Exploring chronic disease
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.
My recent article Bacteria vs. genetic predisposition: the spread of Th1 disease in families discusses how the bacteria responsible for causing chronic disease can be passed from generation to generation. At the same time, the genetic mutations created by these pathogens are also passed from mother to child.
Just this month, researchers led by John H. Werren at the University of Rochester in New York elucidated yet another way that bacterial DNA is likely passed from person to person. This demonstrates just how easy it is for bacterial DNA to become incorporated into human DNA – a reality that is central to biomedical researcher Trevor Marshall’s model of chronic disease in which pathogens are constantly swapping genetic material with each other and their host.
The study describes how due to horizontal gene transfer – or the reality that once inside the body, organisms swap genetic material with each other, and also with the host – bacterial DNA often ends up integrated into human DNA. This integrated genetic material is then passed from generation to generation, and it is very likely that many of these acquired segments of DNA may help bacteria survive more easily in the body. “Our data are indicating that [DNA transfer] is going on all the time,” says Werren.
“The mechanism therefore provides an alternative to mutation of existing DNA as a way for the species to acquire new genetic traits,” states Patrick Barry ofScience News. “The transfer of DNA from bacteria means that an individual could acquire and pass on genes that it had not inherited.”
Warren’s team looked at several species of insects and roundworms infected by a parasitic bacterium called Wolbachia pipientis. The bacterium lives inside the animals’ cells, including their egg cells, giving it ready access to the chromosomes that are passed on to the animals’ offspring.
When the researchers compared the genetic code of the bacterium with the code of 11 other species: four roundworms, four fruit flies, and three wasps, they found that all but three of the fruit fly species had segments of the bacterium’s genetic code embedded in their DNA.
The team also scanned an archive of published genomes for 21 other invertebrate species and found bacterial genes in nine of them – proving that bacterial DNA can indeed be passed from mother to child. Whether this occurs in humans has not yet been demonstrated, but in principle, seems quite possible.
But this process has been taking place for centuries. Why hasn’t it been analyzed sooner?
“Such bacterial genetic code is routinely ignored during the sequencing of animals’ genomes because most scientists have assumed that the foreign DNA is a sign of contamination, Werren says. However, the new research rules out the possibility of contamination, says the scientist.
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.