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Let’s face it. We don’t hold the contents of our intestine in high regard. They are unsightly, malodorous, and when not disposed of appropriately in areas with high concentrations of people, they can lead to disease. The less time spent in their presence, the better. In fact, the whole philosophy behind toilets seems to revolve around giving us the power to immediately make our droppings disappear with the flip of a handle. Our disgust with what comes out of the business end of our intestine is even reflected in our language where we have a large number of epithets to equate worthless objects or persons we find to be truly despicable with, well…excrement. All this negative focus is a great shame as the lowly turd is a vital part of the exams that clinicians perform to diagnose a host of diseases, as was pointed out (with some exaggeration) in the famous “Poo Song” in the television series “Scrubs”. However, our dung has very important functions in both health and disease beyond serving as mere diagnostics. With some hindsight this concept seems obvious, considering that the number of bacteria in our bowels is the same as the number of cells in our bodies, and that all these bacteria and other microorganisms actively metabolize foodstuffs in close proximity to the lining of our intestines. But, only recently have scientists begun performing in depth studies of the functions of what is formally called the “intestinal microbiome”. What they are discovering is amazing. For example, the US and other industrialized nations are currently dealing with an obesity epidemic, and scientists have found that the intestinal microbiome plays a role. As it turns out the bacterial makeup of the intestinal contents of obese and non-obese people is different. Obese people seem to have bacteria that promote obesity! Scientists working with germ-free mice have found that these animals are resistant to obesity caused by a high-fat diet. Furthermore, by recolonizing these mice with specific strains of bacteria, scientists have found that not only do some bacteria promote obesity, but others protect against the effect of the obesogenic bacteria. The mechanisms by which this happens are not yet clear but gut bacteria may modulate the levels of satiety hormones released from the intestine or may affect the immune response and the physiology of adipose tissue by means of bacterial components that leak through the lining of the intestine into the blood. This suggests that we can reduce a person’s propensity for obesity by populating their intestinal tract with the right type of bacteria.  Another finding from studies with germ-free animals is that these animals have changes in their behavior compared to animals with an intact intestinal microbiome. That’s right: the levels of several brain molecules that regulate mood and cognition can be affected by the makeup of the bacterial content of the gut! In fact, in humans there are various conditions involving changes in gut bacteria such as irritable bowel syndrome that are accompanied by feelings of anxiety and depression, and certain psychiatric conditions are also believed to be affected by the makeup of the bacteria of the gut. This again suggests that if we find the right bacterial combination to introduce into the gut, we may be able to positively regulate brain function.
But the effect of gut bacteria doesn’t stop here. Gut bacteria also are modified in people suffering from several maladies such as cardiovascular disease, diabetes, cancer, and others. Gut bacteria may even hinder or enhance the effects of certain drugs. The influence of the intestinal microbiome on the human body has led some scientists to claim that it should be considered an independent organ just like the liver or the pancreas. Unfortunately the intestinal microbiome is a fiendishly complicated association of thousands of strains of bacteria and other microorganisms interacting with one another and with the cells of the intestine, and the specific bacterial makeup of the microbiome varies from one person to another and can change with diet. Despite all the claims made by pre- and pro-biotic companies we still do not have a widely applicable way of modifying the intestinal microbiome to achieve specific effects on human health, but this is an active area of investigation. Photo of Escherichia Coli bacteria from the Rocky Mountain Laboratories, NIAID, NIH, is the public domain.
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 I admire former president Jimmy Carter. Although by presidential standards his four years as president from 1977 to 1981 are viewed in a negative light, Carter in his post-presidential years has become a model of what it is to be dedicated to the betterment of humanity. Because of this I was sad last year when it was announced that Mr. Carter had the most advanced form of melanoma (stage IV), a skin cancer that had spread to his liver and brain. This cancer is very difficult to treat, so I thought to myself that this was the end of the road for President Carter. You can imagine how happy I was when I learned towards the end of the year that Mr. Carter had been treated and his cancer was in remission. This does not mean he is cancer-free, it just means that in the scans the doctors have performed they are not able to detect the cancer masses that they had previously found or any others. So how did this happen? Mr. Carter had several treatments. He had surgery to remove a cancer in his liver, and he had targeted radiation for the cancer in his brain. But more significantly, Mr. Carter was also administered a new form of therapy that targets the immune system. This therapy is the result of many years of research in many areas of science, and we will take a look today to see how all this came together to generate a new weapon for oncologists in the battle against cancer. Cancer occurs when the cells of the body undergo a transformation and start dividing uncontrollably. This characteristic is exploited by chemotherapeutic agents and radiation treatments. They affect mostly rapidly dividing cells. Unfortunately, our bodies also have many cells that proliferate rapidly in a controlled fashion such as many immune cells and the cells of the lining of the intestine. The same agents that kill the rapidly dividing cancer cells also kill the rapidly dividing healthy cells, and this leads to toxicities that in many cases limits the usefulness of these agents. Our immune system protects us from pathogens that enter our bodies. Early on in cancer research, scientists wondered whether the immune system could attack cancer cells. Initially it was thought that cancer cells were not targeted by the immune system because, unlike very different entities like viruses or bacteria, cancer cells were cells similar to normal cells. However, many cases were documented where the immune system did attack cancerous cells. As it turns out the immune system does detect cancer cells when they arise and eliminates the majority of them. Eventually cancer cells appear that escape destruction. These cancer cells have marginally survived the onslaught of the immune system, and they may be even be kept in check by it. However, the cells eventually divide and generate new cancer cells some of which are a bit more resistant to the attack of the immune system. Then finally, in an evolutionary process that may take years, a crop of cells emerges that has escaped detection by the immune system and goes on to divide out of control and generate full-fledged tumors. So how do cancer cells evade the immune system?  The immune system cascade that results in the elimination of pathogens or cancer cells is a highly regulated process. And it has to be. The immune system must be able to differentiate self from non-self (e.g. bacteria from human cells). When this detection mechanism goes wrong we can have what are called autoimmune diseases like Lupus where the immune system attacks healthy cells. Also the body has to prevent the overactivation of the immune system and must thus have a mechanism to turn it off. To prevent the immune system from going rogue, its activation proceeds through a number of checkpoints that are controlled by specific receptors present in immune cells. When these receptors interact with specific ligands (molecules that bind to these receptors), the activation of immune cells is shut off. What successful cancer cells do to survive the immune system is that they express these ligands on their membranes thus preventing immune cells that come in contact with them from triggering the immune response. Therefore, scientists conjectured that this inhibition of the immune system by cancer could maybe be antagonized and permit the immune cells to attack the cancerous cells. But how could this be achieved? The answer was antibodies. Antibodies are proteins produced by cells of the immune system that bind with great specificity to those molecules against which they are made. Certain cells of the immune system regularly make antibodies against foreign bodies to flag them for removal. Scientist had learned to grow these cells and to coax them to make antibodies against specific molecules. So they proceeded to create an antibody against one of the molecules that controls an immune checkpoint called PD-1. This antibody blocks the PD-1 receptor on immune cells and prevents the ligands on the surface of the cancer cells from activating it thus blocking the immune response. One of these antibodies called “pembrolizumab” (marketed under the brand name: Keytruda) was the one administered to Jimmy Carter. Of course, Mr. Carter was given several treatments so we don’t know for sure what part of the effect was due to the antibody. Nevertheless, in clinical trials of patients with advanced melanoma pembrolizumab caused tumors to shrink in 21-33% of patients and reduced the risk of disease progression by 42-43%. In fact the administration of this antibody was much more effective than conventional chemotherapy. There are, however, two things that must be pointed out. The first is that only around a third of patients benefit from this immunotherapy. This is probably related to the fact that there are different checkpoints of the immune cascade that are exploited by cancer to avoid detection and the importance of these checkpoints to the survival of these cancers varies from one cancer to another. Second, as expected from blocking the inhibition of the immune system, there were side effects as a result of overactive immune cells, but it must be borne in mind that advanced melanoma is a lethal disease. Scientists are just now unravelling the immense complexity of immune system checks and balances and how they are exploited by cancer. A number of antibodies have been approved by the FDA or are being tested not only for immune system checkpoints but for other mechanisms that allow cancer to thrive like growth receptors or angiogenesis (the process that allows a cancer to create blood vessels to feed its cells). Researchers are even combining antibodies with conventional chemotherapeutic drugs which allows for targeted delivery with less side effects. The future of immunotherapy looks promising, and I feel optimistic about our chances of beating cancers like melanoma, especially with therapies that combine several approaches. As to President Carter, I hope that he fully recovers from his disease and continues his excellent work in favor of humanity. The images in this post are on the public domain. |
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