One on One with... Joe Ecker
Salk professor Joe Ecker made national headlines in December when TIME magazine ranked his most recent study, in which his lab mapped the epigenome of two human cell types for the first time, the No. 2 most important scientific finding of 2009. Interestingly, the techniques Ecker's lab used to map the human epigenome - the mechanism that controls our DNA - were the same he previously developed to decipher the "epigenetic" code in plants. A renowned plant geneticist and member of the National Academy of Sciences, Ecker was part of the team that sequenced the entire genome of Arabidopsis thaliana, a modest weed that has become the model organism for plant biologists. Discoveries first made in plants are now being applied toward better understanding human biology.
Were you at all surprised that the mainstream media picked up
on the epigenome story?
No. We knew it was a big deal. We spent the last two years racing against many other groups. There is a group of scientists in China that got $1.5 billion to work on epigenetics and other projects. And there were others in Singapore and Scripps. So there were some very good people out there working on this, yet here we are, this relatively small group at the Salk Institute that was able to complete the first two examples of the human epigenome and publish first in Nature. The good news for us is that we already had a lot of experience from working with Arabidopsis. So we had already worked out the methods. In fact our competitors were using our sequencing methods.
Can you explain epigenetics in basic terms?
The mechanism that controls the expression of DNA is the so-called epigenome. It sits on top of your DNA, hence the term "epi" (on top of). You can think of it as being the software in a computer. A computer running Windows looks very different from a Macintosh, it just depends on the software you are running. So in similar fashion, the epigenome is controlling the genome, making different cell types using the same "hardware" (genome).
So what controls the epigenome?
What we eat or the environment can cause changes in your epigenome. For example, there's a study that just came out about plastic containers containing bisphenol. It looked at changes in methylation profiles, not using whole genome sequencing, but using an array-based method. And sure enough it looks like bisphenol is having an effect on the epigenome. So that is a clear environmental effect of diet and toxins in the environment that are affecting your DNA methylation profile.
There are drugs on the market that target the epigenome.
Which diseases do they treat? And what other applications are possible
as science learns more about the human epigenome?
There are many places in your genome where the epigenome is in control. If you take a drug that affects the epigenome, you'd want to know specifically which area of the epigenome is being changed. But that's not entirely understood yet. The drugs on the market that affect the epigenome are primarily used to treat cancer. One of the characteristics in cancer is the silencing of tumor suppressor genes. So if these genes are turned off by the epigenome, which is a bad thing, you could potentially turn them back on by removing the DNA methylation. But of course these drugs also cause other changes in the epigenome. So trying to understand exactly what the drugs are doing depends on being able to look across the entire genome. I think physicians will soon begin to treat patients with a drug, isolate the cells from that person after treatment and look at the changes in their epigenome to understand their effect, good and bad. And then maybe in the future drugs can be designed to target the enzymes involved to control specific areas of the epigenome.
In your lab's recent study, your team mapped the epigenomes of two
human cell types: embryonic stem cells and fibroblasts. But this is just
the tip of the iceberg in terms of what still needs to be discovered.
Absolutely. The textbooks tell us that there are 250 or so cell types. Well, we know there is more than that. Our colleagues at Salk who study the retina tell us it alone has 20 cell types, and probably many more. Cell types are designated by their shape and size, but that's probably a very naive view of what cells are because as an embryo forms, for example, those cells are changing and moving. So cells that are in motion may look like the ones that aren't, but yet something is telling them to move. So they are genetically programmed differently. So you can imagine that there are millions of epigenetic states at one extreme, and minimally 250. Somewhere in between is the real number, which we don't know, but we've done two so far. So we're definitely at the tip of the iceberg.
What fascinates you most about plant genetics?
Not only what we eat but a lot of what we wear comes from plant material. And so I think its an area where you can have a lot of impact. So one of the goals of our research is to understand plants well enough to be able to manipulate them for various purposes: energy, biofuels, creating new crops that can withstand the changing environments. There are a lot of things about plants that have an impact on humans. Not necessarily disease, but impact human biology, hunger being at the top of the list.
What's the one scientific question in your field you'd
like to answer in your lifetime?
I'd like to know how much of what we see affecting the epigenome is transmitted into the next generation. That has very profound implications for human biology because some of the things that we don't understand about disease may be due to epigenetics. This is where plants actually help because the information gathered from animal and plant model systems can easily transfer from one another. And one of the things we know very well about plants is that they can have stable epigenetic events that last hundreds of years. So that means that if such an event can be stable and inherited over many generations maybe it's true in people as well.
So trying to understand the impact of the environment on plants and people is one of the goals that we have. What happens to the epigenome when you change your diet or in disease states such as if you have diabetes? Does either have implications for your kids or grandkids? Just like we try to understand how genetic mutations have effects on diseases, this is a whole other area I think that's ripe for trying to understand how people interact with their environment and how it affects them.