Epigenetics - based on Podcast #3 with Randy Jirtle
September 20th, 2021
Link to the podcast if you missed it.
Humans, like most organisms on earth, grow and maintain their biological systems through a complex interplay between the environment and their genes. Epigenetics is the study of the ability of environmental signals to silence or activate these genes, thus effecting cellular function and species survival. I was once given an analogy, by Dr. Randy Jirtle, that your genes are like a computer hard drive. They do nothing until the software inputs change activity. The environmental signals like food, chemicals, stress and much more are the putative software inputs for us. Good lifestyle inputs have been epidemiologically proven to reduce disease risk.
Pregnancy is probably the most critical epigenetic period of human life where the development of a child is affected by many aspects of our lifestyle. What we do know is that negative epigenetic triggers will have a negative effect on a child's outcome. We need to know what the negative triggers are. Once an egg is fertilized and forms into an embryo, the process of rapid cellular growth and gene expression ramps up. Over the entire gestational period, there are day to day changes based on environmental inputs that will silence or express a gene's function. We call this gene expression patterns and they are recorded on the DNA as tags or marks as each cell progresses towards it's ultimate type. Let us look at the research that gave us the mechanism behind how this works and looks.
The beginning of this new scientific understanding came in the year 2003 from the lab of Randy Jirtle, a radiation oncologist at Duke University in North Carolina. His pioneering research with the Agouti mouse revolutionized how we see human genetic outcomes and changed our belief that we are destined to be the sum of our parents inherited DNA, genetic determinism. His lab also proved that mother's have some control over their offspring's genetic outcome by identifying the mechanisms related to alterations in gene expression while not altering the DNA itself.
His lab conducted an experiment with an Agouti mouse. This mouse is predestined, or so we thought, to always produce pups that have a yellow coat color, become obese and are prone to developing diabetes and cancer. This elegant experiment offered the mother mouse an altered diet prior to conception and then throughout pregnancy. They gave the mice dietary sources of a specific carbon complex called a methyl group which is naturally found in choline, betaine, folate, and vitamin B12. The natural food sources of these methyl groups are predominantly vegetables like beets and garlic. They chose food sources of methyl groups for the research because Robert Waterland, a post doctoral fellow in the lab, had a keen interest in nutrition and biology.
What they proved was that this dietary addition had the ability to silence a segment of the offspring's genetic code. This silenced region coded for the Agouti mouse's coat color and predisposition for obesity. The outcome was earth shattering in the scientific world. The mouse pups were born brown and skinny and did not carry the risk of developing diabetes or cancer.
"It was a little eerie and a little scary to see how something as subtle as a nutritional change in the pregnant mother rat could have such a dramatic impact on the gene expression of the baby," Jirtle says. "The results showed how important epigenetic changes could be." (Discover article 2006)
Let me recap! For the first time in history, we now have evidence that a nutritional alteration has the ability to alter the disease outcome of a new baby. Healthy food is the lifestyle choice that had a positive effect on the outcome in a mouse model that was supposed to not be possible!
Dr. Jirtle's group took the research a little farther. They continued the original agouti mouse experiment, but added a wrinkle. They gave the mothers a ubiquitous plastic chemical called bisphenol A, BPA, at the same time as they continued the original experimental design. The outcome was again shocking. The offspring reverted back to the original dysfunctional state of yellow coat, obesity and increased disease risk.
These studies proved that for the first time we were aware that genes could be activated or silenced by environmental signals including beneficially with food and detrimentally with chemicals.
"Epigenetics is proving we have some responsibility for the integrity of our genome," Jirtle says. "Before, genes predetermined outcomes. Now everything we do-everything we eat or smoke-can affect our gene expression and that of future generations. Epigenetics introduces the concept of free will into our idea of genetics." (Discover article 2006)
RECAP: A mother's offspring can have their DNA read or silenced by environmental inputs during pregnancy. The research has been exploding over the last two decades and it is clear that almost any environmental signal can potentially have an effect on our genetic codes interpretation at the cellular level. We have the mechanism now to research effectively in humans how environmental signals alter a genes function real time.
Dr. Jirtle's work gives us 2 pieces of the environmental puzzle, nutrients and toxicants during the pregnancy phase of growth. What about nurturing or behavioral signals post natally? Could a behavioral input have an effect? Does an offspring or a young child alter genetic expression after pregnancy and delivery?
Enter the excellent work of Dr. Moshe Szyf from McGill University in Canada. He has been studying the effects of environmental triggers on the genome for decades and his group along with the work of Michael Meaney has proven that the behaviors and traits that we see as newborns and children are dictated in large part by environmental and lifestyle experiences. He has also shown that the DNA can be affected after conception well into childhood. (Szyf et. al. 2012)
From a transcript:
"So we can't do experiments. We can administer adversity to humans. But God does experiments with humans. And it's called natural disasters. So one of the natural disasters - the hardest natural disaster in Canadian history happened in my province of Quebec. It's the ice storm of 1998. We lost our entire electrical grid because of an ice storm when the temperatures were in the dead of winter of Quebec - minus 20 to minus 30 - and there were pregnant mothers during that time." "And my colleague, Suzanne King, followed the children of these mothers for 15 years. And what happened was that as the stress increased - and here we had objective measures of stress. How long you were without power? Where did you spend your time? Was it in your mother-in-law's apartment or in some posh country home? So all these added up to a social stress scale. And you can ask the question, how did the children look like? And it appears that as stress increases, the children develop more autism. They develop more metabolic diseases. And they develop more autoimmune diseases." (Szyf transcript 2017)
Epidemiological research from Overkalix, Sweden and The Dutch Hunger Winter study have also shown that periods of feast and famine during pregnancy can have an effect on the offspring of the mother regardless of other factors or confounders like socioeconomic status that are usually used to debunk data points. (Bygren et. al. 2014 and Schulz 2010)
Whether these stressful events happened to a child in utero or after birth, the epigenetic marks causing disease worsened with increasing stress. Taking it a step further, it is clear from the collective research to date in the field of epigenetics that there are exponential ways to alter gene expression. They are called daily life. The research has identified some that are clearly detrimental and some that are beneficial to the offspring. The trick is to understand what helps and what harms.
Dr. Szyf goes on to state: "So on one hand, we have an old genome - right? - that's millions of years old that's fixed. On the other hand, we have a changing world that is talking to our DNA. And this balance, probably, was selected by many, many millions of years of evolution to provide with us with this amazing, what we call, plasticity on one hand and fixed characters on the other hand, right? So we need both. We need the immutable and mutable operating together. And that's the amazing paradox and challenge of life."
What he is saying is that this epigenetic changeability is evolutionarily protective in an ever changing environment. However, if our DNA can be read in many different ways depending on the changing world, then why are we falling apart as a species. This question is related in large part to modern society.
The answer is likely related to the fact that humans have altered the environment at such a torrid pace in the last 100 years compared to the previous thousands of years. We are inundated with chemical exposure, increased mental stress and poor quality food driving the majority of the poor epigenetic signals that our children are receiving and processing. We no longer have the historical stresses of food scarcity, temperature swings in a non climate controlled environment and microbial friend exposures of the recent past. In other words, we have a whole new set of lifestyle challenges and we are not evolving fast enough to combat them.
The thrust of the Dr. Jirtle podcast was the identification and acknowledgement of a novel mechanism to explain the changes and disease susceptibility that humans have through differing environmental signals. We now have to do the heavy lifting in the research space to identify all of the major epigenetic risks for a negative human outcome. However, before the research comes to fruition, we have epidemiological data that likely predicts the epigenetics to be seen in humans over time.
To me, here are the likely truisms:
1) A whole foods based diet is the path to optimal genetic activity in a human as this food reality is how our genes evolved to understand
2) Excessive mental stress and chronic mental stress are counterproductive leading to problems. Stress avoidance and stress management techniques are very useful
3) Chemicals in all forms are potentially problematical for a fetus. Thus, maternal exposure is a route to trouble. (Gulati et. al. 2018) We should encourage the complete avoidance of chemicals and drugs during this period
4) A lack of exercise is very important trigger of dysfunctional epigenetics
5) Viral infections are a net negative prenatally with increased risks of autism and schizophrenia. (Cattane et. al. 2020)
6) Maintaining a healthy intestinal microbiome prepregnancy appears to be very important.
For a really deep dive, read the Danchin Biological Reviews Article - Link Below
A mother's and father's choices matter in many if not all ways,
Utah Genetics Site
M. Szyf Article
Project Ice Storm
M. Kundakovich Article
R. Jirtle Article
D. Dolinoy Article
L. Schulz Article
Gulati Seminars in Arthritis and Rheumatism
Cattane Neuroscience and Behaviors
Danchin Biological Reviews