Making Real Life X-Men

By E.E. Giorgi

EVEN THOUGH I’VE NEVER BEEN a huge fan of the human/animal hybrid in science fiction (Sabretooth, Beast, “The Island of Doctor Moreau”), the concept has always intrigued me. Not so much the genetic explanations, rather, the idea of a predator in human disguise. After all, before we developed the opposable thumb that gave us the ability to hang from trees, we were already predators, weren’t we? And yet, none of the human mutation scenarios out there ever satisfied my appetite for a real human predator. That’s how, in my quest, I came to learn about epigenetics and pseudogenes.

Pseudogenes are bits of DNA that we inherited from our ancestors and, at some point during our evolution, got turned off. In other words, they stopped producing the protein they were originally coding for. For example, TAS1R2, the gene that encodes for the taste receptor for sweetness in humans is, in fact, a pseudogene in felines. As a consequence, cats don’t have a sweet tooth: they literally can’t taste sweetness.

Our DNA is riddled with regions that we inherited from our ancestors. We inherited mitochondria from bacteria, and roughly ten percent of our genome from viruses. As we evolved from amphibians to reptiles to mammals, new genes arose and the old ones became inactive and turned into pseudogenes. Can these old, inactivated genes ever be turned back on? As it turns out, some can. For example, viral pseudogenes that we inherited millions of years ago are now expressed in the placenta. Furthermore, the largest set of known pseudogenes is made of olfactory receptors, which can indeed be reactivated and become functional again. Ever wondered why pregnant women suddenly start smelling the weirdest things?

All this raises the question: how can genes be turned on or off? And what does it mean for a gene to be on or off? To answer these questions we need to take a step back and look at our own evolution.

How the Environment Changes Us

In 1809, Jean-Baptiste Lamarck first described his theory of evolution in his book “Philosophie Zoologique,” which we all learned in school as the “giraffe example.” According to Lamarck’s soft inheritance theory, giraffes’ necks grew longer as the animals tried to reach for higher branches when feeding. Darwin’s theory of evolution, on the other hand, tells us that giraffes randomly born with longer necks had access to better food and therefore slowly outnumbered the giraffes with shorter necks by having more offspring and a better chance of survival.

In reality, Lamarck never studied giraffes; plants and flowers were his passion. And as it turns out, plants’ incredible ability to adapt to the most diverse environments heavily relies on what is known today as epigenetics. Lamarck was not completely wrong, after all.

Epigenetics studies the mechanisms that affect gene expression and how these changes can be inherited from one generation to the next. We are all familiar with concepts like genes and evolution, but too many times I hear these concepts used improperly. Things like “I’ve got my mother’s genes,” or “I’ve got the Alzheimer’s gene,” don’t mean much when you realize that DNA is only the starting point of who we are. We not only carry our parents’ genes, in some scrambled assortment, but we also inherit their fears, their anxieties, their metabolism, and even their bacteria. These are changes that are not encoded in the genes, rather, in the way the genes are expressed.

DNA is made up of three billion pairs of nucleotides (A, C, G, and T), of which genes comprise roughly a mere two percent. Any given cell in our body, at any given time, expresses only a subset of those genes. If you think of genes as “switches,” then every cell has some of those switches turned on and some off, and the on/off pattern changes not only from cell to cell but also throughout our lifetime.

In 1994, by altering these “on/off” gene switches, researchers were able to breed mice that were genetically identical yet looked strikingly different: one was fat and yellow, the other lean and brown. In order to understand how this is possible, we need to look inside the cell nucleus, where DNA is tightly packaged in a structure called chromatin.

Mechanisms That Regulate Gene Expression

DNA can be thought of as long strand of yarn wrapped inside the cell nucleus. The yarn is not static but moves, and as it does so it exposes some genes, making them available for transcription (“on switch”) while hiding others (“off switch”). This happens through chemical changes inside the cell nucleus. Proteins called histones function like spools around which the DNA is wrapped. When the histones are tightly packed together, the genes wrapped within are hidden and therefore cannot be transcribed into proteins. On the other hand, when the histones “loosen up,” they expose the genes and make them available for transcription, and the genes are therefore expressed.

Whether histones are tight together or not is regulated by molecules that bind to the DNA. For example, when a molecule containing one carbon atom bonded to three hydrogen atoms (a “methyl group”) binds to the DNA, the histones “tighten” together and the genes are inactivated (or “off”). This process is called DNA methylation. Other epigenetic factors can attach to the DNA and cause histone modifications that have the opposite effect, activating the genes instead.

Traits are determined not only by mutations randomly scattered along our DNA, but also by which genes are expressed at any given time and which aren’t. Several environmental factors can alter gene expression by causing changes in the histones: diet, stress, trauma, for example. Infancy and childhood in particular are times when the growing body is most susceptible to the environment. Early life epigenetic changes can affect us well into our adult life. Experiments in mice have shown that mothers nurturing their pups trigger positive epigenetic changes in the pups’ brains that later in life enable the mice to deal better with stress. Pups that had not been nurtured by their mothers had a harder time dealing with stress as adults.

Although genetic mutations are irreversible, changes in gene expression are reversible and can, in some instances, be inherited (even though they are not encoded in the actual DNA). This is why studying the mechanisms that alter gene expression is so important, especially when such changes affect our health.

In the mouse nurturing experiment, the researchers found that when the GCR gene, the glucocorticoid receptor, is activated in the brain, mice are less sensitive to stress. Indeed, it is exactly this gene that the nurturing mothers were able to activate in their pups.

Epigenetic Inheritance

Plants are far more susceptible to the environment than animals. They tend to flower at the beginning of spring when, after the cold winter, temperatures start rising again. This process, called vernalization, is independent of the length of winter. But how does the plant know when it’s time to bloom again? The changes in temperature prompt epigenetic changes that regulate the inactivation and reactivation of flower-suppressing genes with every change of the season.

Epigenetics is also responsible for the ability of some plants to survive through long periods of drought. Because these changes in gene expression can be inherited by the offspring, plants can pass on the temporary adaptation to a more hostile environment to future generations. It’s not a coincidence that Lamarck formulated his theory of evolution after observing plants.

While animals are not as susceptible to the environment as plants, similar epigenetic mechanisms that trigger temporary adaptation to the environment after a time of stress have been observed in humans. Pregnant women who undergo severe dietary restrictions, for instance, trigger epigenetic changes in the unborn fetus that cause higher responses to glucose and a higher risk of developing diabetes in adult life. This has been shown by studies that have followed adults who were born during a period of famine or a restricted caloric intake.

Responses to the environment and strong adaptation are enhanced in particular during fetal and neonatal development, making these two phases in life extremely vulnerable to epigenetic alteration in gene expression. This is why a pregnant woman’s diet or her stress levels can have long-term consequences on the offspring.

Obesity and a diet high in fats during pregnancy can trigger epigenetic changes in the offspring that raise their chances of developing obesity later in life. Animal studies have shown that maternal obesity and a high-fat diet during pregnancy can activate genes that regulate appetite in the offspring, making it harder for them to lose weight in maturity. Nutrients like folate and choline, on the other hand, affect the regulation of gene expression in cells; studies have shown that diets poor in these nutrients during either fetal development or early childhood can cause deleterious epigenetic changes that last throughout life.

Epigenetics and Cancer

Cancer is the result of genetic and epigenetic changes involving oncogenes and tumor-suppressor genes. [Graphic, below, illustrates the stages of how a normal cell is converted to a cancer cell when an oncogene becomes activated. Courtesy National Cancer Institute.] Somatic mutations that accumulate over time can eventually lead to cancer, but typically cancerous cells also show alterations in gene expression. Some genes have an active role in repairing DNA or triggering cell death when the damage is beyond repair. Down-regulation of these genes has been observed in several types of cancers. Furthermore, because these changes in gene expression are inherited by the daughter cells as the cells keep dividing, once triggered they promote tumor growth.

Studying the mechanisms that alter gene expression in carcinogenesis is particularly important because, although genetic mutations are irreversible, epigenetic alterations can indeed, in some instances, be reversed. Current research is focusing on drugs that are able to reactivate tumor-suppressor genes that have been silenced in cancer tissue. The major obstacle to overcome, however, is to make these drugs gene-specific rather than have them up-regulate all genes indiscriminately.

Epigenetics and Aging

Expression levels of genes change as we age, with a tendency to lose methyl groups—the molecules that inhibit gene expression—as we age (hypomethylation). Whether these mechanisms are the product or the cause of the progressive decline that comes with aging, though, is unclear.

Cells use oxygen to produce energy. As we age, their capacity to use oxygen declines. This decline can be reduced with exercise and a diet rich in antioxidants. Indeed, both exercise and a healthy diet induce epigenetic changes that alter the expression levels of numerous genes, in particular mitochondrial genes that are involved in cell metabolism and oxygen pathways.

Exercise can also suppress the activation of genes like TNF, or tumor necrosis factor, which is typically up-regulated in inflammatory responses. Because cancer can be a long-term consequence of chronic inflammation, the fact that exercise can down-regulate inflammatory responses could explain its protective effect against cancer.

Another hallmark of aging is the shortening of the telomeres, bits of non-coding DNA found at the end of our chromosomes. These regions wear out as the cells keep on dividing, until they become so short that further divisions would alter the coding part of the DNA. Therefore, when the telomeres are so short that no other cellular division is possible, the cell dies. In a child, normal telomeres are long enough to allow a cell to divide over a dozen times. In seniors, the shortened telomeres only allow for two or three cellular divisions before the cell dies. Studies have shown that exercise can induce epigenetic changes that stabilize the length of the telomeres and therefore reduce their shortening due to aging.

Epigenetics and Fiction

Back to my original quest: could human/animal hybrids really exist? Once I learned about the pseudogenes we inherited from our predator ancestors, and all the epigenetic mechanisms that can reactivate these old genes, my imagination was reeling. I ended up creating not a hybrid but a police detective, one whose olfactory sense was extremely enhanced. That’s right: because of all the olfactory receptors encoded in our pseudogenes!

The main character in my detective thriller “Chimeras” is an epigenetic chimera. A viral infection when Detective Track Presius was a child triggered a cascade of epigenetic changes in his cells that awakened ancestral pseudogenes, empowering him with the sense of smell like that of a bear but also with the instincts of a predator.

Wait a minute: I’ve talked about epigenetic changes induced by diet, stress, and exercise. Where did the viral infection come from?

Granted, I did use a bit of a poetic license in my novel, but yes, viruses can trigger epigenetic changes and alter gene expression inside the host cell. Many viruses induce inflammatory epigenetic responses that, because of their heritability to daughter cells, persist to a point that cells enter a precancerous state. This is the mechanism of human papilloma virus or hepatitis B and C viruses, which can lead to cancer in roughly ten percent of the infected patients.

In some cases, the epigenetic changes are triggered by the host cell as a defense against the viral infection. This is what happens during HIV infection, for example. HIV-1 uses the cell’s own machinery to reproduce because it’s so small that it couldn’t possibly contain all the genes it would need to reproduce on its own. After it enters the cell, HIV inserts its genetic content inside the cell’s nucleus and exploits cellular division to make many copies of itself. However, conformational changes within the cellular DNA can silence the viral genes and prevent its genes from being transcribed.

Unfortunately, in the case of HIV-1, this leads to many cells being latently infected (i.e., the cells are infected but not actively producing new virions). The virus is not reproducing, but it’s not being cleared either. In fact, when patients stop taking antiretroviral drugs, these latently infected cells start releasing the virus again, resulting in a new wave of infection.

Turns out, I’m not the only one to have used a viral infection as a means to trigger epigenetic changes. Nicholas Sansbury Smith used it, too, in his bestselling apocalyptic series “Extinction Cycle.” In his trilogy, Smith imagines that the deadly Ebola virus combines with an old bioweapon to start an epidemic of unprecedented proportions. By activating ancestral pseudogenes, this new, mutated virus is able to turn infected people into some kind of human-insect hybrid.

“I’ve always wanted to write a zombie book,” Smith told me in an interview on my blog, “but I didn’t want to write the same story that’s been told so many times before. So I decided to try and find a way to describe an outbreak using real science. Epigenetics seemed to be the answer, and after talking with an author friend and scientist I decided to go that route.”

Whether it’s X-Men, zombies or human/animal hybrids with enhanced senses, epigenetics gives writers a new realm of phenomena to explore. One can’t help but wonder: is reality truly stranger than fiction? 

Further Reading

The Seductive Allure of Behavioral Epigenetics.
Epigenetic Differences Associated With Prenatal Exposure to Famine.
Genetics and Epigenetics of Obesity.
Maternal Obesity and Fetal Metabolic Programming.
The Epigenomics of Cancer.
Epigenetic Regulation on Gene Expression by Physical Exercise.
Epigenetic Reprogramming of Host Genes.
Control of HIV Latency by Epigenetic and Non-Epigenetic Mechanisms.

E. E. Giorgi is a computational biologist at the Los Alamos National Laboratory, an award-winning photographer, and a writer. She normally works in HIV research. Her debut novel, “Chimeras,” was a 2014 International Book Award winner.