Biopharma employees read, as you might expect, a wide spectrum of scientific journals and trade publications. What might be surprising is that their reading lists appear to have expanded recently to include classic Marvel comics. What’s led me to this conclusion? The Belgian pharmaceutical company UCB has sponsored an Innovation Challenge on the InnoCentive Website with a goal to “identify individuals, families, groups or communities who possess rare phenotypes – for example people who possess great self-healing abilities, incredible memory or who are protected from disease.”
This immediately brought to mind the Marvel series of X-Men comics (and the big screen movies based on them) that focused on people harboring mutations that conferred extraordinary abilities. The X in the X-Men name originally stood for the X-gene, which normal humans lack and which is responsible for their unusual powers. Most of the X-Men have just “regular” mutations that render them special, but a few have “Omega-level” mutations that generate the most powerful type of unique abilities. Some X-Men (the title actually includes X-Women as well) can control the weather, freeze objects, fly, breathe underwater, or have telepathic or telekinetic powers. The X-Men, as Lady Gaga would tell you, were “born this way.” This is in contrast to other heroes in the Marvel universe, like Spider-Man and the Fantastic Four, who acquired their powers (often through radiation exposure) as adults.
UCB is not the only organization seeking out individuals with unique abilities. Entrepreneur Jonathan Rothberg and physicist Max Tegmark have launched “Project Einstein” at the Massachusetts Institute of Technology. They intend to sequence the genomes from some 400 mathematicians and physicists in order to identify genes that are associated with exceptional mathematical abilities. Similarly, BGI (formerly the Beijing Genomics Institute), the Chinese DNA sequencing company, is in the process of mapping the genes of 1,600 people who have an average IQ of 150. They aim to identify common genetic variants that are associated with human intelligence. The likelihood of success in these projects has been widely debated in the science community. Many social critics are opposed to these types of studies due to fears about using the information for either selective breeding or labeling people based solely on their genetic profiles.
In a similar vein, the National Cancer Institute is combing through trials of failed cancer drugs looking for rare “exceptional responder” patients. Figuring out why these individuals were helped, but others weren’t, may further illuminate the underlying biology and point the way towards developing second-generation drugs that work better. Analysis of the genomes of these people is likely to play a large part in this analysis.
Thousands of mutations have been described that have deleterious effects on human development. How likely is it that the UCB effort to find enhancing mutations will bear fruit? I think it’s highly probable, based on the fact that there are already known examples of the kinds of people and genes that UCB is looking for:
People Who Possess “Great Self-Healing Abilities”
The individual who immediately comes to mind here is Wolverine, one of the most popular X-Men characters. Not only is he immune to most toxins and pathogens, but he can also regenerate seriously damaged tissue within hours as a result of his “healing factor.” The gene encoding this “healing factor” appears to be pretty widespread in the Marvel Universe, as some 77 other mutants share some form of this trait. In the real world, the Lin28a gene is one that appears to be associated with rapid healing. Experiments in mice have shown that activation of this gene leads to faster repair of injuries in adult mice. Similarly, in a 2003 study, researchers found that the Foxm1b gene played a role in the accelerated regrowth of liver tissue in aged mice. These studies represent only the first step down a long and tortuous path that hopefully leads towards eventual applicability in humans.
In 2006, the first report appeared in the scientific literature of individuals who have highly superior autobiographical memory (HSAM). These people can remember details of what happened on nearly every day of their lives starting at a fairly young age. Whether this ability results from genetic differences in brain structure or is a learned behavior is not clear, but one can easily envision a genome-sequencing project that will compare these folks to a control group. A story profiling a small group of these people on the news show “60 Minutes” led to the identification of even more folks who have this unique ability. This type of memory is distinct from the learnable skills acquired by people who can rapidly memorize large amounts of information, as described in Joshua Foer’s entertaining book, “Moonwalking with Einstein: The Art and Science of Remembering Everything.”
People Who “Are Protected from Disease”
Scientists have been interested for years in understanding mechanistically why some people are resistant to diseases that are frequently lethal to others. Edward Jenner established that milkmaids infected with the cowpox virus became resistant to its deadly cousin smallpox; this observation provided the basis for vaccinations to prevent disease. Are there people who are genetically resistant to infectious diseases in the absence of vaccination? In the case of AIDS, several cases were identified in Australia of people who were naturally resistant to HIV infection. Research showed that they had two copies (one from each parent) of a specific mutation (delta 32) in the CCR5 gene that the virus uses to gain entry to cells. Researchers have also been searching out rare individuals who can effectively mount a superior antibody response against HIV. One patient in South Africa was identified who produced HIV-neutralizing antibodies following infection. This discovery points to a potential “Achilles heel” within the virus, and provides the groundwork for the potential development of future anti-HIV vaccines.
The phrase “treasure your exceptions” is well known in the genetics community. It was coined and popularized by English geneticist William Bateson (1861-1926), who was also the first person to use the term “genetics.” In its original context, “treasure your exceptions” was used to point out the value of analyzing unusual traits in various living organisms. This type of work was being done in Gregor Mendel’s breeding of pea plants (being tall or short), Thomas Hunt Morgan’s study of fruit flies (having red or white eyes), and William Castle’s analysis of the coat colors of mice.
Most genetic differences are initially revealed because they have an unusual phenotype (essentially, the physical appearance of an organism). In the real world, not all mutations lead to X-ray vision, give one the ability to fly, or produce claws made of “adamantium” steel. However, there are a number of recently discovered mutations that have given people super strength, invulnerability, and tremendous endurance, all abilities that would make the X-Men proud. The following stories were all nicely told in David Epstein’s book, The Sports Gene: Inside the Science of Extraordinary Athletic Performance.
Super Strength – The trait was first identified in Belgian Blue cattle, which have twice the muscle mass as regular cattle. Molecular analysis of their muscle tissue revealed mutations in a gene encoding the protein myostatin, which normally regulates muscle growth. These mutations lead to a failure to stop muscle growth, which is part of the normal process. As a result, myostatin mutations are associated with extreme musculature, which translates into great strength and, in some situations, great speed. Distinct mutations in this gene in thoroughbred racehorses can be used to predict a horse’s success as a sprinter or a long distance runner. The first human identified with myostatin mutations was a baby born in Germany in 2004; at birth he already had well developed muscles. There are worries that these mutations will negatively affect his heart muscle as well, but so far no developmental problems have been noted. Drugs that modulate myostatin levels or activity have been put into clinical trials in an effort to restore muscle strength in boys with muscular dystrophy, but none so far have proved effective.
Invulnerability – A family was identified in Pakistan whose members felt no pain. They have a mutation in the SCN9A gene, which encodes a type of sodium ion channel. The mutation blocks the pathway that nerve signals take on the way to your brain, and as a result, these individuals feel no pain. Despite what many of us might think, this mutation is no blessing. People afflicted with this mutation tend to die at a young age. This is because they either get seriously injured but don’t seek treatment (pain is nature’s way of telling you it’s time to go to the doctor), or because they don’t continuously shift their weight as the rest of us do (even while sleeping), and this leads to joint infections that eventually prove fatal.
Great Endurance – Mutations in the gene encoding the erythropoietin receptor turned out to be responsible for Eero Mäntyranta’s cross county skiing prowess. Dubbed “the Flying Finn,” and blessed with tremendous endurance, he won medals in the 1960, 1964, and 1968 Olympic Winter games. His victory margin in the 15K race in 1964 was 40 seconds, a margin that has never been bested. Analysis of his DNA revealed that his erythropoietin receptor is truncated compared to other people. As a result, it is overly sensitive to erythropoietin and naturally leads to the overproduction of red blood cells in his system. Having more red blood cells means greater oxygen carrying capacity, which in turn translates into great endurance. Modern blood dopers (e.g. Lance Armstrong) have injected themselves with erythropoietin to accomplish the same task.
The genetic traits identified above, as far as I know, have not led to the affected individuals being ostracized from their communities for being “different,” an event that the X-Men experienced all too often. The Genetic Information Nondiscrimination Act (GINA) of 2008 bars employers from demanding genetic information from employees, and prevents employers and health (but not life, disability, or long-term care) insurance companies from discrimination based on your genetic information. Even with this limited protection, many question the wisdom of having one’s genetic information made publicly available. The identification of people based solely on their DNA sequences has unfortunately turned out to be much easier than previously thought.
The X-Men stories began only 10 years after the discovery of the structure of the DNA double helix in 1953, and DNA sequencing didn’t arrive until the 1970’s. Tales of the X-Men were published in Marvel Comics; reports about interesting mutations in people these days are more likely to show up in journals like Cell, Science, and Nature. The Marvel focus was not on uncovering the genetic underpinnings behind the remarkable powers with which these individuals were endowed. Of greater interest to the writers was dramatizing the way these people were shunned by society for simply being “different,” a recurrent theme in the comic book industry since its early days. It’s part of a continuing commentary on our society where many people (both in comics and in real life) are often ill treated because they’re part of some minority group. These differences, whether in race, sexual orientation, or appearance sometimes evoke fear in the uninformed. As Marie Curie said, “Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.” UCB’s Innovation Challenge may help to do just that in a way that will bring health benefits to all of us.
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