The Importance of Little Ends

by emptypockets

Sometime in the next few hours a phone call will awaken a sleeping scientist (assuming it's an American) with the news that he or she will receive a Nobel Prize. If you want to play a funny joke, call your local university's top biological bigwig at 3 am tonight and say (in Swedish), "Hurllo, ees der perfesser dayre?"

There are always some common guesses for who's due, whether it's the person who first figured out RNA polymerase, or angiogenesis, or axon guidance, or RNAi, or perhaps the founders of FluWiki. One indicator that Nobel-watchers go by is who has recently received a Lasker award, often called "the American Nobel" because so many Lasker recipients go on to pay a visit to the King of Sweden. This year's Lasker recipients include the discoverers of telomerase, a protein inside cells that puts little endings on the DNA of your chromosomes. (One of the Lasker awardees is Liz Blackburn, an outstanding biochemist who has the additional distinction of having been fired by President Bush for refusing to toe the line on stem cells when she served on his Bioethics Commission.)

I want to say a little bit about the discovery of telomerase, as it illustrates a point I've been wanting to make about this country's attitude towards science research. [If you're not interested in the science, please skip to the next paragraph.] As I said, telomerase is a sort of repair protein that adds ends to your chromosomes -- the ends are often compared to the little plastic tips on your shoelaces, simple devices to keep a chromosome from becoming frayed. Your DNA has two problems, both arising because it is organized in a small number of very long double-stranded helices (each of which is called a chromosome). The first problem is that DNA needs to get duplicated when a cell divides, but the replication mechanism always misses a bit at the end. Therefore, each chromosome would keep getting shorter and shorter unless its ends get added back somehow. The second problem is that the DNA strand sometimes breaks -- just snaps -- and the cell has very sophisticated ways of dealing with those broken ends. But if the cell is going to recognize a broken end, it needs to 'mark' the normal ends to make them look different somehow. Telomeres solve both these problems. They are just a nonsense sequence, repeated over and over again, at the ends of each chromosome. That makes it easy to add back to the ends as they get shorter during replication (just add more repeats), and it makes it easy to distinguish chromosome breaks from normal ends (a broken end doesn't have the repeats). Telomerase is the protein that adds those repeats, and it is important in cancer and stem cells -- anytime a cell wants to be able to divide forever without having the ends of its chromosomes shorten to the point where they start looking like they've broken. That's one kind of important little ending.

There's another kind of important little ending that is why I bring this up. The attitude towards biology research in this country is: "What can it do for me?" That is what NIH wants to know when it funds a grant, that is what Congress wants to know when they fund NIH, and that is what taxpayers want to know when they elect their Congressman. "I'm paying for this research, what disease are you going to cure?" Here's how the Times described the discovery of telomerase:

Telomerase is an enzyme that replenishes the tips of chromosomes. Discovery of the enzyme emerged after Dr. Gall and Dr. Blackburn studied two organisms, a pond-dwelling parasite and baker’s yeast. The scientists were driven by curiosity, not because they thought their research was related to human disease, said Dr. Goldstein, who works at the University of Texas Southwestern Medical Center in Dallas.

In fact, Blackburn told me once that when she entered the field no one thought it was interesting. She was not setting out to cure cancer or to learn to make cells divide forever, like stem cells. She just had a simple question -- if a chromosome gets shorter every time it's replicated, what happens to the ends? -- and she and several others have been able, in just a couple of decades of very successful experiments, to get a pretty good answer to that question. It turns out that little ending provided the foundation for tremendous advances in medical fields.

And that's the way it works. When you meet a scientist, or hear about research that seems like a waste of taxpayer funds, you may want to ask "What is that good for?" (which, as I wrote, is what PETA was hoping to get you to ask when they lied about the "gay sheep" experiments -- and many fell for it.) But the question you might like to consider asking is not "What's it good for?" but rather, "What fundamental principles of life are you trying to discover?" Because that's where the progress often comes from. I remember when I began graduate school, having entered with an interest in cancer, a moment of clarity when I realized I could pick between writing two kinds of thesis: one where I make a very small contribution to a very big problem ("the answer to cancer"), and another where I ask an interesting but limited question and actually have a good shot at solving it -- my own little ending.

What makes it into the news is not the little endings. It's the stuff that affects health directly -- new drugs, new diagnostics. Those are like the waves of a river current that lap along the banks. If you're standing on the side, it's what you see the most -- what gets your feet wet. But the energy of research, what pushes it along, is the central current of fundamental discoveries not aimed at curing any single disease.

That's how I feel, anyway. We'll see in the morning if the Nobel committee agreed with me this year. Their track record has been pretty good -- of the prizes from 1995 to 2005, I would count at least six (and probably more) as being "driven by curiosity, not... human disease." Discoveries about the patterning of development in fruit flies, movement of proteins across membranes, how neurons communicate, how yeast cells divide, cell death in tiny worms, and the nature of the sense of smell -- for most of these the connection to disease came long after most of the work was done (and I'm still not sure what understanding smell will cure). But they asked clear questions and came up with reasonably complete answers that fundamentally advanced our understanding of how life works. We can leave it to the drug companies to cure disease -- the public dollar is best spent on the kind of research that wins Lasker awards and Nobel prizes, the search for little endings.

Comments

[MissLaura]

Lovely.

I'll commit it to memory as an answer to those questions not only about science but about learning and knowledge in general.

[AlphaGeek]

Great post, emptypockets. I especially appreciate that you got the expression "toe the line" correct, in that there has been a plague of ignorant perversions of the phrase lately.

As an avid reader of science and science-fiction works, I've known about telomeres for some years now. My interest is more than academic; I am expecting the development of telomere therapy within my lifetime, and I fully expect to receive at least some life-extension benefit even if I'm 50 or 60 before such therapy is viable. Liz Blackburn's work may, in fact, give me years of high-quality life and enable me to meet and enjoy not just my grandchildren, but my great-grandchildren.

[Compound F]

I've had to good fortune to meet Blackburn, and even shared some tissue with one of her students. Best of luck to her. Pavlov began studying digestion, but got serendipitously sidetracked into "psychic secretions."

[Jodi]

Many has been the time when an interesting and perhaps even profitable (yes) idea comes up in math or physics, and an oddity or an obscure little discovery that seemed not too consequential in itself completes the work.

I don't claim any special knowledge or understanding but I thought she had said that her work probably wouldn't extend life beyond the current potential, but that it would help us to have a better life on the way.

And I have to throw this.
"The days of our years are threescore years and ten; and if by reason of strength they be fourscore years, yet is their strength labour and sorrow; for it soon cut off, and we fly away." -KJV

[freepatriot]

thanks for the info

more stuff I never wanted to know, but now I'll never forget it

anybody wanna bet that this research ends up affecting all sorts of medical research ???

the applications of this knowledge might lead to some strange places

the scientists refered to may have cured cancer without trying

curiosity is also a mother of invention

[DemFromCT]

If you want to play the same joke on a Flu Wikian, call them at 3 am and tell them "it's started" in Indonesian.

GREAT POST.

[emptypockets]

And the winner is... Andy Fire and Craig Mello for RNAi! That was my top guess actually -- RNAi was bound to get it eventually, although many thought it still had a few more years to "ripen" before the Nobel committee was comfortable recognizing it. It is heartening that they recognized this discovery while the field is still in a phase of exponential growth, rather than waiting until it is a dusty memory. It is also heartening that they picked these two to receive it -- Andy Fire, imo, was a shoo-in, and Craig Mello would have been my next guess, but there are many people who have contributed to our understanding of this phenomenon in recent years so there could have been other reasonable recipients within the field as well (and our understanding is still incomplete in many ways, another reason many thought the Committee would wait another 5-10 years before recognizing RNAi, as there are surely going to be additional worthy recipients emerging in this field as work quite actively continues.)

What's relevant here is, not only was RNAi not discovered from medically-directed research, it wasn't even discovered from hypothesis-driven research! If you're writing an NIH grant, your top goals are (1) make it relevant to human disease, and (2) have a clear hypothesis based on the literature and your own preliminary results. That's what NIH wants, that's what Congress wants, that's what the taxpayers want. "No fooling around while you don't know where you're going!" If we all followed those rules RNAi would never have been discovered.

I'll try to give a follow-up post later this afternoon and tell you why (or you can read it in the papers).

[DemFromCT]

Uh, you better summarize.

[kim]

You might say that the scientists on the Nobel Committee have a vested interest in headlining the basic research model you've discussed - if the "best" science is produced by basic research, well, we'd better boost the budget for basic research then.

As to your last point about "not following rules," do you really think all those scientists at places like Harvard, MIT, and Caltech, got there by not following very clear rules? Just like DC is where all the high school class presidents end up, science is where the most idealistic and reward driven students end up (the non-idealistic rule breakers go into business) IMO.

If anything can be concluded from great scientific discoveries like RNAi I'd say it is that truly momentous things are discovered mostly randomly, the story of PCR is a great one though.

[emptypockets]

actually I'd say the story of pcr -- or rather the story of kary mullis -- is a really good example of why great intellects SHOULD have some rules they're forced to push against, to keep them from flying into outer space.

creativity and rigor are often in tension -- no one would say either extreme is healthy. Right now we are trending toward an extreme of rigor, as NIH is starved for funds, and it's not healthy for the science.

As Bob Dylan sings on his new album, "The world of research is going berserk -- too much paperwork."

[DemFromCT]

Let's talk stem cells. Any benefit in knowing how things work at the cellular level?

[emptypockets]

The fun question is the other way around. That is, not asking "what benefit is there to understanding stem cells," which is a disease-driven question, but "what does it take to be a stem cell?"

Fundamentally a stem cell is a cell that can divide forever but whose daughters cannot.

We know a lot about how to divide forever, because that's what cancer is. What is interesting is how to divide to make one cell that's still a stem cell and the other daughter that goes on to mature and stop dividing, and become skin or bone or pancreas or whatever. That problem is 'asymmetric division' -- how to divide to make two cells with different fates -- and is a fundamental and really interesting problem in cell biology. It is something that many many organisms do, from yeast to flies to humans. Even bacteria, at least some bacteria.

Of course when we're talking about stem cell research we're usually talking about something much more disease-driven --- taking a stem cell that can produce neurons or glia and learning to coax it to only make neurons for example. There are some fundamental questions there about the nature of cell identity but frankly a lot of it is motivated by whatever diseases are causing trouble right now, and less by an interest in basic principles.

That research is fine to do and important work, but a lot of it can get funded privately anyway, either by biotech and drug companies or by philanthropists who have the disease the research might help. I'd suggest that the best use of public money is on research that's not going to be funded anyway by private sources -- that is, on the basic questions that constitute a long-term investment in understanding life and that will pay off for the common good on a scale of 10-20 years.

I may be proven wrong, but I don't think anyone is going to get a Nobel prize or be remembered by history for learning to turn a stem cell into a pancreas cell (on the other hand, if it cures diabetes single-handedly you probably have a good shot). But to my mind the longer-lasting contribution is understanding fundamentally what makes a stem cell work.

[emptypockets]

AlphaGeek, thanks for noticing, I think the recent Johnny Cash movie led to an increase in people stepping on the 'toe the line' (or sometimes even 'tow the line,' heh, must be an old fisherman writing it that way). It's not clear that making our cells live longer would help us live longer (after all, cancer cells are immortal but their human hosts are not). But there is a good deal of work on the biological basis of aging and some of those scientists do believe there will be significant lifespan-extending therapies as a direct result of their work, and in time to improve their own lifespans. (Who knows if that's just what anyone would think if they're calorically restricted and drinking a glass of red wine a day.)

[Peacerme]

Gregory Bateson used to talk about the dialectical tension between "loose" thinking and "hard"thinking. Also, discussion about science without a reference to good old Thomas Kuhn and the dynamic of paradigm shifts poses an interesting question about the politics of science. It fits with the discussion on rules and those who do and don't follow them. When paradigms shift, the attack begins. So what we do study, and support are often theories that fit within the current framework. There can certainly be random truths that surface but probably the most important ones will be attacked and denied for years before anyone is willing or able to validate them. I often think of Thomas Kuhn when I think about the concept of peace. No one gains more attacks that those who propose that peace is a behavior that is attainable by human beings. Watch the attacks fly if you were to throw that theory out there. I don't see any paradigm shifts occuring out of the research today, but for string theory, which remains controversial.

Just my crazy thoughts as the discussion about rule following and the politics of science (NIH). I find that interaction between the politics of the time and the sciences fascinating. We'd all hope that learning about our universe would not be a political issue but we all know that as long as it's a matter of money, there will be politics involved in the way the truth (about life and our universe) unfolds.

[Meteor Blades]

Great post, ep, at least the parts I understand.

Every time I bring up the possibility of extended life spans, my wife always demands to know whether these will mean she will have to delay her retirement another 10 or 20 years. If so, she says, she's going to support Mister Bush's stance on stem cell research, and probably start campaigning to shut down any government-funded telomerase research, too.

Seriously, though, ep, can you direct us to a good telomerase site understandable to us science dunces?

[DemFromCT]

ep, the same question, really. What it takes to be a stem cell requires an understanding of how cells work. "How cells work" is worth studying because fundamental knowledge is advanced thereby. What comes of it comes of it.

And I'll second myself and third MB. Direct us, or explain. ;-)

[emptypockets]

I'm looking for good telomerase sites but they tend to be in babytalk with flashy pictures that carry little information, or else more technical than what I have here. I'm still looking but what might be best is if you two and others let me know where you got lost -- that would also help me personally improve my powers of explanation.

Are you interested in knowing more about the science of telomerase or about the medical applications like lifespan, stem cells, or cancer? The basic science is what I think is most interesting, the rest at this point is all speculation (mostly for grant dollars).

I should say again that there is quite a bit of work going on in the area of lifespan extension -- the view is coming into vogue that cancer, heart disease, alzheimer's, all these problems are not really separate diseases but all just symptoms of a single disease called "old age." The notion is not just to make people live longer, but to make old people healthier -- why is an 80-year-old more decrepit than a 40-year-old? Can we cure "old age" even if we don't stop death? But what I want to emphasize here is that telomerase is about a cell getting old and this other work is about a whole organism getting old -- and so far, for the most part, those fields have not yet intersected (and it's not clear to me from first principles that they ever will... what makes a cell get old and what makes an organism get old may be fundamentally unrelated -- or not -- it's a question we're very much grappling to think about).

[DemFromCT]

basic science, including terms. The rest we can figure out.

[emptypockets]

ok here we go. Everything you need to know about telomeres in 10 minutes or less, with an emphasis on the vocabulary.

DNA is a polymer of nucleotides (A, T, G, and C) which are small modified sugars. A chromosome is a pair of DNA strands, each of which is about 100 billion nucleotides long. The pair of strands are wrapped around each other in a double helix (each strand is a helix, since there are two strands we say it's a double helix). Each strand has a sequence complementary to the other -- where one has A, the other has T; where one has G, the other has C. The chemical structure of the nucleotides allows A from one strand to make specific atomic bonds with T from the other strand and likewise G with C. A base pair is the name for these complementarily aligned nucleotides. To repeat myself, a chromosome has 100 billion base pairs. The sequence of the base pairs is what encodes genes, and other genetic information. We have 46 chromosomes (23 from each parent). These chromosomes are linear, so each one has two ends, for a total of 92 DNA ends per cell. You can see a picture of some chromosomes with the DNA ends stained with a fluorescent chemical label here (in the picture, chromosomes have just finished being duplicated and are about to be split 46 to one daughter cell and 46 to the other -- until then they are kept in pairs that look like little Xs).

Before cell division, every chromosome gets duplicated. The complementary strands of the double helix are unwound. A protein called a primase binds the unwound DNA and makes a short RNA strand called a primer that is complementary to the exposed DNA. RNA is very similar to DNA but is less stable. I won't explain proteins here, but suffice it to say they carry out most of the chemical reactions in a cell. Another set of proteins called the polymerase binds to the RNA-DNA complex. It pairs complementary nucleotides to the exposed unwound DNA, for thousands (hundreds of thousands?) of base pairs at a stretch. This is happening simultaneously at many points along each chromosome. After all the DNA has been copied this way, the short RNA strands are destroyed, the gaps are filled in with DNA and all the short chains are joined together, called ligation. There are now two chromosomes where there used to be one. There is an animation of it here.

The problem is that at the ends of each chromosome, after destroying the RNA primer, there is no way to replace it with DNA. As a result, the newly synthesized strand of DNA is shorter than the old strand by the length of the RNA primer. [This problem is sort of like painting yourself into a corner, and then not being able to paint the corner.]

The solution is that the end of a chromosome is a short repeated DNA sequence called a telomere. It is the sequence TTAGGGTTAGGGTTAGGGTTAGGGTTAGGGTTAGGG... over and over, about 3000 repeats of TTAGGG. (When I write a DNA sequence I only write what it is on one strand -- on the other strand it would be AATCCC. Because the two strands are read in opposite directions, this is read as CCCTAA.) There are proteins that bind to this sequence and give the telomere special properties. One of these proteins is telomerase, which is a special polymerase that only adds TTAGGG and doesn't need an RNA primer (that is an oversimplification -- the protein actually carries its own RNA primer with it). As the ends get shorter during replication, telomerase adds back repeats to keep chromosomes the same length. The chromosomes you have date back not only to when you were a single-cell embryo but to the beginning of humanity, and beyond. Telomerase has kept their ends from getting too short over all those rounds of duplication. There is an animation of sorts here (use the buttons in the lower right of the screen).

So, writing this has been helpful for me -- mostly because it shows me I need to find a good textbook-y site that I can link to as a glossary when I write a science post! I'll look for one for the future. Wikipedia doesn't cut it.

Feedback is very appreciated -- what is most difficult in writing about science for a general educated audience is I don't have a good sense what is common knowledge and what is obscure. I know everyone knows DNA from watching tv police shows, but does everyone know chromosomes? does everyone know chromosomes are DNA? I'm never sure.

[viget]

Hey excellent summary EP!!!

Not that I work on telomerase (though the lab down the hall does, so I have more than a passing familiarity with it), but I'll also say that telomeres are not the end all and be all of ageing.

For example, those lovely mice we all work with in the lab, all those inbred strains? Guess what, they have telomeres that are tens to hundreds of times longer than humans do (interestingly, mice in the wild apparently do not). Yet as we all know, these lab mice are not immortal (though cage costs sometimes make me think otherwise!).

Turns out that ageing is probably a complex phenomenon that involves telomere shortening, coupled with oxidative damage (remember, oxygen is not only life-giving, but also a deadly poison) to proteins and other cellular structures, and then topped off with cellular suicide (or apoptosis, as it's technically called) of cells that are either inappropriately trying to grow or are making too many abberant proteins or are mucked up with proteinacious goo like the alzheimer's A beta protein. Oh, and then there's stem cell depletion as well, but no one really knows what causes stem cells to stop dividing (or at least stop being stem cells).

And then there's this funny thing called "cellular senescence", which literally means aging, but actually is a permanent withdrawl of the cell from the cell cycle, such that it will never divide again. It doesn't necessarily die, but it won't make any more progeny. So as physical wear and tear, buildup of toxins, damage of DNA, etc., occur, the cell will eventually be eliminated by one of the above mechanisms, but there will be nothing there to replace it. It's essentially organismal death by a thousand cuts, a war of attrition. Of course, this is the by far the MOST important mechanism (telomeres, schemlomeres), and I truly say that in an unbiased manner, it has NOTHING at all do with the fact that my lab happens to work on a protein that may be at the heart of this process (well at least in mice).

But I will say this, and then I'll shut up with the geeky science talk. Recently a paper was published in Nature showing that you could actually divorce two functions of a well known tumor suppressor protein p53, cellular suicide secondary to DNA damage from radiation and the ability to stop incipient tumor cells in their tracks.

Turns out, that if after irradiating mice that have a p53 that can be turned on and off like a light switch (normally, p53 is always there, the ever vigilant guardian of the genome), if you turn the p53 ON during the irradiation, but then switch it OFF 6 days later, the mice do show lots of cell suicide in response to DNA damgage, but still get cancer (a lymphoma) 6-8 months later.

If, instead, you irradiate the mice and leave p53 OFF for 6 days following the irradiation, THEN switch it ON for 6 days, not only do you NOT get lots of cell suicide, but guess what.... you don't get any tumors either!!!

To cut to the chase, the upshot is this. p53 ON during DNA damage leads to the elimination of a bunch of damaged cells, but not necessarily the cells which will become cancerous because of mutations caused by the irradiation.

To identify those cells, you need another protein (which I happen to work on) that stimulates p53 to eliminate them. And this protein works not by sensing DNA damage, but rather by sensing an inappropriate drive to want to grow and divide (we call it hyperproliferative signals).

And to bring this back to aging and such, it is these hyperproliferative signals that causes many cells to senesce. In other words, getting old may be part of the price we pay for vigilance against cancer. How's that for a cheery thought?

[kim]

Here's a telomere/telomerase review with more links:

http://www.genesdev.org/cgi/content/full/13/18/2353

[Jodi]

I just glanced, and these seem available.

Cell-Lasker & Telomerase

Telemeres, telomerase, and the cancer cell- An Introduction

Immortalizing Human Cells withTelomerase

More on Telomerase

Telomerases. Telomeres. and.Cancer.3HAXA

Telomeres and their control

y2006_Telomeres_story

Remember though the good doctor herself indicates a better "full" life, not necessarily a longer life.

[emptypockets]

viget, provocative thoughts, but let me play devil's advocate on this one:

And then there's this funny thing called "cellular senescence", which literally means aging, but actually is a permanent withdrawl of the cell from the cell cycle... So as physical wear and tear, buildup of toxins, damage of DNA, etc., occur, the cell will eventually be eliminated ... It's essentially organismal death by a thousand cuts, a war of attrition. Of course, this is the by far the MOST important mechanism

Yet in the tiny worm C elegans (helpfully popularized by today's Nobel) EVERY cell is "senescent" from the time the worm hatches. Yet worms still go on to age -- and there are genes that control the rate of that aging, in some cases dramatically. I forget what the record is now, but a normal worm lives about 3 weeks and I think they've gotten them to live up to 6 months or so. It is the equivalent of extending human lifespan to about 500 years old. And through it all, not a single cell divides. So perhaps there's more to aging than keeping cell division running. :)

[Chris]

Great points about the value of serendipity and intuition and the challenge of independent thinking. I really enjoy the molecular biology-themed posts.

[kim]

"why great intellects SHOULD have some rules they're forced to push against, to keep them from flying into outer space"

That's a very interesting idea that I'll have to think more about (reflecting on scientists that I have known). I'll also have to get that new Dylan album, hard not to love him, amazing that there's a track about research.

[4jbk4ia]

Very cool post! This explains why there is so much junk before the start codon and after the stop codon. Reminded me of the deep satisfaction of knowing something fundamental.

[emptypockets]

kim, fyi the track is "Nettie Moore" and at least I *think* that is what he's saying. But the rest of the song is not about research unless you want it to be. Like so much of Dylan's repertoire, and perhaps the source of its timelessness, you can hear in it whatever you are looking to hear.

4jbk4ia, thanks -- and just to be clear, there IS a lot of junk before the start codon and after the stop codon and also a lot junk in between that isn't coding sequence, but that junk is not directly related to telomeres. Telomeres are at just the two ends of the chromosome, and each chromosome is some 100 billion A/T/G/Cs long, with in the neighborhood of a thousand genes scattered along it. Much of the DNA sequence of a chromosome, as you point out, is junk (not genes) and a lot of that is repetitive sequence (like the telomeres' TTAGGGTTAGGG...) but the telomeres are special junk, and that particular repeated sequence has special functions (binds to specific proteins) and is found only at the two tips of a chromosome,

[viget]

EP-

Heh, that was just some science snark there. Just like my med school professors all said 2nd year, "Now I know you've heard this before, but this time it's true. The x is the most important thing you're going to learn about this year." (where x= organ system, specific disease process, signaling pathway, diagnostic approach, etc.)

Good point about C. elegans though. And according to a lab at my institution (I actually know the student who did the work, and it was published in Science) giving anticonvulsant drugs can also increase lifespan in c elegans. While the data is certainly convincing in c elegans though, given that we KNOW c elegans is essentially a "senescent" organism, will the same hold true in mammals? I guess time will tell.

The larger takeaway from my post, I guess is that ageing is a complex phenomenon. And we really don't have a clue as to what's causing it yet, especially in complex multicellular organisms like mammals. Most likely it's multifactorial. And as such, I'd be skeptical of any claims that there's a fountain of youth out there. I think the best advice is still the simplest: eat well, get a variety of foods, exercise and avoid bad habits.

Oh, and I was also sort of railing against imporantance of telomeres.... since mice have long telomeres and yet still age normally. I think more important than the LENGTH of telomeres is their end structure, and how well that's kept intact. That could also tie back in to oxidative damage of proteins, depeletion of physiological reserve in the cell, etc. I could go on and on, but this isn't really a science blog, and I've said enough already. :)