We are ready to go.
So, our first presentation will be by Dana Dolinoy,
our Searle Assistant Professor doing some amazing work in epigenetics.
Thank you. Can hear me? It's working. You may not be able to see the mic,
but there is, indeed, one.
So, welcome students, faculty, colleagues, alumni, of the University of Michigan School of Public Health
Department of Environmental Health Sciences.
I'm delighted to be with you here today to share a story,
a story that expands upon the DNA double helix,
first portrayed here on the cover of "Nature" in 1953 by Watson & Crick.
What this extraordinary discovery has accustomed us to is thinking about how our genes shape our lives.
But today, I'd like you to think about how our lives shape our genes.
"So, what's the moral of the story?" you may already be asking yourself.
Well today, I hope to show you and convince you that DNA is, in fact,
not necessarily your destiny.
And to do so, I'd like to introduce you to two mice, the Agouti Sisters.
And as you can see, the yellow mouse is quite obese, and she's also susceptible to diabetes and cancer.
On the other hand, the brown mouse remains lean and slender,
and has a lower risk of developing disease.
But, what is so interesting about these two mice is that they're genetically identical.
They are identical twin sisters from the same mother.
And today we're gonna learn what makes them look so different.
Many of us in this room will member the great public/private race, or partnership,
in the late 1990s and early 2000s,that resulted in a sequencing of the human genome
and the identification of the approximately 23,000 genes,
their location, and make up.
But what this extraordinary endeavor fell short in doing
was identifying the instruction books that tells these genes
when to turn on, where to turn on, how much to turn on,
and of most interest to those of us in this room, how to react
to various environmental stressors or nutritional stimuli.
So, that's where our story begins. It turns out, there's a second genome called the epigenome.
Epigenome literally means, "in addition to or above the genome."
And it turns out, that this epigenome is what gives cells plasticity,
it allows them to react to various environmental factors,
and it also helps determine how a stem cellbecomes a liver cell, a heart cell, or even a hair cell.
So, what are these epigenetic marks?
They are molecular switches and markers.
They not only give genes plasticity,but help compact the approximately two meters of DNA sequence
into cells that are only the size of ten to a hundred micrometers.
One of the most extensively studied epigenetic marks is DNA methylation,
in which a core set of atoms, called a methyl group,
attaches to the DNA and shuts genes down.
DNA methylation has often been compared to a dimmer on a light switch.
So, a gene that is unmethylated can be brightly expressed, conducive to a reading environment.
On the other hand, that same gene can become methylated and become dimly expressed,
conducive to a romantic setting.
Other epigenetic markers are histone modifications,
and these wrap around little spools called nucleosomes, and help compact the DNA into
the cell while allowing those genes to remain poised for action.
Well, it turns out, the epigenome has gained significant momentum over the past several years.
And, in fact,it played a starring role in Michael Crichton's book called "Next."
And in this book, Professor Garfield is testifying before Congress.
And he says, "It's not surprising
that researchers are moving towards what we call 'epigenetic studies,' which look exactly at how
genes interact with the environment to produce the individual that we see."
He then goes on to explain this epigenetic science in great detail
and intricacy. And the Congressmen begin to fall asleep
while the Congressional aids get out their cell phones and start texting.
Which, I hope this work of fiction is not a premonition for the rest of our story here today.
So, back to the Agouti Sisters.
In the yellow mouse, the agouti gene is unmethylated,
and it's turned on all the time, when it normally should be on during one period of development.
And this causes the mice to feel less satisfied after eating,and, therefore, go back for just one more helping.
On the other hand, the brown mouse has an agouti gene that is methylated and shut down.
And these mice feel full.
There are also other mice that are modeled in which half of the cells are methylated
and turned down, and the other half are unmethylated and turned on.
And for that reason, these mice appear to be both yellow and brown.
So we utilize these agouti mice as a visual sensor for how much DNA methylation is present in the body.
And in one study we wanted to determine
whether a mother's exposure to a chemical that's found everywhere in the environment
could effect the epigenetic switches in the offspring, and then their long-term fate.
This chemical is Bishphenol A, or BPA for sort.
Bisphenol A is the monomer that makes up polycarbonate plastic
and it is, indeed, found in many commonly used products, including food and beverage containers,
baby bottles, dental sealants, and the lining of food cans.
The CDC studied this chemical about five years ago
and detected it in 95% of the four hundred individuals that it measured.
BPA is what's known as an endocrine disruptor,
something that we'll hear about in the next talk from Dr. Meeker. Endocrine disruptors
are exogenous chemicals that can interact with natural hormones in the body.
We wanted to determine whether the mom's exposures to Bisphenol A could alter DNA methylation.
So, we fed the moms Bisphenol A in their diet. And once we did this, we observed that the mouse pups
were more likely to be the yellow coat color. And when we looked at the DNA methylation at the gene,
we saw that Bishenol A decreased DNA methylation, and turned this gene on when it normally should be off.
So, we started a second study. And in this study, the mice were still exposed to Bisphenol A,
but now they were nutritionally supplemented with either micronutrients,like folic acid,
or phytoestrogens, such as genistein, which is found in soy.
And once we did this, we observed that the pups were no longer predominantly yellow,
that they were more likely to be brown and slender.
This showed that maternal nutritional supplementation could counteract the effects of Bisphenol A alone.
The traditional thinking in human health and disease
is that it's an interaction between genetics, and the environment, and time.
So, whenever a monozygotic, or an identical twin, has a different disease state,
this was often attributed to a different behavioral choice, such as exercise habits, or diet.
But now, with these agouti mice, we can no longer say whether genetics and the environment
have a bigger role in health because they're inextricably linked through the epigenome.
In fact, unlike the genome, which is static and not modifiable, the epigenome is dynamic
and potentially reversible.
Therefore, as we move from animal models to thinking about humans and population disease susceptibility,
we may be able to use epigenetic switches and markers
to identify individuals who are at risk of developing disease.
And once these individuals are identified,
we may be able to use diet, or pharmacological approaches to counteract the disease progression.
Although, we're probably several years away from being able to do this in humans.
Through efforts such as the Human Epigenome Project, which is ongoing in our country
and many other countries across the world,
we are now beginning to unravel the complex epigenomes of an individual.
This is a snippet of a human epigenome of eight cell types
from one individual. It's actually a male if you can't tell,
at one point in time, and on one human chromosome. And this is chromosome twenty-two,
which happens to be one of the smallest human chromosomes.
So, you can already see that we're dealing with an enormous amount of complexity.
The biggest obstacle now is to figure out how diet, environmental exposures,
behavioral choices,interact with these epigenetic marks and influence or decrease one's risk of disease.
One of the most interesting and potentially alarming things about the epigenome is that
these marks may be inherited transgenerationally.
We know in looking at agricultural records
in an isolated Swedish community back to the 1800s, that if your great-grandfather
was born during a bountiful feast of good crop, you're more likely to die prematurely.
Parallel data from England supports the same effect, if your grandparents started smoking in adolescence.
Another interesting phenomena with the epigenome
is that, although it's vulnerable during multiple time periods, and we'll hear a little
bit more about this with Dr. Rozek later, it's particularly vulnerable during development.
Studies such as the tragic, human experience at the end of World War II, the Dutch Winter famine,
showed that individuals who were conceived during the famine, but not born during the famine,
are more likely to have altered DNA methylation in their growth-related genes at age sixty.
So, through these anecdotes, as well as the tale of two mice, I hope I've showed you today
that DNA is not necessarily your destiny, or my destiny.
But it's also not necessarily the destiny of your children or your grandchildren.
And with that, I thank you, and say "The End."