’s still at about 20% of where it used to be. I’m staying on antibiotics until this issue is completely gone. I can see myself staying on antibiotics for at least another six months, maybe even a year. I have no concerns about staying on them for a longer period of time. Some of the symptoms that I suffered from before the MP started when I was only 5-6 years old, so I had been sick for over 50 years. I have no intellectual concerns about spending 4-5 years on medications in order to reverse disease symptoms that had manifested over such a longer period of time, especially since I know how slowly L-form bacteria grow and how they can become dormant for periods of time. I also feel there are simply no adverse reactions or negative side effects that I need to worry about while taking the MP medications. It’s an extremely safe approach.
It’s sometimes problematic when a patient is also being monitored by other doctors and they are being given incorrect advice about managing the MP medications. That’s why I strongly feel that before putting patients on the MP, doctors should do the treatment themselves. That way they get a good idea of what their patients will experience and are later able to reassure and guide them much more effectively. For example, when a patient comes to see me during the early stages of the treatment I’ll ask, “Is your jaw sore?”, “Do you feel…?” And they’ll say, “Yeah!, yeah!, that’s exactly what I feel!” Then I can assure them that I also experienced those symptoms and say, “well, what you’re feeling is completely normal.”
I think we should continue to work on creating resources that allow the patient to become better at learning how to dose their antibiotics and manage the treatment on their own. Rather than having to ask questions about how to proceed or requiring advice from doctors and the board staff, they can learn to manage and understand their reactions – to be able to say, “Oh, I’ll take an extra Benicar”, or “Oh, I’ll space my antibiotics out to three days rather than two.” The treatment works best when patients are able to intuitively manage their own body responses in this manner.
Doctors should take the time to really understand the science behind the Marshall Protocol. That way they will recognize that 99% of the time the changes observed in their patients, or fluctuations in lab results are the result of immunopathology and not cause for concern. Otherwise they will often incorrectly infer that changes in bloodwork are somehow due to toxicity from the medications. Severe immunopathology reactions are not a sign that something is going wrong, but only a reflection of the fact that the treatment is actually working too effectively. By sitting down and reading about the MP in depth, they will also develop a greater confidence in the safety of the treatment, so that instead of freaking out when a patient’s kidney function temporarily drops, and often blaming Benicar for the situation, they will realize that decreased kidney function is just a result of immunopathology in the kidneys that can be managed. There is simply no evidence that Benicar can affect kidney function – there are even patients on dialysis that take Benicar. It’s also important to learn how to counsel patients during flares in which their immunopathology may kick in very strongly in order to help them manage their antibiotics and keep the reaction under control.
Another thing doctors should understand is that in the case of nearly every patient, immunopathology occurs in the brain. This means that during much of the treatment, patients are not thinking properly and have psychological issues. These mental reactions should not cause doctors to question the stability of the patient, but instead it should be understood that every patient will experience a certain level of confusion, anxiety and neurological symptoms while on the MP.
All images of bacteria in this post are taken, with author’s permission fromClinical Microbiological Reviews, published in 1997, 10(2), 320-344.
Gerald Domingue is a medical researcher and academic who served as Professor of Urology, Microbiology and Immunology in the Tulane University School of Medicine and Graduate School for thirty years and also as Director of Research in Urology. He is currently retired and resides in Zurich, Switzerland where he is engaged in painting and creative writing. At retirement he was honored with the title of Professor Emeritus at Tulane. Prior to Tulane, he served on the faculty of St. Louis University, was a lecturer at Washington University and director of clinical microbiology in St. Louis City Hospital, St. Louis, MO.
Over the course of his thirty-nine year career, Domingue received funding from the National Institutes of Health, Veterans Administration, and a variety of national and international research foundations. He enjoys international recognition as an authority on the basic biology and medical significance of atypical bacterial organisms and is considered an expert on the role of these bacteria in the persistence and expression of kidney and urological infectious diseases.
He first became interested in the role of atypical bacterial forms after noting that a large number of patients with urinary tract infections suffer from continual relapsing illness. Using a direct phase microscope, he examined the urine specimens of several patients with urinary tract infections and found L-form bacteria in his sample.
He began to investigate L-form bacteria, striving to better understand their biology and the role they play in causing disease. Over the course of the next 30 years, he was able to explain much of the mystery behind how the bacteria are able to persist in the body, and published a wide array of clinical and experimental studies on the subject.
Domingue worked with a team that included pre and post doctoral students and fellows along with faculty colleagues and laboratory assistants. Together they discovered that L-form bacteria are able to form tiny dense bodies within parent cells that already lack cell walls. They noted that the forms, which they called electron dense bodies were so small that they could pass through bacterial filters that normally withheld ordinary bacteria with cell walls.
The electron dense bodies could persist inside tissue culture cells in the laboratory. After applying this data to the human condition, Domingue reasoned that in some patients who suffer from chronic bacterial infections, the disease process could be related to the fact that bacteria are able to differentiate into the resistant electron dense bodies that he observed in tissue cultures.
In 1974, he and his graduate student, Mary Green, along with Paul Heidger, a faculty collaborator, published two landmark companion papers in the prestigious journal Infection and Immunity. The papers detail how L-form bacteria inside an experimental human embryonic kidney tissue culture system are able to persist in cells and explains how they are able to revert into the cell wall-containing parent bacterial form. They also proposed a detailed reproductive cycle for L-form bacteria, followed by electron microscopy of the microorganisms.
These papers set the stage for Domingue and his team to delve even further into the role that cryptic atypical bacteria play in causing persistent and recurrent infections.
In 1997, he and a colleague, the late Hannah Woody published an invited extensive review article on chronic bacterial infection in Clinical Microbiological Reviews. Among their conclusions was the claim that “difficult to culture and dormant bacteria are involved in the latency of infection and that these persistent bacteria may be pathogenic.”
He implicated L-form bacteria in several kidney-related diseases including pyelonephritis, glomerulonephritis, idiopathic hematuria, and interstitial cystitis. He also speculated about their role in other diseases such as rheumatic fever, tuberculosis, syphilis, and rheumatoid arthritis.
In the review Domingue stated, “Clearly, any patient with a history of recurrent infection and persistent disability is sending the signal that the phenomenon (infection with L-form bacteria) could be occurring. The so-called autoimmune diseases in which no organism can be identified by routine testing techniques are particularly suspect.”
He went on to conclude, “Bacteriologic advances, which include special culture media and stains, electron microscopy and molecular techniques such as PCR (polymerase chain reaction), have revealed an increasing number of previously unidentifiable organisms in a variety of pathologic conditions. It is unwise to dismiss the pathogenic capacities of any microbe in a patient with a mysterious disease.”
Over the course of his thirty-nine year career Domingue published 160 papers, monographs, and book chapters; 65 devoted to L-form research. He was invited to deliver over fifty international and national lectures about L-form bacteria and wrote a book on the subject, Cell Wall-Deficient Bacteria: Basic Principles and Clinical Significance. His papers are filled with photos of cultures of L-form bacteria taken with an electron microscope. They show the microbes inside human and animal cells.
Although Domingue’s primary research focused on bacterial L-forms, he also published extensively on the relationship between a molecule that stimulates the immune response called the Entobacterial Common Antigen (CA) and certain types of bacteria. He detailed the structure of the antigen and explained how it is able to elicit antibodies in humans and in animal models. He also detailed how the antigen could serve as a possible vaccine against urinary tract infections. He also studied the effects that a vasectomy might have on the immune system and performed studies on the relationship between the host and various species of bacteria in the disease pyelonephritis.
He delved into the effects of antibiotic therapy and chemotherapy on patients with urinary tract infections, and performed several studies on bacteria that produce a substance called chorionic gonadotropin-like hormone, detailing the way the bacteria might be involved in an experimental tumor model. He was even the co-author of a publication that characterized the oral microbial flora of alligators in order to develop better therapy for alligator bites.
When asked recently about his work Domingue replied, “I worked in a controversial research area for decades, and I found that sticking to the facts and hard data are the best ways to make progress in a field. Meaningful experimental designs and careful interpretation and discussion of the results are of prime importance in science. The ultimate aim was always to seek the truth about the problem at hand. Unfortunately, in the area of L-form or cell wall-defective bacteriology, too often there have been conclusions (anecdotal) drawn without supporting scientific data. In my opinion, many of these studies have hampered progress in the field and especially the role of these cryptic organisms in bacterial persistence and expression of disease. Sometimes the controversial issues have become political, which is unfortunate.
As far as I am concerned, modern technological tools are presently at hand to support all of the above microbiological and immunological findings at the molecular level… which is really what present day medical scientists, clinicians, pathologists are willing to accept as proof (maybe) of the role of such aberrant bacteria in disease.”
Indeed, molecular modeling has revealed how L-form bacteria are able to persist in the body and disable the immune system. Over the past few years, L-form bacteria have been linked to a wide array of chronic diseases, many of them previously considered to be autoimmune in nature. In 2002, biomedical researcher Trevor Marshall created a medical treatment that effectively kills L-form bacteria.
Now that L-form bacteria are known to cause a wide array of chronic inflammatory diseases, Domingue’s work is of utmost importance in allowing researchers to correctly demonstrate and understand their behavior.
Domingue, G., Lloyd, K., & Schlegel, J. U. (1974). In vitro phagocytosis of transitional phase bacterial variants utilizing autoradiography. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.), 146(2), 635-42.
Domingue, G. J. (1980). Filterable cell-associated cryptic bacterial forms in immunologic renal diseases. Urological survey, 30(1), 1-4.
Domingue, G. J., Ghoniem, G. M., Bost, K. L., Fermin, C., & Human, L. G. (1995). Dormant microbes in interstitial cystitis. The Journal of urology, 153(4), 1321-6.
Domingue, G. J., & Schlegel, J. U. (1970). The possible role of microbial L-forms in pyelonephritis. The Journal of urology, 104(6), 790-8.
Domingue, G. J., & Schlegel, J. U. (1977). Novel bacterial structures in human blood: cultural isolation. Infection and immunity, 15(2), 621-7.
Domingue, G. J., & Schlegel, J. U. (1978). Novel bacterial structures in human blood. II. Bacterial variants as etiologic agents in idiopathic hematuria. The Journal of urology, 120(6), 708-11.
Domingue, G. J., Thomas, R., Walters, F., Serrano, A., & Heidger, P. M. (1993).Cell wall deficient bacteria as a cause of idiopathic hematuria. The Journal of urology, 150(2 Pt 1), 483-5.
Domingue, G. J., Woody, H. B., Farris, K. B., & Schlegel, J. U. (1979). Bacterial variants in urinary casts and renal epithelial cells. Archives of internal medicine, 139(12), 1355-60.
Domingue, G., & Woody, H. (1997). Bacterial persistence and expression of disease. Clin Microbiol Rev, 10(2), 320-344.
Domingue, G. J. (1982). Cell-wall Deficient Bacteria: Basic Principles and Clinical Significance. Reading, MA: Addison-Wesley Publishing Co.
Green, M. T., Heidger, P. M., & Domingue, G. (1974a). Demonstration of the phenomena of microbial persistence and reversion with bacterial L-forms in human embryonic kidney cells. Infection and immunity, 10(4), 889-914.
Green, M. T., Heidger, P. M., & Domingue, G. (1974b). Proposed reproductive cycle for a relatively stable L-phase variant of Streptococcus faecalis. Infection and immunity, 10(4), 915-27.
Ponig, B., Domingue, G., & Schlegel, J. (1972). The role of in vitro induced microbial L-forms in experimental hematogenous pyelonephritis. Investigative urology, 9(4), 282-5.
Amy Proal graduated from Georgetown University in 2005 with a degree in biology. While at Georgetown, she wrote her senior thesis on Chronic Fatigue Syndrome and the Marshall Protocol.