Investigating telomeres and what they mean for aging-related diseases

December 10, 2012

When molecular biologist Carol Greider was 25 years old, she was studying a minute pond creature and its telomeres, the tips of its chromosomes. Greider knew that as chromosomes naturally divided, their telomeres became shorter, but in this particular animal they did not.

She wondered why, and guessed that an enzyme was involved. Her hunch panned out. According to Greider’s research, the enzyme, telomerase (pronounced “ta-LAW-mer-ace”), helps maintain the length of telomeres, replenishing them with each cell division. This discovery led to the 2009 Nobel Prize in Physiology or Medicine for Greider and two colleagues, and to further study of the connection of telemeres to diseases associated with aging, such as pulmonary fibrosis, and to some cancers.

Greider, now 51, is director of molecular biology and genetics at the Institute for Basic Biomedical Sciences at Johns Hopkins School of Medicine. She recently spoke to The Post about telomeres and whether understanding how to manipulate them may someday lead to treatments of age-related diseases.

— Laura Hambleton


Molecular biologist and Nobel prize winner, Carol Greider, discusses the connection between telemores and age-related diseases. (Handout)

What are telomeres, exactly?

They protect chromosomes. They are like the tip of shoelaces, that plastic piece that protects the shoelace from unraveling. With age, telomeres naturally shorten. [But] just looking at someone’s telomeres without their age doesn’t tell you much.

Tell me about discovering how telomerase works.

We were working in this single-cell animal called a tetrahymena. It is a pond-dwelling creature, like a paramecium. A single cell has 40,000 telomeres, whereas a human cell only has 92. What I set out to do was make an artificial telomere in the test tube, then see if that telomere could be elongated. I did that by making a cell extract from the tetrahymena. If a tetrahymena had 40,000 chromosomes, it would have a lot of the stuff needed to elongate telo­meres. And it turns out that was correct. It was using this tetrahymena where I discovered this enzyme called telomerase.

What are some of the implications of your discovery?

The first implication is cancer. A cancer cell is a cell that is dividing many more times than it should. It has to solve the telo­mere problem because every time that cells divides, the telomere shortens. It turns out over 95 percent of the different cancer types have more of this telomerase enzyme, so it solves the telomere problem. If you could block this enzyme, then you may be able to block the growth of cancer cells. We’re not at a stage where we have a clinical inhibitor of telomerase. There are some that have been tested, but the biology [of different cancers] is a little bit more complicated.

The other place where telo­meres play a role is in normal cells in the body that have divided many times just for normal upkeep of the body. It turns out human families where you have inherited diseases that don’t have enough telomerase, they have bone marrow failure. The bone marrow is an easy example to understand because the bone marrow is where all the blood comes from. Every day there are new blood cells that are born and circulate around.

Blood cells have very short life spans, and new ones have to be made. Bone marrow has to be able to divide many, many times to replenish all the blood. If the telomeres get too short, the bone marrow dies. You can’t go on and replenish the blood.

There are a number of age-related degenerative diseases where short telomeres play a critical role. The one that has the largest impact in society is pulmonary fibrosis, which is a lung disease that over 20,000 people a year die of and has no known cause and no treatment. Now that we know that lung disease is caused by telomeres shortening, we can begin to move toward ways of thinking of therapeutics.

Again, there aren’t any therapeutics there, but there is a whole lot of promise. In that case, what one would want to do is elongate telomeres.

Can that be done?

Even though we don’t have anything therapeutic to make someone’s telomeres longer, knowing that a patient has short telomeres would allow a clinician to make different decisions about their care.

My telomeres are different from yours. Is that genetic?

Telomere shortening is both genetic and environmental. One example of an environmental component is [that] a patient with HIV has shorter telomeres than would be expected. The thought is the HIV is killing off a number of the blood cells, so their blood cells have to divide more times to keep up. Therefore, their telomeres are shorter.

Does age shorten telomeres?

You are born with telomeres a certain length. These diseases are age-related degenerative diseases because the cells have to divide a certain number of times before short telomeres become manifest. Pulmonary fibrosis is a disease people get in their 70s. It is combination of both this cell division and this environmental component. You have more time for the environment to have an impact.

If you could lengthen telo­meres, have you found the secret to the fountain of youth?

Telomeres don’t determine the maximum life span. Mice that have different telomere lengths have no difference in life spans. If we think of the maximum human life span as 100 to 120 years, most people don’t make it that long. The health span is what is happening between when you’re 15 years old and when you get up to 90. Simply changing telomeres isn’t going to change life span, but it can dramatically help [with the health span] in the patient with an age-related degenerative disease.

How do you see age-related diseases treated in the future?

[In a few years, we might be able] to take cells — bone marrow, for instance — and treat it with some compounds that would elongate the telomeres and give them back to patients. Or perhaps you could inject small-molecule drugs that would allow telomeres to lengthen. This is still at the early-stage level. It could be a major treatment.

Have you ever measured your telomeres?

I haven’t looked at my telomeres. We joke in the lab sometimes when we do something forgetful: We say it must be my telomeres are too short. What if they found out if someone had really short telomeres? You are in an ethical dilemma. You might find out things you don’t want to find out.

What drew you to science?

I wasn’t a kid who had a chemistry set. I never went to science fairs. I like solving the puzzle. When I was an undergraduate — I went to UC Santa Barbara — I thought I wanted to study marine biology. I learned that was not how I think. The marine biology was much more statistics and ecology, numbers and graphs. When I got into a biochemistry lab, I liked that kind of thinking of things: This molecule is working with this molecule. If I make this particular change, what would it do to this experiment? We call it mechanistic thinking. When I went to graduate school and I was interviewing, I met Liz Blackburn. [Elizabeth Blackburn was also awarded the Nobel Prize in 2009 for her work on telomeres.] She had this fascinating puzzle of telomeres. I went to UC Berkeley because I was fascinated by the puzzle.

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