Melissa Kim and Anis Hassan ’18
Imagine that you are a 5-inch field mouse running for dear life from a hungry snake eager to have you as a tasty snack. Not only is your focus sharpened, but your senses are heightened, allowing you to hear every slithering movement and smell the terrifying odor emanating from this predator. If you could successfully outrun this snake, what is the most important lesson you might take away from this dramatic episode? What lessons would you want to pass down to your future offspring? Nature has come up with two answers to these questions:
(1) An exaggerated sensitivity to the odorants emanated by the predator that almost
killed you—this induced defense could act as a preventative shield in future predator encounters.
(2) The ability to somehow pass on this predator-induced shield to your future offspring.
In recent years, there has been a growing public awareness about the ways in which our diets and exposure to synthetic chemicals may impact our own health, and even the health of our subsequent generations. It is not uncommon to shop for a reusable water bottle at the local Target and have more than half of them be marketed as “BPA-free.” Many people are aware that consumption of water stored in BPA-containing bottles may expose our bodies to this chemical, bisphenol-A, resulting in unintended disruption to our endocrine systems. But our surrounding environments can exert influence on our health at the level of our cellular DNA, too. In fact, there is an entire field of biomedical research, called epigenetics, that seeks to understand how the environment (i.e. diet, maternal care in early childhood, exposure to BPA and other manmade chemicals) may affect our DNA, causing perpetual changes in our gene expression that may be passed down to our children and grandchildren10.
Source: https://www.sportco.com/store/pc/Nalgene-Tritan-Narrow-Mouth-Water-Bottle-16-Oz-Bpa-Free-525p49721.htm
Our DNA is the master blueprint that provides each of our cells the instructions to develop specific characteristics and functions. The building blocks of DNA are small molecules called nucleotides. DNA is basically a long string of these nucleotide building blocks whose unique combinations make up the countless genes that ensure that some of our cells will develop into heart cells while others will develop into kidney cells. Interestingly enough, every cell in our body possesses the same DNA—that is, the same set of genes that make up our entire genome. Thus, the vast diversity in our cell types arises from the different ways that certain genes will be used to make proteins in some cells but not others. In other words, what gives a cell its unique set of characteristics is the way that that very cell expresses certain genes but not others.
The idea that the cells in our hearts and our kidneys—two organs that are vastly different in function and structure—contain the same exact DNA is inherently confusing.
It helps to think of DNA as the instrumental sheet music that lays out all of musical notes to be played by an orchestra. This master musical score is composed of sequences of beautiful chords. Each chord is like a different gene. In this metaphor, the violinists and pianists are like the heart cells and the kidneys cells in our body, respectively. Both the violinists and pianists have access to the same instrumental sheet music, but they do not necessarily play every chord of the symphony. Above all, is the conductor. The conductor is the master of the orchestra. In one moment, the conductor will point to the pianists, instructing them to play a specific chord. The next moment, the conductor will point to the violinists, instructing them to play a different chord.
You see, if the organs that make up our body together comprise an orchestra, our DNA is the sheet music that provides the master instructions to which all of our cells have access. Our epigenome is the master conductor that individually instructs each cell in our body to express the exact genes that that specific cell needs. Thus, out of the ~20,000 protein-coding genes that make up the human genome, our heart cells are “opening up” and expressing the fraction of these genes that are required for its survival as a heart cell. Meanwhile, it is “closing away” and silencing the other fraction of these genes that are tailored more for our kidney cells.
By coordinating the set of genes that will be open versus closed, the conductor is representing the essence of epigenetics.
So, how does the environment fit into all of this? Remarkably, certain foods that we eat are enriched in an amino acid known as methionine. Methionine is able to provide our bodies with methyl groups that can become attached to DNA itself, like little chemical “tags.” These chemical tags can then act as physical blockades that hide away certain genes. If DNA is a master blueprint that contains countless sets of instructions for the cell to make different proteins, methylating DNA is like applying white-out over specific instruction sets so as to hide them from being read. Consequently, these methyl groups are like the conductor of the orchestra who points specifically to the pianists and shouts, “DON’T PLAY THIS CHORD!” As we will go on to discuss shortly, this DNA methylation provides a way in which the environmental exposures of even our grandparents may impact our own gene expression without changing the DNA code itself6.
Perhaps one of the most cited examples of the transgenerational impact of epigenetics is that of the Dutch Hongerwinter. Towards the end of World War II, Nazi-occupied Holland began to dip into a massive famine as the overland transport of foods into cities like Amsterdam were halted amidst a cold winter, leading to the death of 18,000 people in the course of one year. Children that had been conceived during this famine were prone to diabetes, obesity, and schizophrenia—what’s more, these increased risks perpetuated down to the next generation of offspring as well. Although this famine occurred more than half a century earlier, investigations into these Hongerwinter individuals found decreased methylation of the insulin-like growth factor II gene, a gene that encodes for vital growth hormones. This change would go on to impact the normal homeostatic balance of hormones responsible for proper growth and development2.
Source: Ahmed (2010)
Yet what if there was a way for parents to equip their offspring with good defenses against life-threatening environmental conditions based on their own experiences? In 1999, a collaboration of researchers from the United States and Germany published findings that suggested that non-lethal exposures of animals to predators and plants to herbivores induces defenses in those organisms. What’s more, these defenses then seem to persist into the next generation of offspring. In this study, the researchers found that wild radish plants that had been non-lethally damaged by caterpillars had induction of higher concentrations of chemical poisons against these caterpillars. These plants even displayed an induction of higher amounts of protective leaf hairs—all changes that increased the plants’ survival in future predator encounters. Strikingly, these changes in phenotype were also seen in the offspring of these predator-exposed plants. This means that plants derived from seeds of parent plants who had been partially eaten by hungry caterpillars were born with stronger chemical defenses and denser leaves, compared to plants derived from seeds of parent plants who had never encountered a caterpillar1.
The researchers found a similar pattern of defense induction in a species of water fleas. Exposure to the chemical kairomones released by their natural predators led to a doubling of the helmet size of these organisms. Despite the absence of changes in their genetic code, these predator-exposed water fleas were then able to pass down this induced defense by endowing their offspring with increased helmet sizes as well1.
Source: https://www.livescience.com/55297-how-water-fleas-grow-body-armor.html
These instances demonstrate the rapidity with which certain organisms are able to induce defensive tactics. It is as if the predator-prey interactions are catalyzing evolutionary biology itself by inducing the surviving prey to obtain stronger, more potent shields against their predators—defenses that these prey are able to transmit down to their own offspring long after the initial predator-prey interaction.
Of course, this leads to the million-dollar question: How are these experience-induced phenotypic changes occurring? In recent years, molecular biologists and geneticists have made strides in elucidating how traumatic or extraordinary experiences may leave epigenetic marks on our cellular DNA, thereby imprinting a molecular “memory” in our DNA that we may pass on to our future children and grandchildren. One such study looked at a strain of pond snails originating from The Netherlands. Researchers found that if these snails were exposed to crayfish (their natural predators) kairomones, then these snails would gain perpetual changes in their ability to form long-term memory. This enhanced memory would in turn strengthen the snail’s respiratory breathing patterns to increase the efficiency with which these animals could survive future predator attacks.
Normally, predator kairomones are likely causing certain memory-associated genes to become “tagged” with methyl groups. Consequently, these genes are becoming silenced, hidden from view the way written instructions can be hidden with white-out. Thinking back to our original orchestra metaphor, it helps to imagine the entirety of the snail’s cells as an orchestra. The various genes that are associated with memory are like different sets of musical chords. Here, the master conductor is looking at brain cells, pointing to specific chords (learning and memory genes), and shouting, “DON’T PLAY THIS CHORD!” However, if these snails were injected with a drug that inhibited them from methylating their own DNA, they were no longer able to form enhanced long-term memory following predator exposure. This finding suggests that DNA methylation is necessary for these snails to acquire enhanced memory. It helps to think of each of the conductor’s commands as new experiential layers that together make up a cell’s epigenetic memory. The animal can then use this molecular memory in future predator attacks to increase its chances of survival. Yet if you administer drugs that debilitate the conductor from properly coordinating the orchestra, you are essentially ripping away layers and layers of the cell’s epigenetic memory 4.
Even mammals have been shown to induce effective defenses to protect themselves from predators. In recent years, a group of scientists discovered that adult mice can transmit life-saving information to their own offspring. These scientists exposed the mice to acetophenone (a scent resembling a mixture of oranges and cherries) while simultaneously shocking their feet. Quickly, the mice began to associate the acetophenone scent with a painful foot shock, causing them to freeze in fear when presented with this specific odor.
When a mouse is within the vicinity of a predator (or in this case, acetophenone), the odorants from the predator travel through the air into the nose of the mouse. Within the mouse nose are specialized cells that are each able to make molecular structures called receptors that stick out of the cells like antennae. Much like antennae, these receptors connect these nose cells to the outside world. When odorants emanated from predators and plants travel into the mouse nose, they are detected by these receptors. Then, the receptors signal back to the cell onto which they are attached. Like a domino effect, the nose cell will send its signal to other cells, and eventually this signal will reach the brain and allow the animal to react to the scent.
Remarkably, when these mice were trained to associate acetophenone with pain, they began to display structural changes in the neuronal organization within their olfactory system! Receptors that had been specialized to detect acetophenone became enlarged, as did the regions of the brain to which these receptors were connected. Behaviorally, these mice displayed a heightened sensitivity to the original acetophenone odor.
When these mice were bred to produce offspring, their pups also displayed the same brain region enlargement seen in the parents. These structural changes persisted again, onto the next generation of offspring as well, suggesting that there is some sort of ancestral transfer of information taking place3.
But how are such changes occurring, considering these second and third generations of offspring were never exposed to the fear-training that their parents had experienced? The answer lies in a key gene called Olfr151. Olfr151 is the specific DNA code that provides certain cells with the instructions to make a receptor that is specialized to detect acetophenone. Astonishingly, the offspring of the mice who had been trained to fear acetophenone have a version of the Olfr151 gene that is stripped of its methyl tags. In other words, the instructions to make the special acetophenone-detecting receptor is fully unmasked.
What happened was that the acetophenone-fearing parent mice passed down their “smell memory” in the form of a demethylated Olfr151 gene. In their offspring, the unmasked gene readily provided the instructions for nose cells to make tons of receptors specialized for acetophenone detection. It is as if the orchestra conductor was pointing to the pianists and telling them to play chords they had never before played. The result: the creation of a new symphony. Through this epigenetic transgenerational inheritance of traumatic memory, both the parents and their future generations are better shielded to acutely sniff out danger3.
Returning to our original scenario in which we imagined ourselves as mice successfully outrunning a hungry snake—if the snake were to have excreted a specific scent while chasing us, the ability to remember and avoid such a scent in the future could be the difference between life and death. Whether it be a plant inducing chemical secretions against a caterpillar or a mouse inducing odorant detection against a snake, the heritability of epigenetic marks has opened up a way in which experienced parents can pass their induced defenses down to their progeny. Ultimately, in an act of catalytic evolution, the game of “survival of the fittest” seems to have utilized epigenetics to allow prey another means for survival.
References
- Agrawal, A. A., Laforsch, C., & Tollrian, R. (1999). Transgenerational induction of defence in animals and plants. Nature, 401(6748), 60–63. https://doi.org/10.1038/43425
- Ahmed, F. (2010). Tales of adversity. Nature, 8(2737), S20. https://doi.org/10.1038/468S20a
- Dias, B. G., & Ressler, K. J. (2014). Parental olfactory experience influences behavior and neural structure in subsequent generations. Nature Neuroscience. https://doi.org/10.1038/nn.3594
- Forest, J., Sunada, H., Dodd, S., & Lukowiak, K. (2016). Training Lymnaea in the presence of a predator scent results in a long-lasting ability to form enhanced long-term memory. Journal of Comparative Physiology A: Neuroethology, Sensory, Neural, and Behavioral Physiology, 202(6),99–409. https://doi.org/10.1007/s00359-016-1086-z
- Forsythe, M. Epigenetics [Illustration]. Alumni Magazine: McGill News, Montreal. In H. Hoag (Author).
- Kim, J. K., Samaranayake, M., & Pradhan, S. (2009). Epigenetic mechanisms in mammals. Cellular and Molecular Life Sciences, 66(4), 596–612. https://doi.org/10.1007/s00018-008-8432-4
- Latzel, V., Zhang, Y., Moritz, K. K., Fischer, M., & Bossdorf, O. (2012). Epigenetic variation in plant responses to defence hormones. Annals of Botany, 110(7), 1423-1428. doi:10.1093/aob/mcs088
- Nalgene® Tritan® Narrow-Mouth Water Bottle – 16 oz. BPA Free [Advertisement]. (2018). Retrieved April 17, 2018, from https://www.sportco.com/store/pc/Nalgene-Tritan-Narrow-Mouth-Water-Bottle-16-Oz-Bpa-Free-525p49721.htm
- Pappas, S. (2016). Armor Up! Water Fleas Grow Helmets and Spines for Battle. Live Science. Retrieved April 17, 2018, from https://www.livescience.com/.
- Tracey, R., Manikkam, M., Guerrero-Bosagna, C., & Skinner, M. K. (2013). Hydrocarbons (jet fuel JP-8) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. Reproductive Toxicology, 36(1), 104–116. https://doi.org/10.1016/j.reprotox. 2012.11.011