In scientific research it often happens that significant discoveries or methodological advancements get christened after the person who made them. For example, the process by which we treat milk in order to reduce harmful bacteria is called pasteurization after the French Biologist Louis Pasteur. The fecal bacterium E. Coli (Escherichia Coli) is named after its discoverer: Dr. Theodor Escherich. The sequence of reactions involved in generating most of the energy that cells use is called the Krebs cycle after the British biochemist Hans Krebs. Even pieces of laboratory glassware are named after people! The Erlenmayer flask is named after the German chemist Emil Erlenmeyer, the Dewar flask is named after the Scottish chemist James Dewar. The Büchner flask is named after the German chemist Ernst Büchner.
The field of science that has assigned more person names to entities is chemistry. There are hundreds of reactions in chemistry that are named after the researchers who discovered or studied them. There are reactions such as the Birch reduction (after the Australian chemist Arthur Birch), the Wohl degradation (after the German chemist Alfred Wohl), the Robinson annulation (after the English chemist Robert Robinson), and countless others that meander the nightmares of chemistry students worldwide before exams.
Today I am going to write about a curious chemical reaction that I encountered. I was reading about an enzyme called pyruvate dehydrogenase (PD). This enzyme is part of the PD complex which is responsible for the conversion of the substrate pyruvate (an end product of carbohydrate metabolism) into another substance called Acetyl-coenzyme A, which is one of the first substrates of the Krebs cycle mentioned above. The PD complex is important for many reasons. For example, head trauma can lead to a reduction in the levels of this enzyme which compromises the energy state of the nerves and can lead to neuronal death.
I was trying to search for a fact about PD without having to wade through countless pages of erudite reviews, so I quickly Googled “pyruvate dehydrogenase” and among the hits was a Wikipedia entry. So, even though I am mindful of the perils of using Wikipedia, I (mea culpa, mea culpa, mea maxima culpa…) clicked on the Wikipedia page of pyruvate dehydrogenase. To begin the conversion of pyruvate to acetyl-coenzyme A, this enzyme carries out the decarboxylation of pyruvate, whereby carbon dioxide (CO2) is removed from the molecule. What caught my attention is that this process, the decarboxylation of pyruvate, was referred to as the “Swanson conversion”. I thought this was odd. I did not remember ever reading this during my education as a biochemist or in my whole professional career thereafter. I found a Wikipedia entry that cited a link from the Rensselaer Polytechnic Institute to justify naming this reaction in this way. But this link did not have any such information. I checked my old biochemistry books, and there was no mention that this process is called the Swanson conversion. Who was Dr. Swanson and when did he/she perform the research on the decarboxylation of pyruvate?
I checked the scientific databases. The PubMed database has no entries regarding the Swanson conversion. Also, although this database has 1068 entries regarding pyruvate decarboxylation, none of them are associated with anyone named Swanson. Switching the term of the search to “pyruvate dehydrogenase” yields 18,080 hits of which only 8 are associated with a person named Swanson, but none of these articles are specifically about this mechanism. I performed searches with Google Scholar, Science Direct, and WorldWideScience but no luck either. None of these or other bona fide science websites seemed to have any mention of the Swanson conversion or of the pioneering work of Dr. Swanson on pyruvate decarboxylation that led to this process being named after him or her.
I then proceeded to google “Swanson conversion” along with the term “pyruvate” (to eliminate from the hits religious conversions experienced by people named Swanson and conversions (as in scoring) by sport players named Swanson). I came up with 687 results. These hits include entries in sites like the World Heritage Encyclopedia, the World Library, and in the Chemical Entities of Biological Interest (ChEBI) website, which is associated with the European Bioinformatics Institute (EMBL-EBI). I also found entries in study websites in the form of study sets, lecture and exam flashcards, and even an AP video. There is a generation of students out there who is learning that the pyruvate decarboxylation step of the pyruvate dehydrogenase reaction is named the Swanson conversion!
As I was going over the links to webpages that mentioned the Swanson conversion, I noticed that many of them where either from Wikipedia or contained or referenced Wikipedia content. Finally in the website “Answers.com” I found the following unsettling claim:
“The Swanson Conversion is another term for Pyruvate Decarboxylation. It is part of the process by which cells produce ATP and takes place before the Krebs Cycle. The origin of the name "the Swanson Conversion" is unknown, but the story goes that there was a high school biology teacher named Swanson who wanted something named after himself, so he told his students to put "the Swanson Conversion" down as another name for pyruvate decarboxylation on its wikipedia page and spread the name around the internet to gain it credibility, and now the name is commonly used as a substitute for "pyruvate carboxylation".
Of course, I have no way of knowing if this is true, but it would be consistent with the apparent lack of information regarding this topic. And if this was a joke, it seems to have caught on. Eight of the google hits I obtained also claimed that the Swanson conversion is also known as the “Naypyidaw Reaction”. One even called it the “Metallica reaction”.
I don’t know if the people responsible for this will one day come out (like the jokesters who made the crop circles in Britain or the ones that faked the iconic photograph of the Loch Ness monster) to alert the world of its gullibility and the perils of online sites, but I am a bit miffed by this occurrence. Scientists devote their lives to grueling research that more often than not produces dead ends, anxiety, and depression. Along the way there are small victories and the pleasure of small discoveries, but sometimes with the right mix of genius, vision, and luck a scientist discovers or achieves something important enough to have an impact on society and to be associated with their names. I consider this joke to be a slap in the face of these generations of scientists that have made and still are making the world a better place.
Update 10-22-17: The mystery of the Swanson Conversion has been solved!
Image of Pyruvate Dehydrogenase Complex Reaction by akane700 (CC BY-SA 3.0).
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.