Telomerase can reverse the aging process... sort of

Biologists are, at long last, beginning to understand the molecular processes responsible for aging in complex (multicellular) organisms – and to investigate ways to counteract these processes. We discussed one line of research in this recent article about a particular sirtuin (SIRT3) that helps relieve oxidative stress that can lead to DNA damage, which generally leads, in turn, to cell senescence or death.

While oxidative stress is certainly a significant factor in aging, possibly the most significant, there are others. One of these is the limitation on a cell's ability to undergo cell division in order to produce new cells of the same type. This is especially important in tissues that regularly need to regenerate, such as skin and intestinal tissue. Everyone now knows about telomeres, whose main function is to constitute protective end caps on chromosomes. The limitation on number of cell divisions happens since about 100 base pairs are lost from telomeres during each cell division. When telomeres eventually become too short signals that are similar to those associated with other kinds of DNA damage shut down a cell's ability to divide further. This mechanism indirectly helps mitigate the risks of DNA damage that are present every time a cell divides – an inherently tricky process.

However, this limitation on cell division isn't acceptable during embryonic development, when an organism's cell count is doubling most rapidly. So evolution has provided an enzyme – telomerase – that can rebuild telomeres, but is most active only during embryonic development. Except, of course, in cells that have become cancerous, where the ability to divide without limit is the name of the game. We discussed telomeres and telomerase in some detail a little over a year ago in this article, so you can go there for more.

Because of the risk of cancer, it seems imprudent to reactivate telomerase for the long term within an organism, especially in long-lived animals such as humans. (In animals like mice, which live fast and die young, it's a different matter. Telomerase may remain somewhat active in mice during adulthood. (Mentioned here.)) But what if it were possible to reactivate telomerase for a relatively short period of time (compared to the whole lifespan)... might that provide an opportunity to rebuild telomeres to some extent? Even better, might that reverse, at least to some extent, the ravages of aging?

We now have some research that seems to provide a fairly unambiguous affirmative answer... in a rather special case: Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice.

But didn't we just say that mice may retain telomerase activity throughout their lives? Yes, however it's a relatively simple matter to "knock out" the main telomerase gene in mice (Tert). When that's done the resulting strain of knock-out mice – after several generations – have shortened lifespans and a general phenotype of age-related debilities, as one would expect. (The first few generations apparently still have sufficiently long teleomeres.)

Unfortunately, that's not a good enough model, since without a Tert gene, the organism has no way to manufacture telomerase. Simply giving the knock-out mice repeated infusions of telomerase is not a good way to ensure uniform distribution of the enzyme to all of the organism's cells. What to do? The experimenters came up with a rather clever solution. Normally the way that telomerase is activated in cells is by means of an "estrogen receptor" (ER), to which a form of the hormone estrogen (17β-estradiol to be precise) can bind and enable transcription of Tert. This ER can be tweaked so that estrogen binds to it only in the presence of another chemical, 4-hydroxytamoxifen (4-OHT).

A special form of the Tert gene that includes this special ER can be "knocked-in" to the mouse germline. It then turns out that 4-OHT can be efficaciously supplied to a TERT-ER mouse (in the form of a time-release subcutaneous pellet) to turn telomerase expression on and off at the experimenter's will. With that technology in place, the researchers were then able to perform a series of experiments demonstrating, in these special mice, that a month-long burst of telomerase could actually reverse a number of the ill effects of telomerase deprivation.

The first step was to show that without 4-OHT the TERT-ER mice (after a few generations) had many of the same problems, in the same degree, as later generations of knock-out mice that lacked Tert entirely. The TERT-ER mice (all of which were male) showed no signs of telomerase activity. Tissues in highly proliferative organs such as testes, spleen, and intestines showed notable atrophy. Lifespan of TERT-ER mice was about half that of normal ("wild type") mice.

The first test to investigate the effects of telomerase reactivation by means of 4-OHT was done in vitro. Fibroblast cells from TERT-ER mice were cultured and found to be essentially senescent and not undergoing cell cycles. But when the cells were placed in media containing 4-OHT, teleomerase was reactivated, telomeres lengthened, and cell proliferation resumed.

Some TERT-ER mice were then given a 4-week treatment of 4-OHT (subcutaneous pellets). At the end of that treatment there was a marked reversal of the degeneration that has occurred in testes, spleen, liver, and intestinal tissues, as well as resumption of sperm production. Survival time of these treated mice also increased. At the same time, 4-OHT had no effects on control mice that weren't lacking in telomerase and didn't have tissue degeneration.

Noteworthy results were obtained from tests to assess nervous system condition. Proliferation of neural progenitor cells was found to resume in TERT-ER mice treated with 4-OHT. Normal numbers of mature oligodendrocytes reappeared. Lastly, high-level neurological functions were restored, as indicated by resumption of nearly normal olfactory sensitivity.

An interesting conclusion that can be drawn from the neurological results is that neural progenitor cells probably survive loss of telomeres, so that they can rebuild neural cell populations if telomeres are repaired.

The really interesting question, of course, is the extent to which these results may apply, in some form, to humans. Unfortunately, there are a number of reasons to be skeptical. For one thing, telomere shortening is only one factor, and quite possibly not the main one, in human aging. Aging can be thought of as a complex disease, like cancer, with many contributing factors. The consequences of telomere truncation are only one factor.

Further, murine biology has signficant differences from human biology. Mice are less complex organisms, with rather short lifespans. Mice seem to retain some degree of telomerase activity throughout their lives, so they are not as well adapted to going for long periods without it.

It is noteworthy that evidence was not found that TERT-ER mice treated with 4-OHT became more susceptible to cancer. Still, mice don't live very long, and they are adapted to maintain active telomerase. Humans are different. If telomerase is artificially kept active for years in humans, incipient tumorigenicity could be accelerated.

Lastly, it's not necessarily easy to raise human telomerase activity levels in the first place. Although some telomerase-activating factors are known, they have not been tested extensively in humans for long periods of time, so their safety and efficacy profile is not known.

These research results are quite interesting – but they only indicate the need for much more investigation.

Jaskelioff, M., Muller, F., Paik, J., Thomas, E., Jiang, S., Adams, A., Sahin, E., Kost-Alimova, M., Protopopov, A., Cadiñanos, J., Horner, J., Maratos-Flier, E., & DePinho, R. (2010). Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice Nature, 469 (7328), 102-106 DOI: 10.1038/nature09603

Further reading: (* = especially recommended)

* Telomerase reverses ageing process (11/28/10)

* The Curious Case of the Backwardly Aging Mouse (11/29/10)

* Partial reversal of aging achieved in mice (11/29/10)

Harvard scientists reverse the ageing process in mice – now for humans (11/28/10)

Gene reactivation reverses aging-related brain deficits in mice (11/30/10)

Age-Reversing Drugs on the Horizon? Not So Fast (11/29/10)

Telomere Tweaks Reverse Aging in Mice (11/29/10)

Alzheimers and aging advances uncovered (11/29/10)

An enzyme leads the dance of immortality and death (11/29/10)

Scientists Find Way to Partially Reverse Aging in Mice (11/29/10)

Telomerase and Wnt signaling

Now that research into telomeres and telomerase has (finally) garnered a Nobel Prize, it's a good time to write about recent research on the subject.

Seminal work on telomeres by Elizabeth Blackburn, one of the Nobel winners, was published way back in 1978, and active studies have been going on ever since. So perhaps it's not surprising that the rate of new findings is not so rapid as occurs in newer areas – such as stem cells.

But fascinating new results on telomeres and telomerase do still appear, and one of them connects with more recent research areas – such as Wnt signaling and... stem cells.

Here's the press release:

Discovery pinpoints new connection between cancer cells, stem cells (7/1/09)

A molecule called telomerase, best known for enabling unlimited cell division of stem cells and cancer cells, has a surprising additional role in the expression of genes in an important stem cell regulatory pathway, say researchers at the Stanford University School of Medicine. The unexpected finding may lead to new anticancer therapies and a greater understanding of how adult and embryonic stem cells divide and specialize.

Don't bother getting excited about the "new anticancer therapies" bit. That's just boilerplate that about 77.3% of all press releases dealing with cell biology contain, presumably to impress the rubes. If you need something to get excited about, you might recall that telomerase is also being investigated intensively in connection with issues of aging and longevity, independently from cancer. However, while it's possible that something of medical significance may come from this research, that's probably way down the road.

Before discussing the new research, let's review some of the background on telomeres, telomerase, and Wnt signaling.

To begin with, a telomere is a series of short repeated segments of DNA found at the ends of chromosomes in all eukaryotic cells. In cells of vertebrate animals the repeated segment is TTAGGG (where the letters represent nucleobases: T=thymine, A=adenine, G=guanine).

The total number of nucleotides in these repeated segments varies a great deal from species to species, but in humans it is (initially) about 10,000 nucleotides (or ~1700 complete segments). I say "initially", because part of the telomere is lost every time a cell divides – perhaps 50 to 200 nucleotides per division. Obviously, this means that an adult cell newly derived from a stem cell can divide at most 50-200 times before the telomere is all gone. In practice, the number is a lot less than the maximum, perhaps 40 to 60 times, which is called the Hayflick limit. Cells are programmed to stop dividing on reaching this limit, since otherwise useful DNA would be lost or damaged upon further division.

Why does this loss occur? It seems to be somewhat of an accident of the nitty-gritty details of how DNA replication occurs during cell division. I won't go into that, since it's best explained with some diagrams; you can read about it at Wikipedia. In fact, in the early days of molecular biology (around 1972), what happens at the end of chromosomes during DNA replication was rather puzzling, and the puzzle was called the "end replication problem". Now it's pretty well understood, though somewhat messy.

In any case, the loss of DNA from the telomeres during cell division is a fact, and it conveniently explains the existence of the Hayflick limit, which had been recognized since 1965. What happens when the teleomere is all used up and the limit is reached? Cells that have reached the limit don't necessarily die (though they might), but they do stop dividing, and they enter a static phase of cell life known as senescence.

If you think about it, senescence can be a problem, especially in certain tissues that need to continually replenish their cells, such as skin and the lining of the intestines, as well as hair, fingernails, etc. How is senescence circumvented in such tissues? The answer is (adult) stem cells. It turns out that stem cells are not subject to the Hayflick limit. It's not clear whether they are subject to limits at all.

Like any other cell type, stem cells also divide (by the process technically known as mitosis). But there is one difference from the way "ordinary" cells divide. Stem cells can divide asymmetrically, where one daughter cell is another stem cell, but the other daughter is a "progenitor cell", which is close to a normal, fully-differentiated adult cell of a fixed tissue type. Progenitor cells differentiate further into the final form when they divide, and they are able to divide only a limited number of times.

So how is it that stem cells are able to escape the Hayflick limit, dividing an indefinite number of times, even though they are also subject to the same loss of telomere nucleotides with each division? The answer is the enzyme telomerase, which is able to rebuild shortened teleomeres. It's fortunate for the longevity of complex organisms that telomerase exists, otherwise stem cells would not be able to divide often enough to allow tissues exposed to harsh conditions (such as skin and intestinal lining) to be replenished.

In order to explain the results of the research to be described here we need to say more about telomerase, but first let's summarize the function of telomeres. At first it may seem that all they do is compensate for the sloppy way that DNA replication works, by providing long stretches of expendable DNA at the ends of chromosomes. But there is one other notable function: teleomeres are a useful "cap" at the end of a chromosome that is recognizable to cellular mechanisms responsible for detecting DNA damage. If it weren't for the telomeres, the ends of chromosomes would be indistinguishable from DNA damage, which can result from errors in the replication process, as well as damage due to external agents such as ionizing radiation or harmful chemicals. Cells have various mechanisms for repairing many kinds of damage, but even if repair isn't possible, other mechanisms exist that recognize the damage and prevent further cell division or cause programmed cell death (apoptosis).

Not all DNA damage can be repaired or compensated for by apoptosis or cessation of cell division. Unrepaired DNA damage (however it occurs) is the main cause of cancer (though not the only one). So the existence of the Hayflick limit as a result of teleomere shortening acts as one defense against cancer. Cancer can be defined as the uncontrolled proliferation of cells as a result of DNA damage (affecting existing mechanisms that normally control proliferation) or other causes. So fixed limits on the number of times a cell can divide is one of a number of mechanisms organisms have to guard against cancer.

Before moving on, here's a quick summary of the functions served by telomeres: (1) compensate for the chromosome "end replication problem"; (2) make it possible for cells to distinguish chromosome ends from damaged chromosomes; (3) provide natural limits to the number of times ordinary cells can divide, as protection against cancer.

As noted above, the third of these functions is a problem for stem cells that do need the ability to divide an indefinite number of times. Repair of tissues exposed to harsh conditions is not the only circumstance this ability is needed. Another very important case is that of embryonic development. Multicellular, sexually-reproducing organisms start from a single cell (zygote). Yet there are close to 10¹⁴ cells in an adult human.

It is true that a single cell that underwent 47 cycles of cell division could theoretically produce that many cells. But that's really pushing the limits, since some cell types are needed in much larger numbers than others. The bottom line is that embryonic development is the other main circumstance when limits on cell division need to be overcome.

Telomerase is what makes this overcoming of telomere limits possible. And it does it in a pretty straightforward way. Telomerase is a complex molecule with three distinct parts. Two of these are proteins: Telomerase Reverse Transcriptase (TERT) and dyskernin, which are coded for by distinct genes. TERT does most of the work. The other part is a short piece of RNA, called the telomerase RNA component (TERC), which contains and is somewhat longer than the repeat unit (TTAGGG in vertebrates). Like any other reverse transcriptase enzyme (other examples of which occur in RNA viruses such as HIV), TERT simply translates a piece of RNA into DNA and inserts it into a chromosome. In the case of telomerase, the RNA is carried inside the enzyme complex itself. Telomerase does its job simply by replacing the telomere DNA that is lost from chromosomes during mitosis.

So telomerase performs the function of rebuilding telomeres, and this is essential in tissues where cells must proliferate rapidly, such as in embryonic development and tissue regeneration. But as we noted above, if the restriction on cell division is circumvented, the risk of cancer goes up. Although telomerase serves an essential purpose in specialized contexts, it also makes it possible for cells to become cancerous. Consequently, telomerase is not expressed in most adult body cells. However, telomerase is expressed in about 90% of tumor cells.

It might seem as though one approach to controlling or even destroying cancer could involve either inhibiting telomerase or developing a vaccine using telomerase to induce an immune response against telomerase-rich cancer cells. There are in fact various clinical trials exploring both techniques. But this is tricky and rather risky, because as we've observed, telomerase is needed in stem cells required for tissue regneration, at least once the cells have begun proliferating. Those cells need to be protected while they are simply doing their job – replenishing skin and intestinal linings, for example. We need to understand how such cells are controlled so that they work without leading to cancer.

Anyhow, TERT is a protein that is an essential component of telomerase, which plays an important role in cell proliferation. The new research we're finally almost ready to discuss shows that, surprisingly, TERT also plays a role in a completely different aspect of cell proliferation having nothing to do with telomeres. That's where Wnt signaling comes in.

Wnt signaling is a subject we've looked at several times before. Some of the relevant articles are here, here, here, and here. Wnt was first noticed in connection with embryonic development and tissue regeneration. This article has many examples. The name Wnt alludes to a gene called "wingless", because the gene causes fruit flies to lack wings when the gene is mutated.

Recently Wnt's importance in stem cells has also received a lot of attention. Some of our discussion of that may be found here, here, here, and here. Wnt's relevance to cancer and cancer stem cells is often touched on in most of all the articles listed.

Basically, Wnt is the name of a family of proteins that play an important role in signals promoting cell proliferation, especially in the context of embryonic development and tissue renewal (skin, intestines, hair, and immune system cells). Since Wnt proteins promote proliferation, they also play a role in cancer.

The fact, then, that new research shows teleomerase can enhance Wnt signaling is signficant as a second, entirely separate route through which it plays a role in both normal stem cell function and cancer.

Here's the research abstract:

Telomerase modulates Wnt signalling by association with target gene chromatin (7/2/09)

Stem cells are controlled, in part, by genetic pathways frequently dysregulated during human tumorigenesis. Either stimulation of Wnt/β-catenin signalling or overexpression of telomerase is sufficient to activate quiescent epidermal stem cells in vivo, although the mechanisms by which telomerase exerts these effects are not understood. Here we show that telomerase directly modulates Wnt/β-catenin signalling by serving as a cofactor in a β-catenin transcriptional complex. The telomerase protein component TERT (telomerase reverse transcriptase) interacts with BRG1 (also called SMARCA4), a SWI/SNF-related chromatin remodelling protein, and activates Wnt-dependent reporters in cultured cells and in vivo. TERT serves an essential role in formation of the anterior–posterior axis in Xenopus laevis embryos, and this defect in Wnt signalling manifests as homeotic transformations in the vertebrae of Tert^-/- mice. Chromatin immunoprecipitation of the endogenous TERT protein from mouse gastrointestinal tract shows that TERT physically occupies gene promoters of Wnt-dependent genes. These data reveal an unanticipated role for telomerase as a transcriptional modulator of the Wnt/β-catenin signalling pathway.

That's a pretty good summary of the paper, but I imagine most people would like a bit more explanation of what's going on.

Previous research had disclosed some interesting "coincidences" involving stems cells and embryonic development, in which both telomerase and Wnt signaling seemed to have similar effects, even though no obvious connection was known. For example, epidermal (skin) stem cells spend most of their time in a quiescent (non-dividing) state. The main function of Wnt proteins is to carry signals between cells that inform target cells of a need to start dividing, for example during various stages of embryonic development or to heal wounds. The curious thing is that telomerase was known to have a similar effect as Wnt signaling on some stem cells. This coincidence is enough to motivate looking for a connection.

If you are really into this sort of thing, you might want to refer to this diagram of various cell signaling pathways, including that of Wnt. One of the things it illustrates is the position of β-catenin in the Wnt pathway. β-catenin operates at the end of the pathway, where it becomes a part of a protein complex that includes transcription factors (known as TCF/LEF), and the complex causes expression of a variety of Wnt-regulated genes, which go on to enable cell proliferation.

One of the main findings of the research is that TERT interacts with another protein called BRG1 (or SMARCA4), and together these become important parts ("cofactors") of the gene-regulating protein complex. It was also determined that TERT is the only component of telomerase that is involved with Wnt signaling.

Apparently TERT is more important for some instances of Wnt signaling than for others. For example, low levels of TERT in embryos of the frog Xenopus laevis resulted in very abnormal development of the frog embryos (in terms for the anterior-posterior axis of the body). But low levels of TERT at a later stage of development caused only somewhat more subtle defects in formation of ribs in the embryo. Similar somewhat minor effects also occured with low levels of TERT in mouse embryos, and these defects were much like the effects of low levels of β-catenin.

So what, then, is so interesting about this research? It's satisfying to know the reasons for what were previously just observed coincidences, such as the fact that telomerase is not only very important for the ability of stem cells to divide freely (during embryonic development and tissue regeneration) but that it also can help stimulate stem cell division.

But what makes this research especially significant is the importance of the biological processes in which both telomerase and Wnt signaling play major roles – namely embryonic development, tissue regeneration and repair, and cancer. The latter two processes are especially important for medical reasons, although we're still a long way from being able to use this knowledge about telomerase and Wnt signaling for therapeutic purposes.

As far as cancer is concerned, we need to understand much more about how telomerase and Wnt signaling work in various types of stem cells, given that stem cells may play a big role in some types of cancer (though not in others).

But tissue regeneration and repair are also of significant medical interest, since it is the eventual inability of various types of tissues to replenish themselves in old age that is responsible for the many debilities that appear in old age. Many people have speculated that telomerase could help alleviate this problem – provided it does not also lead to facilitating the development of cancer.

Finally, we are left with the puzzle of how it is that TERT happens to play important – yet quite distinct – roles in two very separate processes that are, neverthelesss, both important for cell proliferation. We don't know the answer to this, but we can speculate. Perhaps it's because TERT has to be around anyway for stem cells during embryogenesis and tissue regeneration. That being the case, perhaps at some point in evolution, TERT also happened to help boost Wnt signaling a little. The effect of amplifying Wnt signaling in the same contexts that telomerase was needed would be advantageous and worth conserving. This kind of double duty should lead to more efficient use of cell resources.

Park, J., Venteicher, A., Hong, J., Choi, J., Jun, S., Shkreli, M., Chang, W., Meng, Z., Cheung, P., Ji, H., McLaughlin, M., Veenstra, T., Nusse, R., McCrea, P., & Artandi, S. (2009). Telomerase modulates Wnt signalling by association with target gene chromatin Nature, 460 (7251), 66-72 DOI: 10.1038/nature08137

Further reading:

Cell biology: The not-so-odd couple (7/2/09) – expository article in Nature about the telomerase-Wnt research

Nobel in medicine honors discoveries of telomeres and telomerase (10/5/09) – news article in Science News

Nobel for insights into ageing and cancer (10/5/09) – news article in New Scientist

Chromosome protection scoops Nobel (10/5/09) – news article in Nature

Three Americans Win Physiology or Medicine Nobel (10/5/09) – news article at ScienceNOW.com

Work on Telomeres Wins Nobel Prize in Physiology or Medicine for 3 U.S. Genetic Researchers (10/5/09) – news article in Scientific American

Nobel Winners Isolate Protein Behind Immortality, Cancer (10/5/09) – news article at Wired.com

Tags:

telomeres, telomerase, Wnt signaling

Readings, 5 August 2007

I'm trying a new approach to this, so we have a bumper crop of readings this week. Don't count on as much every time, but have fun with the current list.

The text following each item is quoted material, except for editorial comments, which are in color.

General and physical science

Open Access and the Progress of Science

The power to transform research communication may be at each scientist's fingertips.

Open access publishing seems very important to me. It's quite frustrating – for both the writer and the reader – to present an overview of some important scientific research, yet have the actual research publication be inaccessible to most readers, and at best accessible to a few only by jumping through hoops. This is especially frustrating in the case of research that may have personal importance to certain readers, as with health and medical issues. It's also a major barrier to raising the scientific literacy of the public when there is no practical way for the public to gain a better understanding of a subject – by going to the original research papers – than provided by the mass media.

The chemistry of space grows more complex

The chemistry of outer space continues to amaze astronomers. After several decades of doubt, they know that chemical processes around and between stars produce complex molecules including precursors of organic life. But recent discoveries with a new observing technique show they have barely glimpsed what's really going on.

Space station's future in doubt

NASA has only a slim margin of error for completing construction of the international space station before the space shuttle is retired -- and more concerns about supplying it after that date....

And even if no unforeseen scheduling issues arise, experts said NASA faces problems dealing with changes to its work force as the agency moves to a future moon-Mars exploration program. And there is a shortage of science being done on the space station, conceived as a 200-mile-high floating laboratory.

In order to support real scientific research, NASA should be provided with a little of the hundreds of billions of $$ now being squandered on military boondoggles. Failing that, it would be a blessing if funding for real science came from savings that would result if the space station were simply abandoned, or at least mothballed for a few years. For comments regarding better use by NASA of its budget, see this and this.

The Great Global Warming Swindle Swindle

With all those other endangered species going extinct it's nice to know there's still a handful of global warming skeptics kicking around. ABC Science Online's Bernie Hobbs looks at the facts behind the vitriol in the film that's got everyone looking up the word 'polemic'.

Nice exposé of a propaganda film put out by global warming skeptics.

Self Assembly

Hofstadter's new book, deeply thought-provoking though it is, is less engaging than either Gödel, Escher, Bach or Le Ton Beau de Marot. Yet I Am a Strange Loop carries the high hopes of its author, not just those of its readers. Hofstadter feels that his first book, despite its massive popularity, has been widely misunderstood. Its fundamental message seems not to have been noticed: "It sometimes feels as if I had shouted a deeply cherished message out into an empty chasm and nobody heard me." This new volume is his attempt to set the record straight.

The core intellectual claim, then, is much the same as that of Gödel, Escher, Bach: namely, that a proper understanding of Gödel's proof helps us to see that life, mind and self are all constituted not by biochemistry but by the higher-level patterns that biochemistry makes possible. In particular, human selves are abstract self-referential (reflexively looping) patterns that arise spontaneously out of the meaningless base of neural activity.

Margaret Boden's review of Douglas Hofstadter's new book is brief, but should not be missed.

Do Loops Explain Consciousness? Review of I Am a Strange Loop

Another review of Hofstadter's book, by no less than Martin Gardner, who opines on its place in the philosophy of consciousness.

Mathematics

Poincaré, Perelman and proof

This is a review of Donal O'Shea's The Poincaré Conjecture: In Search of the Shape of the Universe. Both author and reviewer (Nigel Hitchin) are professional mathematicians, so the indications are this book is a must-have if you're even vaguely interested in the subject. The review itself nicely summarizes both the technical issues and the personal story of Grigori Perelman, who proved the Poincaré conjecture.

GEOMETRY AND THE IMAGINATION: Pricey Proof Keeps Gaining Support

No report on advances in topology is complete these days without an update on Russian mathematician Grigory Perelman's proof of Thurston's Geometrization Conjecture and its million-dollar corollary, the Poincaré conjecture (Science, 22 December 2006, p. 1848). After poring over Perelman's papers for 4 years, topologists are confident of the result, says John Morgan of Columbia University, who gave an overview of the proof at the Thurston conference.

There were other interesting results presented at the conference in honor of William Thurston. You can access accounts of these results here (subscription required for full access).

Tom Lehrer's Derivative Ditties

Should you be not old enough for the name Tom Lehrer even to ring a bell for you, Ivars Peterson offers a summary of the mathematician-songwriter's work having special appeal to the mathematically inclined. Such as "New Math". Somehow, he neglects to mention "Lobachevsky". Or perhaps you'd just like to know of a catchy little tune that's a hilarious send-up of Catholicism: "The Vatican Rag". (Needs to be heard sung to be really appreciated.) And for chemistry devotees there's "The Elements".

Technology

Building an Immersive Web

Early virtual worlds such as ­Second Life demonstrate that highly visual, 3-D online environments hold the potential to transform the way humans interact not only with computers but with each other .... Hyped as they are, these immersive environments address two fundamental aspects of being human: our visual and social natures.

A Smarter Web

New technologies will make online search more intelligent--and may even lead to a "Web 3.0."

This longish article may be for you if you have ever puzzled over questions like "What comes after Web 2.0?" or "What the heck is this 'Semantic Web' thing?"

At last, semiconductor industry begins embracing nano

Even though the conservative semiconductor industry, with its extreme performance and manufacturing demands, has done much of its manufacturing in nanoscale dimensions for years, it hasn’t yet had much use for the unique properties of nanoparticles, fullerenes, nanowires, quantum dots, etc.-the technologies usually considered “true” nanotech. Nor have the nanoscale patterning processes developed by the chip makers been of much use to the rest of the nanotechnology world.

But the old ways are starting to change.

A bot's life

Robotic designs based upon natural organisms are as diverse as the animal world itself. There are devices in the works that mimic caterpillars, spiders, dogs and octopuses. Their goals and purposes are equally varied, from new medical treatments to space labor to being a soldier's best friend.

Life sciences

What Do Mirror Neurons Mean?

The discovery of mirror neurons in the frontal lobes of macaques and their implications for human brain evolution is one of the most important findings of neuroscience in the last decade. Mirror neurons are active when the monkeys perform certain tasks, but they also fire when the monkeys watch someone else perform the same specific task. There is evidence that a similar observation/action matching system exists in humans.

This is a symposium comprising several papers on mirror neurons published in the last three years. I wrote about the subject here and here. These papers are technical but worth a look.

Genetic Engineers Who Don’t Just Tinker

FORGET genetic engineering. The new idea is synthetic biology, an effort by engineers to rewire the genetic circuitry of living organisms.

The ambitious undertaking includes genetic engineering, the now routine insertion of one or two genes into a bacterium or crop plant. But synthetic biologists aim to rearrange genes on a much wider scale, that of a genome, or an organism’s entire genetic code. Their plans include microbes modified to generate cheap petroleum out of plant waste, and, further down the line, designing whole organisms from scratch.

Can Adult Stem Cells Do It All?

Scientists may have turned mouse skin cells into embryolike stem cells, but prior claims for the power of adult cells have yet to stand the test of time.

Don't believe everything you read by opponents of embryonic stem cell research, such as the supposed power of adult stem cells to do whatever ESCs can.

An Elegant Molecular Dance

Her team's strategy is to spy on biological machines in action, watching as individual molecules fold, interact with one another, and do their work. They use sensitive optical imaging techniques to collect extraordinarily detailed pictures of this activity—watching, for example, as a single molecule of RNA folds into its functional shape or a tiny polio virus invades a mammalian cell. Combining those images with findings from their experiments in molecular biology and biochemistry, the scientists are revealing how the structural dynamics and movements of molecules drive biological processes. ...

One of the lab's most recent successes, however, is developing a precise portrait of the molecular dance that creates telomerase, a complex of molecules that protects the ends of chromosomes during DNA replication. Michael Stone, a postdoctoral fellow in Zhuang's lab, led the study published in the March 22 issue of Nature. The enzyme is essential for rapidly dividing cells, such as those in a developing embryo, but is usually shut off in healthy adult human cells. Upregulating the enzyme's activity allows adult cells to achieve a dangerous immortality. The enzyme is inappropriately active in the vast majority of human cancers, making it a potential target for new cancer therapies. ...

With experiments like these, Zhuang says biophysicists and biologists are steadily moving their field toward the kind of fundamental and quantitative ways of explaining the world that first attracted her to science.

Arresting developments

Dr Harel has been working on a computer model of C. elegans. He hopes this will reveal exactly how pluripotent stem cells—those capable of becoming any sort of mature cell—decide which speciality they will take on. He thinks that a true understanding of the processes involved will be demonstrated only when it is possible to build a simulation that does exactly—but artificially—what happens in nature.

There are interesting ideas in this short piece, the nature of which you would never guess from the dreadfully useless title. For example, the idea of computer modeling of entire, albeit simple, organisms. Inevitably, with the ever-increasing power of supercomputers, it will be possible before long to model more complex animals, like, say, jellyfish. This will enable zoologists who study such critters to gauge the quality of their understanding by observing how lifelike their computer models are.

Brain Boosters

Two days from now I'm planning to further tweak my mind by taking a brain-boost pill. Called Provigil, it differs from its predecessors in that it is believed to home in on a section of the brain that helps govern alertness and memory. The pill is manufactured by ­Cephalon of Frazer, PA, and its active ingredient is called modafinil. The drug's targeted delivery is supposed to prevent the side effects of stimulants that diffuse throughout the brain and rev up everything.

In addition to the Provigil the writer discusses electrical stimulation devices for the brain, which supposedly enhance performance, however slightly. Personally, I find caffeine works pretty well, and abundant evidence that's pretty well-known to all suggests I'm hardly alone. But did you know that the caffeine, plus exercise, may lower risk of skin cancer too?

Health and medicine

Gene therapy trial on hold

As the US Food and Drug Administration prepares to investigate the death of a patient in a phase I/II gene therapy trial for inflammatory arthritis, researchers in the field say the treatment's delivery vector, an adeno-associated virus (AAV), was unlikely to be the culprit.

It will be very good news if these researchers are correct, as a number of mainstream media accounts are portraying this gene therapy trial problem as yet another black eye for the whole concept of gene therapy.

Obesity: A Link to Rare Gene Variations

Sometimes, the rarest of the rare can still have an impact. A multi-institutional team of scientists led by Berkeley Lab geneticist Len Pennacchio has found that extremely uncommon gene variations likely contribute to obesity.

How and why — and to what extent — remain a mystery, but the research adds another clue to the problem of obesity, which is reaching epidemic proportions in developed nations. Overeating and lack of exercise loom as the chief culprits. But heredity and gene defects are implicated too, and now scientists have a better understanding of their role.

AIDS Abated: Genome scans illuminate immune control of HIV

Some people who contract HIV, the virus that causes AIDS, maintain low amounts of the virus in their bodies for years. These long-term nonprogressors—so called because a decade or more can pass before they develop full-blown AIDS—have attracted great attention from researchers.

Now, using powerful, whole-genome scans, researchers have identified three genetic variations that partially explain why some HIV-infected people develop AIDS quickly while others keep it at bay.

Readings, 29 July 2007

Comments, if any, apply to the article that precedes them.

Sea Anemone Genome Provides New View Of Our Multi-celled Ancestors

The first analysis of the genome of the sea anemone shows it to be nearly as complex as the human genome, providing major insights into the common ancestor of not only humans and sea anemones, but of nearly all multi-celled animals.

A new type of spin valve that uses graphene

“Some people think that graphene, a form of carbon, is the material of the future,” Allen Goldman tells PhysOrg.com. “It’s of high scientific interest because of its unusual electronic properties.”

Secrets of a Heavyweight

A dozen years after it first appeared on the world stage, the top quark is still one of the hottest topics in particle physics. Why is it so much heavier than any other particle? And what can it tell us about the origin of mass and other quantum mysteries? Here’s a look at the top’s quirky nature, its fevered past and its promising future.

[Comment: This is not a bad overview of top quarks – if you can stand the odd formatting and silly cartoons in here. -ed.]

Finding Clues to Aging in the Fraying Tips of Chromosomes

When Time magazine named Elizabeth H. Blackburn, a cell biologist, one of this year’s “100 Most Influential People in the World,” it listed her age as 44.

“Don’t think I’m going to ask for a correction on that one,” Dr. Blackburn, 58, a biochemistry professor at the University of California, San Francisco, said in a recent visit to New York City. “If they want to turn back the clock, that’s lovely.”

Dr. Blackburn, a winner of the 2006 Albert Lasker Award for Basic Medical Research, studies aging and biochemical changes in cells that are related to the diseases of old age.

Whatever Dr. Blackburn’s own chronologic age, the buzz in scientific circles is that she is likely to be the next woman awarded the Nobel Prize in Medicine.

[Comment: Here's an example of much better than average New York Times science writing. It's structured as an interview, so the expert's insights don't get obscured by the reporter's paraphrasing. The interviewee has eye-opening things to say about telomeres, telomerase, and the significant harmful effects of psychological stress. As well as the inner workings and unethical practices of the government's phony "Council on Bioethics" with regard to embryonic stem cells. -ed.]

Vitamin C Is Not Much Help Fighting Colds, Study Shows

A large review of placebo-controlled trials of vitamin C for cold prevention and treatment has concluded that it is largely ineffective.

In 30 trials involving 11,350 participants who took at least 200 milligrams of vitamin C a day, researchers found no reduction in the incidence of common colds. Vitamin C did reduce the duration and severity of cold symptoms slightly, but the effect was so small as to be clinically insignificant.

[Comment: True believers in the value of vitamin C advocate daily doses of a few grams, not fractions of a gram. It's hard to tell from this article whether the review in question focused at all on the possible efficacy of large doses. And the reporter fails to raise that important issue. The ambiguity regarding dose size and lack of objectivity that can be seen in the press release leaves one still wondering about the real truth of the matter. -ed.]

At Fermilab, the Race Is on for the ‘God Particle’

For physicists, this is a summer of rumors, hope and hype as rival collaborations race to capture the legendary particle known as the Higgs boson.

[Comment: Here's another specimen of overwritten New York Times science journalism, heavily laden with gooey, sticky "human interest" and pop sociology of science – on top of that fatuous theistic epithet in the headline. There's interesting information on the high-energy physics culture in here, but you may need an extra shot of insulin after reading it. -ed.]

Cancer Genes Tender Their Secrets

Gina Kolata has written a fine article on progress in cancer research. It hits some of the high points through anecdotes offered by some of the leading cancer scientists.

Slowly, Cancer Genes Tender Their Secrets

Dr. Brian Druker, a Howard Hughes investigator at the university's Cancer Institute, who led the Gleevec study, sees Mr. Weinstein as a pioneer in a new frontier of science. His treatment was based not on blasting cancer cells with harsh chemotherapy or radiation but instead on using a sort of molecular razor to cut them out.

That, Dr. Druker and others say, is the first fruit of a new understanding of cancer as a genetic disease. But if cancer is a genetic disease, it is like no other in medicine.

With cancer, a person may inherit a predisposition that helps set the process off, but it can take decades - even a lifetime - to accumulate the additional mutations needed to establish a tumor. That is why, scientists say, cancer usually strikes older people and requires an element of bad luck.

"You have to get mutations in the wrong place at the wrong time," Dr. Druker says.

Other genetic diseases may involve one or two genetic changes. In cancer, scores of genes are mutated or duplicated and huge chunks of genetic material are rearranged. With cancer cells, said Dr. William Hahn, an assistant professor of medicine at Harvard Medical School, "it looks like someone has thrown a bomb in the nucleus."

Perhaps a bit more background may make it even clearer what's happening.

Most people now understand that one thing all cancers have in common is defects in the genes of the cancerous cells which allow the cells to proliferate without effective limits. Not all cancer cells have the same defects. Indeed, even in cancers of specific tissue types (breast, colon, prostate gland, lungs, etc.), the set of defective genes may vary from person to person having the "same" type of cancer.

The defects do not occur all at once. Instead, they accumulate slowly, over many years. A variety of different "causes" can produce gene defects. Some defects are inherited at birth, which is why predisposition to particular cancers run in a family. Other defects occur "naturally" due to errors in copying DNA when cells divide. Still other defects are caused by chemical agents, which may be either produced naturally in the body (e. g. "free radicals") or come from outside (e. g. combustion products from cigarette smoking). And the list of agents that can damage DNA goes on: certain viruses (like HPV which can lead to cervical cancer), ultraviolet light (skin cancer), other high-energy electromagnetic radiation (X-rays), and radioactive materials (such as radon gas).

Fortunately, almost all DNA damage does not lead to cancer. In the first place, most DNA is "noncoding DNA" that does not correspond to a gene. The purpose (if any) of most of this noncoding DNA is still a mystery. But damage in this area probably has little effect. The remainder of the DNA does code for genes, of which humans have about 25,000. And of these 25,000, probably only a few hundred, at most, can lead to cancer if damaged. (Cataloging all such genes is a high-priority research project, known as The Cancer Genome Atlas).

And even if a critical gene is damaged, the effect is usually nothing. Cells have several ways of checking, and possibly fixing, DNA that is damaged in the process of cell division (when a fresh copy of all the DNA must be created). There are additional mechanisms for detecting errors in DNA that occur for any reason, with the results that cells having damaged DNA usually self-destruct through a process called apoptosis.

Genes that are involved in producing proteins which handle either DNA testing and repair or apoptosis are key genes which can lead to cancer if they themselves are damaged. The result is that in cells where such genes don't function properly, there are many more errors in the DNA that go unrepaired. There may be hundreds of damaged genes, though most don't contribute directly to cancerous characteristics. Yet the cell itself, because it doesn't undergo apoptosis, may survive and continue to divide and proliferate. Many cells with DNA damage may eventually cease to divide, or even die, because they are so messed up. But in a process of evolution and natural selection, some cells with damaged genes for DNA upkeep or apoptosis will survive -- the ones that do not develop fatal abnormalities.

Normal cells have an upper limit on the number of times they can divide, which is enforced by the length of the telomere structures at the end of chromosomes. A little bit of each telomere is lost every time a cell divides. However, there is an enzyme called telomerase which is active mainly in embryonic cells. Its function is to rebuild the telomeres in the cells of young embryos so that the cells can continue to divide. But at some point in development the telomerase gene becomes switched off, so that the clock regulating cell division starts ticking. Once the telomeres become too short, the cell stops dividing. The cell doesn't necessarily die, but it enters a phase called senescence.

As a result of damage to other genes which keep the telomerase gene switched off, it is possible for the enzyme to start being produced again. Cells which produce enough telomerase are potentially immortal, and can divide without limit. In other words, they become cancerous. So another key step on the way to cancer is for production of telomerase to resume in a cell that also has compromised DNA checking/repair and apoptosis function.

As unlikely as it is, damage to critical genes will inevitably occur, given that there are trillions of cells in a human body. Eventually, everybody will have many cells that contain some kind or another of damage in a critical gene. But fortuntately, again, even this is not enough to produce cancer by itself. For a given cell to become cancerous, several critical genes must be damaged in the same cell -- perhaps 10 or 20 more, depending on the type of tissue involved. For example, a tumor needs to attract blood vessels (in the process called angiogenesis) in order to receive oxygen and nutrients. A potentially cancerous cell must be able to hide from the body's immune system, which could otherwise destroy it. And in order for a tumor to metastasize, its cells must acquire the ability to separate from the tumor, enter the blood stream or lymphatic system, and finally invade other organs of the body. In brief, there must be a number of genes in any given cell that must all be defective for the cell to lead to a life-threatening cancer.

So on one hand, the chance of any particular cell accumulating all the necessary damaged genes is almost vanishingly small. But on the other hand, with trillions of cells in a body, the probability that eventually one cell will have damage to enough critical genes is not insignificant. Especially since damage is cumulative: mutated genes are passed along, with their mutation, to future generations of the cell. And remember, the process is not entirely haphazard. Because of a process of natural selection of cells that have just the "right" abnormalities, cell masses that have some cancerous properties evolve towards malignancy -- even though, along the way, vast numbers of cells that don't have the "right stuff" to become dangerous fall by the wayside.

The path to effectively dealing with cancer, then, requires figuring out just what the critical defects are and then devising ways to stop or interfere with the effects of the defective genes, so that cancerous tissue cannot grow and proliferate to other locations in the body.

Kolata describes how research progressed in the case of colon cancer:

Although there were scores of mutations and widespread gene deletions and rearrangements, it turned out that the crucial changes that turned a colon cell cancerous involved just five pathways. There were dozens of ways of disabling those pathways, but they were merely multiple means to the same end.

People with inherited predispositions to colon cancer started out with a gene mutation that put their cells on one of those pathways. A few more random mutations and the cells could become cancerous.

However, this all took a great deal of time. Cancer in types of tissue other than the colon doesn't necessarily work quite the same way. Fortunately new technology has come along that makes identification of active genes easier, and also allow experimentally turning genes on and off to figure out what they do:

The turning point came only recently, with the advent of new technology. Using microarrays, or gene chips - small slivers of glass or nylon that can be coated with all known human genes - scientists can now discover every gene that is active in a cancer cell and learn what portions of the genes are amplified or deleted.

With another method, called RNA interference, investigators can turn off any gene and see what happens to a cell. And new methods of DNA sequencing make it feasible to start asking what changes have taken place in what gene.

So, suppose we can determine all of the gene abnormalities that are really necessary for a malignant cancer. What then?

In the end, all those altered genes may end up being the downfall of cancer cells, researchers say.

"Cancer cells have many Achilles' heels," Dr. Golub says. "It may take a couple of dozen mutations to cause a cancer, all of which are required for the maintenance and survival of the cancer cell."

Every normal gene produces proteins which participate in various cellular processes. Each process is sort of like a relay race. For instance, one protein (a "receptor") in the cell wall reacts in some way, as a result of something in the cell's environment. The first protein acts as a signal to another protein to do something, which in turn signals other proteins, and so on. This chain of events is called a pathway. Mutated genes produce mutated proteins, or perhaps normal proteins at a time they ought not to be around. The net result is the activation of a pathway that causes cancerous behavior in the cell.

If scientists can find chemical entities that disrupt a cancerous pathway, then the cell's abnormal behavior can be thwarted. Finding these molecules is the ultimate goal of cancer research -- if successful, these are potent anti-cancer drugs. And the beauty of this is that drugs like this (ideally) affect only the abnormal pathways in cancer cells. They should not affect normal cells, unlike chemotherapeutic drugs which poison all cells, but cancer cells more than others only because the cancer cells divide more rapidly.

The "war on cancer" may actually be finally turning a corner towards success. We are now acquiring information quite rapidly about cancer-causing gene mutations and cancer pathways, thanks to our new technologies. We can now, in principle, design drugs to deal with each pathway. It's still going to take time before we have drugs for most of the serious cancers, because every potential drug has to go through a testing process of clinical trials, which can take ten years and hundreds of millions of dollars.

Dr. Golub said he expected that new drugs would strike the Achilles' heels of particular cancers. The treatment will not depend on where the cancer started - breast, colon, lung - but rather which pathway is deranged.

"It's starting to come into focus how one might target the problem," Dr. Golub said. "Individual cancers are going to fall one by one by targeting the molecular abnormalities that underlie them."

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Tags: cancer, biology, medicine