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Interview with Professor Paolo Sassone-Corsi

This leader in genetics talks about your internal clock and why it may be key to the future of medicine.

RALPH PALUMBO

We’ve all stayed up too late, or experienced jet lag, or indulged in a midnight snack. So it’s probably not news to you that those actions mess with what we like to call our “internal clock.”

But what might surprise you is that the concept of an internal clock is actually an age-old biological function – known as circadian rhythms – found in up to 20% of your cells. And “messing” with those rhythms too much or too often might put you at heightened risk for a number of disorders, ranging from insomnia and obesity to diabetes and cancer, says UC Irvine professor Paolo Sassone-Corsi, one of the world’s leading researchers on the genetics of circadian rhythms.

“For instance, flight attendants, or nurses working odd hours, or me, because I fly too much; we are at a higher risk for a number of cardiovascular diseases, diabetes, inflammatory responses, even cancer,” says Sassone-Corsi.

Now for the good news: Sassone-Corsi, who is the Donald Bren professor of biological chemistry and director of the Center for Epigenetics & Metabolism at UC Irvine, has been studying circadian rhythms for the past 20 years and has made recent breakthroughs in identifying new molecular-level compounds that could treat disorders triggered by circadian rhythm dysfunction.

Though he has not yet done trials with humans, he has been able to readjust the cycles in cells of lab mice. “I think that’s very promising for the future of medicine,” he says.

Or for your jet lag. Could you imagine flying to Europe, popping a pill, and instantly setting your body clock to Paris time? Ooh la la!

OK, that might be a ways off. But don’t take your circadian rhythms lightly, says Sassone-Corsi. These are some of nature’s oldest and best-formed biological phenomena. In fact, all life forms on earth have developed based on the simple 24-hour cycle created by the rotation of the planet.

It’s in our DNA. Literally.

So we sat down with the professor and asked him about our internal clocks, and how best to keep them running on time.

What are circadian rhythms?
They’re the cycles that are common to every life form on the planet, and they’re based on the 24-hour cycle, being dominated by light and dark, or day and night. They dominate all metabolism and physiology in most life forms.

So it’s more than just a concept of an “internal clock”?
Yes. For many years people thought the internal clock was something minor in our physiology. Everybody thought it was concentrated in the hypothalamus, a specific area in the brain. Instead, we have clocks everywhere, in every cell in our body. We have a clock in the liver, in the muscles, in the spleen, in the heart, everywhere. This is a major discovery from a physiological and endocrinological point of view.

Why?
First, understand that everyone has, in every cell, 6.5 feet of DNA, all compacted into a tiny nucleus. If you took all your DNA, in every cell, and put it one on top of the other, you’d cover the distance from the earth to the moon 100 times. Now, in every cell, we have about 25,000 genes. Not too many if you think about how complicated we are. And of those, 3,000 to 4,000, or about 10 to 20%, are under the control of the circadian, or “internal clock,” system.

And you’ve found that disrupting these internal clocks can be detrimental to health?
Very. The synchrony among all these clocks is critical for health and well-being. So the asynchrony that you impose to your body can induce a number of metabolic problems and pathologies. Insomnia, depression, diabetes, obesity, accelerated aging, even some forms of cancer have been linked to a disruption of the internal clock. Disruption can occur with untimely exposure to sources of light, such as television or computer screens that an increasing fraction of the population tends to watch until late at night.

What about diet? Can what you eat help or hurt?
Good nutrition, as well as proper sleep, is the best way to insure a good metabolism. But it’s not just a matter of what or how much you eat. When seems just as crucial. We have done really revealing experiments about this. You take two mice, which are exactly the same from a genetic point of view. They are identical twins. You feed them the exact same food, in the same amounts. But you feed one at the normal time for its internal clock and the other you feed at the wrong time for its internal clock.

The one that you feed at the normal time stays normal. The other gets fat. That tells you that the stress induced by eating food at the wrong time for your metabolic cycles is huge. At the wrong time, the body is not able to cope with the food, so it stores it as fat. So the same cheeseburger can be good or bad for you depending on when you eat it.

So, are we all to eat on a specific schedule?
No. Remember, humans are not mice. We are a lot more complicated. A lot depends on social habits, or tradition and culture. But one thing is clear: If you have food late at night, say after nine or so for a normal schedule, it’s not good for your body. You don’t want to go to sleep with food in your stomach. Instead you want that food to be digested before you go to sleep.

How much sleep do people need?
It’s very individual. However, it’s important to realize that you need a minimum amount of sleep, which for most people is at least five to six hours. Otherwise, they have all the sleep-deprivation symptoms: increased blood pressure, headaches, migraines, metabolic imbalances. Proper sleep is key to healthy circadian rhythms and health. Instead, in urban areas the duration of sleep has, on average, decreased by about two hours in the past 50 years.

How did you first become interested in the circadian rhythms?
Twenty years ago, when not too many scientists were thinking about this, I was studying a certain gene for another reason and had a [research fellow] in the lab who studied the level of expression of this particular gene in the brain. He found it was very strongly present. I was staggered by the amazingly strong result, so I told the research fellow to do more studies, while I told a technician to redo the experiment, just to confirm the results. The technician came up with the exact opposite effect – no expression, zero.

What had happened?
I had some suspicions about how the experiment was done, but in the end the answer was very simple. The fellow had [taken the sample] at night while the technician had [taken the sample] in the morning. Many researchers would have just said, “Wow, that’s weird,” and forgotten about it. I thought it was supercool. And that was the beginning of my study of circadian rhythms.

What is the study of epigenetics?
Let’s go back to that 6.5 feet of DNA that’s in every cell. The DNA that you have in your retina or your brain cells is the same DNA you have in your liver cells. So how is it possible that the same DNA can make such different things? That is the study of epigenetics: how genetics is used by a cell. I like to use the analogy of genetics being the written notes of a musical piece, and epigenetics being an orchestra that plays them. The notes are written on a piece of paper, but they’re not music. You need to give it the right tone, strength, timing. Your cells play the music in different ways so that you’ll have an eye, or a muscle, or a liver.

Can we mess with that?
Definitely. There are things that can change the “orchestra” and the way they “play” the notes of the DNA. And those can be the light/dark cycle, nutrition, drug abuse. Cocaine, for instance, is like a stick of dynamite; it changes your epigenetics completely. So today’s revolution, after the one of 60 years ago when DNA structure was discovered, has been that if we understand how epigenetics works, how this orchestra is playing the DNA notes in different ways, then we’ll be able to direct how we can play with our own genes, with respect to changes in our environment, or our nutrition, or other factors, to do everything from curing disease to slow aging. All the research on stem cell biology that has been promoted for the past 10 years is based on this logic.

How is epigenetics related to circadian rhythms?
One of the key discoveries we made is that the molecular machinery that is directing the expression and the function of those 3,000 to 4,000 clock genes that are functioning in a cyclic manner is an epigenetic machinery. So there is a very strong link between the circadian clocks and epigenetics.

Do you see big implications for the future of medicine?
Yes. Here’s an example of how we believe this is all-important. There is such a huge variability among humans – some are big, some are small, some athletic, some not, we have different genetic profiles, different lifestyles. So I think the future will be all about personalized medicine. Each person will have their own, very specific medical profile for better and more precise testing.

Can you give an example?
Sure. Blood tests, for example. Right now, typically, people get their blood drawn in the morning and the doctor checks it against general ranges. But in the future those ranges will be adjusted to the particular individual in terms of age, size, shape, gender, medical history, and genetic history. That will be a much better readout than we can do today. And it will need to be done in accordance with the day’s cycle.

We might take a blood sample every four hours. Then you will have the perfect profile for that person. Because we know from our studies that all those readings might change dramatically from day to night. That “morning” blood is not the same as what you get in the evening, or in the midday. So it’s very important to know that those levels are normal in their cyclic physiology, because that’s what gives you a much better picture of a person’s health. For example, if you have the right amount overall of insulin or glucose, but it does not oscillate properly, that’s not good.

Are doctors starting to do that now?
In a few select places in northern Europe, countries like Sweden and Finland. But it’s going to happen more and more around the world. A few years from now, people will realize this is really important.

Is it merely the light/dark cycle that dictates our circadian rhythms?
No. People think in terms of day and night, but everybody knows that if you’re in constant darkness, you still have cycles. Because the internal clock is probably the most ancient biological system you can imagine.

What do you mean?
What has been constant on this planet since the appearance of life? The rotation of the planet on its axis, and therefore the 24-hour cycle. So even more than adapting to the 24-hour cycle, life has developed on this planet because of the 24-hour cycle. In fact, if you go back in evolution and look at animals that are really ancient, like really tiny phytobacteria, or very early life forms like plants, insects, worms, they all have a clock, and it’s always on a 24-hour cycle. So we are the way we are because of the rotation of the planet and that 24-hour cycle. We would not be the same creatures on a planet with, let’s say, a 48-hour cycle.

When did you first become interested in science on a grand scale?
When we were 10 and 11, my brother and I got really, really interested in astronomy. We were fascinated by the night sky. We were not very rich, but our parents made a big effort and bought us a small telescope. And I was very lucky because the very first thing we saw happened to be Saturn. That was probably the most important moment in my life. It was so amazing. From that moment on, there was nothing else but nature and science for me.

And from studying the biggest objects in the universe, you went to studying some of the smallest: genes.
Right, but now by exploring circadian biology we unite both. So it’s an interesting path. And actually, I think it’s a really cool one.  


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