Science You Want to Know: Epigenetic Research Actually Explains What Makes us Human

"Epigenetics is now the hottest thing in biosciences."

That quote from Randy Jirtle, PhD, director of the Epigenetics and Imprinting Laboratory at Duke University, captures the challenge and the promise for exploring the topic in health writing today, too.

Epigenetics research is growing at an exponential rate. And it's breaking into mainstream health reporting also, with major coverage in Time, Newsweek and Nova.

Whether you're working on an article analyzing trends in NIH funding, or looking for a hook to lead your story about obesity in pregnancy, how are you going to deal with the epigenetics references popping up all around?

After all, if the dramatic rise in research on this topic only took off in 2003, how many of us are likely to understand both the field's promise and its limitations?

As a journalist, you may be thinking that the word "epigenetics" gives you post-traumatic flashbacks to the last time you tried to figure out the exact difference between RNA versus DNA (hey, it's one letter - right?). Or you may be the kind of health-science writer who can toss off a "mono-allelic expression" joke as you're also tossing back a cold one.

Either way, Dr. Randy Jirtle's Thursday keynote address to California Endowment Health Journalism Fellows gathered this week in Pasadena, "Epigenetics: How Genes and Environment Interact," provided great insights into this important topic.

It began, appropriately enough, at our human beginnings. We each have half our DNA from our mother, and half from our father. Our genes are present (with a few notable exceptions) in every cell of our body. But even though our cells have the same genes, we have gobs of very different cell types. How does that happen? How is it that a plump beer-churning liver cell knows how to be completely different from a two-foot long neuron snaking down your leg and zinging your toes whenever you sit too long typing? If they've both got the exact same genes, shouldn't they be exactly the same? Well that's where epigenetics comes in. As we develop, Dr. Jirtle pointed out, we have over 200-300 cell types that emerge from our fetal clump of cells. It is the epigenome that tells those cells what they should be and how to develop.

Epigenetics is the software that tells the DNA hardware (the genes) how and what to do -- without altering the gene sequence. And it is at the early stages of development that epigenetic changes can cause lifelong health effects. Understanding these mechanisms holds enormous promise for health prevention.

Let's dive down into that coiled helical strand of chromosome to see how epigenetics does its tricks. DNA is not always active. Right now, there are two known ways to detect triggers that switch on and off gene activity. The adding of methyl to the DNA is one such chemical mark of epigenetic activity. Another chemical mark of epigenetic activity is when histones are wrapped in DNA – histones can cause the chromatin to be open and functional, or wrapped and not-functional. So we've got many genes that are sleeping as well as stretches that are turned on and chugging away, says Jirtle. The factors that influence whether those tags are added or taken away are known as "epigenetic influences."

Epigenetic activity can be seen in both methyl group markers, and histone coiling/uncoiling activity. Epigenetic patterns are passed on from cell to cell, but can be changed, especially during times of great developmental change – such as during puberty, or pregnancy.

Dr. Jirtle said he often gets asked, "What's more important in diseases - genetic changes or epigenetic changes?"

His response to that question is, "What's more important for you getting your report out - the Word program you're using or the computer running the program? It's an unanswerable question."

Laboratory research suggests that epigenetics plays a major role in human disease development. .Ghost in Your Genes, the Nova documentary which prominently features Dr. Jirtle's work illustrates this well.

The Nova documentary profiles research by Manuel Estellar, who directs the Centro Nacional de Investigaciones Oncológicas in Madrid. It asks, "So what might cause the difference in health outcomes for identical twins who share the same DNA?"

The researchers took DNA samples from 40 pairs of identical twins, aged 3-74. DNA was then separated and fragments were amplified. The patterns were cut out and overlapped. Based on looking at color differences in that overlap, the greater the age of these identical twin pairs, the greater the differences in their magnified patterns. The hypothesis is that epigenetic differences emerge over time, especially when lifestyles differ.

The question raised by this research is: as our cells age, can these epigenetic differences trigger diseases like cancer in one twin and not in the other – because one has different genes that are silenced or activated through epigenetics?

AMD, for example, is a blood-based cancer - is it epigenetically mediated? While it might be scary to think that a few mis-placed tags could trigger cancer, finding an epigenetic link can also be a cause of hope. Changing tags, by activating or silencing them through nutritional supplements or drugs is feasible today while trying to change DNA is a much more challenging (if not impossible) task.

Preliminary, experimental treatments using epigenetics turn on or off genes by manipulating epigenetic markers. One scientist likens epigenetic treatments to diplomacy instead of war. Instead of trying to destroy cells, as chemotherapy might do, the goal is to remind cells how to behave by turning on or off their epigenetic activity. You're human, the negotiator might say, and you aren't behaving that way. So can such an approach work? An epigenetic treatment for AMD in early trials resulted in half of those treated going into remission.

Dr. Jirtle was among the first to demonstrate the powerful effects of an epigenetic treatment approach. In his animal studies, Jirtle used an Agouti mouse, a mutated mouse whose genes were altered so it would eat excessive amounts. The effect of that mutant gene was blocked by giving the pregnant mouse folic acid and phyto-estrogen based compounds - both of which can correct epigenetic activity in the Agouti mouse. So, some of the negative effects of the mutation can potentially be blocked through nutritional treatment to alter epigenetic activity.

But mice aren't people. It's so easy for us to extrapolate animal results to humans. The animal results suggest how mechanisms could work similarly in humans. But because humans – and the way epigenetics function in humans - are so different, it's dangerous to leave out those important qualifiers.

Epigenetics may even be the explanation (finally!) for what that's true. After all, why IS it that mice aren't human? All our last 10-20 years of DNA sequencing efforts have shown us that we're not that different from other mammals, if you just look at our total DNA. Interestingly, epigenetics, at a slightly more advanced, dynamic level, may even be the key to understanding, finally, what it is that (literally) makes us human.

To understand, we once again have to go back the beginning. Of conception, that is. But when it comes to epigenetics, even the seemingly simple statement that we get one set of genes from our dad, and one from our mom isn't that simple. You can think of having two sets of genes at all times as akin to having a back-up for your hard-drive, Jirtle tells us. If one hard drive is defective, or fails, the hope is that the other will kick in, or balance things out and prevent a mutation that can have disastrous health consequences. But even though they're both present and functional, a certain small but critical number of genes have only one operational hard drive making them much more fragile and unstable. Those genes are called "imprinted," which means they have been tagged by epigenetics to be silent. In other words, even though you have two genes (one from mom and one from dad), you're working with only one functional gene from one parent, and the other is, essentially, gagged. This is when things can get really interesting and have critical implications for our health. Or, as Dr. Jirtle put it: "All genes are important, but some are more important than others." .

These imprinted genes aren't floating around randomly. They occur in only certain settings (not in all genes in all cells), and have been found in some rare disease states.

In our vast human array of genes, there are between 150-200 of these imprinted sets out of 20,000-25,000 total genes and they tend to be associated with development and the brain. And, to add a new twist to this tricky way in which one gene is imprinted (or gagged into inactivity), while another is left to soldier on alone - it seems that mother and father genes are not functionally equivalent.

What does this mean? Imagine that you've got a fertilized embryo. It has all the cell machinery working fine. The nucleus, where the DNA lives, is made up of half dad and half mom. You decide to take that nucleus out and replace it with your own, custom made combination, just to see what would happen. Instead of putting in half dad and half mom DNA, you put in double mom genes, no dad. Or, you could strip genes out of two sperm and put in double dad genes (no mom). The number and types of genes should be fine - right?

But even though the number and type look okay, things don't develop normally because the imprinted (or gagged into silence) genes are different. If you put two genes from the mother into an embryo, there is embryo development but it's always smaller than expected at every stage of development. Yolk sac is fine, but the placenta is small. If you put both from dad, the yolk sac is small, the embryo is too small to live and the placenta is huge.

These mis-fires happen naturally (but rarely) in humans. A double-dad set of genes in an otherwise normal embryo leads to a condition called hydatidiform mole. If it's a double set of mom genes, it results in dermoid cysts, or even teratomas.

These misfires of nature show us that epigenetic marks are placed early in the egg/sperm formation, just to make sure there's always only one mono-allelic gene functioning.

Finally, Dr. Jirtle discussed how imprinting and epigenetic activity may play a role in the way in which species developed. When it comes to our total genes, humans aren't that different from other mammals.

The explanation for how we may be so very different from, say, a whale may be found through epigenetics. The clues to how this might work were found by looking at not total genes, but at epigenetic activity. If you look back over time on the mammalian genetic tree, you'll eventually come to the lowly monotreme. Monotremes are mammals that lay eggs, and...do not have imprinted genes. Everything above them on our mammalian genetic tree (from marsupials on up) does have imprinted genes.

The thinking is that 150-200 million years ago, imprinting evolved.

The theory now is that the imprinting phenomenon was used to speciate or create differences within species.

Because these biological mechanisms impact different species in such profoundly different ways, Jirtle cautions against extrapolating lab mouse impacts to humans in your journalism. We've known this for years, but now, with epigenetics, we can finally begin to see why.

What does all this mean for the average health reporter? So we now know that epigenetic activity is what turns genes off and on, and it's also what tells each cell what type to be. Epigenetics may also be the key to how we change over time - even if we had the exact same DNA as a brother or sister. When it comes to health, you might be thinking that's plenty for one little field of study to cover. But epigenetics may also be the way our health is affected by the environment around us. And it may even be the answer to what, after all, truly makes us human.

Pretty neat, huh? No wonder epigenetics is the hottest thing in biosciences today. And now that you've got a handle on this hot new field, you'll want to go toss out a few "mono-allelic expression" jokes of your own...

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