Scientists and magicians

In the U. S. and many other places around the world, attitudes towards science are decidedly ambiguous.

This shows up in many different ways. During the last election, for example, various issues, about which science has much to say, were matters of contention. Global warming and climate change provide one example. Many issues related to sex and reproductive biology, including sex education and contraception, yield other examples. And of course, tangentially related to those issues was the embryonic stem cells issue. Then there's the matter of the need for protection of biodiversity and endangered species. Finally, opponents of evolution were afraid to make it a serious campaign issue, yet one of the presidential candidates was notably evasive on the question of how evolution should be taught in schools.

To the relief of most people who value science, the election turned out well:

Obama to restore science to its rightful place (1/20/09)

So, the 44th president of the United States has spoken. And what he said will please many supporters of science. Likewise, without explicitly mentioning the environment, president Barack Obama made it clear in his inaugural address today that the US needs to tackle global warming and switch to renewable sources of energy.

The speech will also please internationalists who feel that the US has lost touch with the rest of the world. Significantly for a US president, but less surprising given his African heritage, Obama called on Americans to reach out to and help the world's poorest citizens, clearly referring to the humanitarian and agricultural crises in parts of Africa.

But the nod to open science will be most welcome, given the political and ideological interference of his predecessor, who obstructed stem cell research and only grudgingly accepted that humans are driving climate change.

"We will restore science to its rightful place, and wield technology's wonders to raise health care's quality and lower its cost," said Obama.

(That, of course, received widespread attention. Other reactions: here, here, here, here.)

There are several factors at work under the covers that help explain the political opposition to relatively straightforward science. Religious factors, obviously, play some part. Also economic factors, especially in cases where scientific considerations (related to the economics of energy production, and various public health issues, related to tobacco usage, for example) are in conflict with powerful economic interests.

So, what do magicians have to do with any of this?

Well, I've been re-reading Shakespeare's The Tempest, because I've also been re-watching Peter Greenaway's film adaptation, Prospero's Books.

Prospero, the protagonist, is the former Duke of Milan, who has been overthrown by his treacherous brother and exiled to a remote island. He's also a powerful magician, whose enrapture with intellectual pursuits rather than statecraft led to his overthrow.

Prospero can also be seen as a scientist of his era. Greenaway's film elevates the books to a starring role, acknowledged in the title. But this follows Shakespeare, who has Prospero explain how a sympathetic man of Naples (which city was the enemy of Prospero's Milan) furnished the deposed duke upon his exile with many of life's necessities – including books:

Knowing I loved my books, he furnished me
From mine own library with volumes that
I prize above my dukedom.

Greenaway links Prospero's books and his magic with more modern science. The books deal not only with occult arts (as was frequently the association in Elizabethan times), but more scientific topics like natural history, anatomy, and (especially) water.

In linking magic and science through the character of Prospero, however, Shakespeare was hardly alone among notables of Western literature. A recent (May 2008) essay by Philip Ball in Nature touched upon this theme. (Unfortunately, access to the article requires a subscription, but I'll quote a little.)

The topic at hand was the widespread panic last year, among nonscientists, but somewhat legitimized by journalistic sensationalism, that operation of the Large Hadron Collider could lead to the destruction of the universe. (How's that for human hubris?) Ball connects this hysteria with traditional literary associations between scientists and diabolical forces:

Of myths and men (5/2/08)

When physicists dismiss as a myth the charge that the Large Hadron Collider (LHC) will trigger a process that might destroy the world, they are closer to the truth than they realize.

In common parlance, a myth has come to denote a story that isn’t true, but in fact it is a story that is 'psychologically true'. A myth is not a false story but an archetypal one. And the archetype for this current bout of scare stories is obvious: the Faust myth, in which an hubristic individual unleashes forces he or she cannot control.

Fictional characters Ball mentions as being associated with intellectual overreaching include not only Faust, but also Dr. Frankenstein:

In part, the appeal of these stories is simply the frisson of an eschatological tale, the currency of endless disaster movies. But it is also noteworthy that these are human-made apocalypses, triggered by the heedless quest for knowledge about the Universe.

This is the template that became attached to the Faust legend. Initially a folk tale about an itinerant charlatan with roots that stretch back to the Bible, the Faust story was later blended with the myth of Prometheus, who paid a harsh price for daring to challenge the gods because of his thirst for knowledge. Goethe’s Faust embodied this fusion, and Mary Shelley popularized it in Frankenstein, which she explicitly subtitled ‘Or The Modern Prometheus’. Roslynn Haynes, a professor of English literature, has explored how the Faust myth shaped a common view of the scientist as an arrogant seeker of dangerous and powerful knowledge.

Many other mythological figures could be mentioned, such as Prometheus. Roslynn Haynes' book, titled From Faust to Strangelove: Representations of the Scientist in Western Literature is, unfortunately, out of print.

However, a slightly more recent book by Christopher Toumey – Conjuring Science: Scientific Symbols and Cultural Meanings in American Life – is still in print, and makes the connection between the diabolical-mad-scientist stereotype and social and political attitudes towards science in the U. S. (and elsewhere).

Other sterotypical mad scientists that Toumey mentions include Robert Louis Stevenson's Dr. Jekyll, H. G. Wells' Dr. Moreau, and Ian Fleming's Dr. No (and Ernst Stavro Blofeld as well, I might add).

Does this hoary literary mythology of mad scientists influence public attitudes towards science? Like Philip Ball, I rather suspect the answer is yes, definitely. We see this all the time in the public hysteria surrounding biotechnology and "genetically modified organisms" and "frankenfoods", as the hysterics like to call them. There's also the ridiculousness over the resistance of the public to the possibility of food from cloned animals, even milk from cloned cows. (See here for an example.)

Now, apparently, this hysteria has spread to nanotechnology as well. There are, to be sure, legitimate concerns about health aspects of some current nanotechnology products. These certainly need to be carefully studied – and that is happening, due to the proper concern of many people who haven't forgotten all the major public health problems of a few pharmaceuticals (e. g. Thalidomide, Fen-phen (see here)) – not to mention things like tobacco and asbestos, which are problematical yet hardly products of modern science.

However, the objections to biotechnology are not only based on public health, but on "moral" issues as well (especially with respect to stem cells, cloning, chimeras, etc.) And we're seeing the same thing happen with nanotechnology – which some now think is also a "moral" issue:

For Nanotechnology, Religion In U.S. Dictates A Wary View (12/7/08)

When it comes to the world of the very, very small — nanotechnology — Americans have a big problem: Nano and its capacity to alter the fundamentals of nature, it seems, are failing the moral litmus test of religion.

In a report published Dec. 7 in the journal Nature Nanotechnology, survey results from the United States and Europe reveal a sharp contrast in the perception that nanotechnology is morally acceptable. Those views, according to the report, correlate directly with aggregate levels of religious views in each country surveyed.

In the United States and a few European countries where religion plays a larger role in everyday life, notably Italy, Austria and Ireland, nanotechnology and its potential to alter living organisms or even inspire synthetic life is perceived as less morally acceptable. In more secular European societies, such as those in France and Germany, individuals are much less likely to view nanotechnology through the prism of religion and find it ethically suspect.

But it's about more than nanotechnology. It's about attitudes towards science in general:

The survey findings, says Scheufele, are important not only because they reveal the paradox of citizens of one of the world's elite technological societies taking a dim view of the implications of a particular technology, but also because they begin to expose broader negative public attitudes toward science when people filter their views through religion.

"What we captured is nanospecific, but it is also representative of a larger attitude toward science and technology," Scheufele says. "It raises a big question: What's really going on in our public discourse where science and religion often clash?"

I'll come back to this aspect of things another time.

Tags: biotechnology, nanotechnology

Where are the books on cancer for general readers?

This is a question about a situation that seems very odd to me.

I mean books about the biology of cancer, of course, not cancer in general and how to cope with it. There must be thousands of those, as there should be.

Browsing around at Amazon for books about cancer biology I could find a few textbooks, but almost nothing, for a non-professional reader, that goes into the science in terms of cell biology, molecular biology, etc. Something a general reader could get into and find interesting, even if a little diligence is required.

For other scientific topics, especially related to physics, astronomy, Earth science, and so forth there are are plenty of books, some written by very eminent people in the field.

As far as I can tell, however, there are very few such books for cancer biology.

One that I have, and have enjoyed reading, is Cancer: The Evolutionary Legacy, by Mel Greaves, who is (or was) a professor at the Institute of Cancer Research in London. I can highly recommend it, even though it was published in 2000, so isn't entirely current.

Another is One Renegade Cell: How Cancer Begins, by Robert Weinberg, an even more eminent name in cancer biology. That's a must-read for anyone who wants an introduction to cancer biology. But it was published in 1999, so is even less current.

So I'm just throwing the question out there, in case anyone has suggestions for something more recent. Please leave suggestions in the comments.

DNA repair and cancer II

I just wrote about this at some length, here.

It's funny, sometimes, how there are a bunch of results released in a short time period on the same topic. Usually it's because there's a big meeting that covers the topic, or else the editor of some journal wants several papers on the topic.

I've just come across three more papers on the topic and can't recall such a flurry of activity related to it. The papers were all published in different journals, and there doesn't appear to have just been a meeting on the topic, but it's understandably an active area of research.

The issue is whether or not variants of genes for DNA repair proteins make good biomarkers for cancer risk. As I discussed before, the recent meta-analysis suggests that in general this isn't as great a place to look for biomarkers as one might expect.

Compared to the most common allele of a DNA repair gene, less common alleles may correlate with either increased or decreased cancer risk, depending on the type of cancer and type of DNA repair involved.

In neither case can one automatically conclude that the common allele yields protection against cancer. By repairing DNA, the repair enzyme might actually help cancerous cells survive, offsetting any benefit from preventing further genome damage.

As a result, if one finds that a specific allele reduces cancer risk, it could be because the allele is actually less effective at repairing DNA. Conversely, if another allele increases cancer risk, it could be because the allele is too effective at repairing DNA.

Just looking at the situation from an anticancer perspective, when DNA damage is detected, the smart thing to do is to sacrifice the cell via apoptosis. But that's not the way nature looks at things. The type of damage involved may be so common that it's smarter to try to fix it, and then hope for the best cancer-wise. After all, most cancer depends on the presence of other, unrelated and probably very uncommon, kinds of genomic damage.

Research studies in this area really need to try to suss out what is actually happening, and that could be rather difficult. Basically, this is an evolutionary problem, with the outcome depending on what happens, statistically, in millions or billions of cells over a period of time. Which alleles will ultimately win out? The ones trying to fix DNA damage, or the others trying to exploit the damage? All the "players" in this game have different interests at stake.

Progress here may require some heavy-duty computer simulations trying to sort it all out. Cancer research could turn out to be a lot like climate modeling.

What would better understanding mean therapeutically? It could be possible to discover biomarkers – alleles that indicate significant cancer risk. Where serious risk is indicated to exist, then standard interventions like surgery or chemotherapy may be appropriate.

On the other hand, developing drugs that attempt to silence an allele which is found to predict significant cancer risk may not be very rewarding, for all the usual reasons that drugs may fail (e. g. side effects). That's what clinical trials are for – and trials are very expensive.

The first study we'll look at here involves fairly unique circumstances. It does not address many of the issues we'd like to know about, in particular concerning a direct mechanistic relationship between DNA repair and cancer.

But let's look at what it does say, with a view towards where further research could go. The study, first, determines that a specific type of DNA repair ("nucleotide excision repair") rises and falls substantially with the circadian clock. Second, it finds that levels of a specific repair-related protein (xeroderma pigmentosum A, or XPA) also rises and falls with the clock. Third, it shows levels of XPA are directly related to DNA repair activity.

Now, it's well known that certain types of chemotherapy have a circadian dependency. Quoting from the paper, there exists "empirical observation that circadian time of delivery of chemotherapeutic drugs such as cisplatin, whose major DNA lesions are cisplatin-d(GpG) and cisplatin-d(GpXpG) diadducts (6, 7), may be a significant contributing factor to the efficacy of the drug and the severity of its side effects (4, 5)." Thus it's at least plausible that circadian variability of the levels of repair-related proteins could account for this.

However, that hypothesis remains to be checked directly. It will be interesting to see how this develops.

Here's a press release:

Chemotherapy Most Effective At Time Of Day When Particular Enzyme At Lowest Level (1/13/09)

For years, research has hinted that the time of day that cancer patients receive chemotherapy can impact their chances of survival. But the lack of a clear scientific explanation for this finding has kept clinicians from considering timing as a factor in treatment.

Now, a new study from the University of North Carolina at Chapel Hill has suggested that treatment is most effective at certain times of day because that is when a particular enzyme system – one that can reverse the actions of chemotherapeutic drugs – is at its lowest levels in the body. ...

The study, published in the Proceedings of the National Academy of Sciences, provides the first solid evidence that the daily oscillations of the cell's repair machinery can affect the potency of cancer drugs.

Meta-observation: It's apparently difficult to pin down specific mechanisms at work here, so a fair amount of indirect inference is needed to draw conclusions. We'll see the same thing in two other recent studies (below).

Research paper:

Circadian oscillation of nucleotide excision repair in mammalian brain

T.-H. Kang, J. T. Reardon, M. Kemp, A. Sancar (2009). Circadian oscillation of nucleotide excision repair in mammalian brain Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0812638106

---

Next up is a a case-control study that looked at nine single-nucleotide polymorphisms (SNPs) of seven DNA repair genes. The researchers were looking for correlations with the occurrence of pancreatic cancer. They studied 734 pancreatic cancer patients and 780 individuals without cancer. The strongest association was with a variant allele of one gene (LIG3), where individuals with the allele were 77% less likely than carriers of the normal gene to have cancer. The next strongest association was with a variant allele of another gene (ATM), carriers of which were in excess of 100% more likely to have cancer. (ATM also figures prominently in the third study, discussed below.)

Further investigation considered other cancer risk factors, such as smoking, heavy alcohol consumption, excess body weight, or diabetes – factors which might be responsible for excess DNA damage. The most significant factor turned out to be diabetes. In individuals with diabetes, carriers of an ATM allele were more than 200% likelier to have cancer, while carriers of a LIG4 allele were more than 100% likelier to have cancer.

So here's a study that successfully found several biomarkers, but involving only a few of the DNA genes studied.

Press release:

Abnormal DNA Repair Genes May Predict Pancreatic Cancer Risk (1/15/09)

Abnormalities in genes that repair mistakes in DNA replication may help identify people who are at high risk of developing pancreatic cancer, a research team from The University of Texas M. D. Anderson Cancer Center reports in the Jan. 15 issue of Clinical Cancer Research.

Defects in these critical DNA repair genes may act alone or in combination with traditional risk factors known to increase an individual's likelihood of being diagnosed with this very aggressive type of cancer. ...

With this in mind, [lead author Donghui] Li and her colleagues set out to identify DNA repair genes that could act as susceptibility markers to predict pancreatic cancer risk. In a case-control study of 734 patients with pancreatic cancer and 780 healthy individuals, they examined nine variants of seven DNA repair genes. The repair genes under investigation were: LIG3, LIG4, OGG1, ATM, POLB, RAD54L and RECQL.

The researchers looked for direct effects of the gene variants (also called single nucleotide polymorphisms) on pancreatic cancer risk as well as potential interactions between the gene variants and known risk factors for the disease, including family history of cancer, diabetes, heavy smoking, heavy alcohol consumption and being overweight.

Research abstract:

DNA Repair Gene Polymorphisms and Risk of Pancreatic Cancer

These observations suggest that genetic variations in DNA repair may act alone or in concert with other risk factors on modifying a patient's risk for pancreatic cancer.

---

The last study we'll consider here is a little more tangential to the issue of DNA repair genes and cancer. It's primarily about how defects in DNA repair genes may be responsible for two related neurological diseases – ataxia telangiectasia-like disease (ATLD) and Nijmegen breakage syndrome (NBS).

The two diseases result from defects in the proteins Mre11 and Nbs1 (respectively), which are part of a protein complex called MRN (Mre11-Rad50-Nbs1). MRN is a part of a mechanism that repairs double-stranded DNA breaks.

The research used mouse models. Mice engineered to have an ATLD-like disease had defective genes for Mre11, while those with the NBS-like disease had defective genes for Nbs1. In both cases, DNA-damage stress was induced either by radiation or by knocking out another DNA repair enzyme. The idea was to trigger disease effects due to inadequate damage repair by MRN.

A further relevant fact is that part of the MRN damage-repair process invokes a protein kinase called ATM. Part of the role of ATM is to trigger apoptosis if the damaged DNA cannot be repaired.

For our purposes here, the relevant finding was that neurons of the ATLD mice were resistant to apoptosis, and consequently DNA-damaged neurons survived longer than they should, in view of their defects. The disease pathology results from the persistence of damaged neurons that cannot perform as required. However, neurons of the NBS mice were not unusually resistant to apoptosis, so the neurons died more rapidly, and pathology results from the excessive cell death.

How Defective DNA Repair Triggers Two Neurological Diseases (1/14/09)

To explore the differences between ATLD and NBS, the researchers used mice engineered to have defects in the causative genes, which produce two proteins that help form a critical component of the DNA repair machinery, called the MRN complex. The MRN complex zeroes in on broken DNA segments and attaches to them. It then recruits another important DNA repair protein, called ATM, to launch the repair process. However, if the damage is too severe, ATM may also trigger programmed cell death called apoptosis.

"It happens that defects in ATM also lead to a disease similar to ATLD, highlighting the connections between diseases resulting from defects in this DNA repair pathway," [senior author Peter] McKinnon said.

The mice engineered to mimic ATLD, like their human counterparts, had defective genes that produce a protein called Mre11; while NBS mice were engineered to have defects in the gene for the protein called Nbs1.

The key point may be this: when Mre11 is defective and ATM is then activated, it does not always trigger apoptosis when it should. But when Nbs1 is defective, ATM is able to do its job properly. In any event, when either Mre11 or Nbs1 is defective, MRN does not repair DNA damage as well as it should (in cells other than neurons). This may raise the risk of cancer due to randomly damaged DNA.

"There is a suspicion that people who carry these mutations may be predisposed to cancer and also more susceptible to chemotherapy agents or even to standard X-rays," McKinnon said. "Those agents induce the type of DNA damage that requires the MRN complex and ATM for repair. More generally, studies of the MRN complex and ATM are fundamental to understanding how to prevent changes to DNA that lead to cancer.

"Understanding more about how these proteins signal and interact, and how different cells in the body transduce the DNA damage signal, is of fundamental biological importance," McKinnon said. "This knowledge is necessary not only for understanding DNA repair diseases but for understanding the broader implications of maintaining of the stability of DNA."

Tags: cancer, DNA damage, DNA repair

Hubble Snaps Images of a Nebula Within a Cluster

Hubble Snaps Images of a Nebula Within a Cluster

The unique planetary nebula NGC 2818 is nested inside the open star cluster NGC 2818A. Both the cluster and the nebula reside over 10,000 light-years away, in the southern constellation Pyxis (the Compass).

NGC 2818 is one of very few planetary nebulae in our galaxy located within an open cluster. Open clusters, in general, are loosely bound and they disperse over hundreds of millions of years. Stars that form planetary nebulae typically live for billions of years. Hence, it is rare that an open cluster survives long enough for one of its members to form a planetary nebula. This open cluster is particularly ancient, estimated to be nearly one billion years old.

The spectacular structure of NGC 2818 (also known as PLN 261+8.1) contains the outer layers of a sun-like star that were sent off into interstellar space during the star's final stages of life. These glowing gaseous shrouds were shed by the star after it ran out of fuel to sustain the nuclear reactions in its core.

NGC 2818 – click for 1000×566 image

DNA repair genes and cancer

DNA encodes genes needed for the production of essential proteins in a cell, and this DNA is vulnerable to damage in a number of ways. Perhaps the most common way is a consequence of inevitable errors that occur in the copying of all of a cell's DNA during cell division.

But there are a number of other ways that DNA damage can occur, such as damage due to reactive oxygen species or carcinogenic chemicals, ionizing radiation, or retroviruses, which insert their own DNA at random locations in the genome. (Technically, there's a distinction between DNA damage and DNA mutations, but we'll gloss over that for a moment.)

Most DNA damage affects only a single cell, and then, at most, only in the cell's ability to make certain proteins needed for normal cell function. Damage that occurs in DNA regions that don't affect protein production may have no effect at all. If important proteins are afffected, the cell may be unable to do its job properly, such as being a neuron or muscle cell. At worst, the cell dies, but its function is probably duplicated by billions of other cells in the same tissue or organ. Over a long enough period of time, of course, eventually a large percentage of cells will die due to DNA damage – and then the organism dies of "old age", if nothing more traumatic occurs first.

Against the relative improbability of one DNA damage event having serious consequences for a particular cell has to be weighed the frequency with which damage occurs. Most cells divide fewer than 100 times in their whole lifespan, though many errors can occur during each division. External factors like radiation, however, can cause millions of DNA damage events per day in a single cell. (Don't go sitting in front of an X-ray source all day! Or even under a source of UV radiation, like the Sun.) Internal factors, such as reactive oxygen species produced during normal metabolism, can cause many 1000s of mutations per cell per day, so DNA damage isn't something that cells can just ignore.

There are a couple of exceptions, when DNA damage can be an even more serious problem. One is in case the cell is an egg or sperm cell (a gamete), in a multicellular, sexually-reproducing organism, and the cell goes on to generate a new individual, which will inherit the damaged DNA. Since gametes are only a small proportion of all cells, and very few gametes are ever "lucky" enough to become new individuals, this is a fairly rare event. But it is how errors accumulate in genomes, over long periods of time. Such errors, being random events, are seldom beneficial to a species. But rarely they can be helpful and drive species evolution to adapt to a changing environment.

The other exception, which is much more consequential for the individual in which it occurs, is when the DNA damage affects one of the relatively small number of proteins responsible for keeping cell division and proliferation under control. Then you have a circumstance that can lead to cancer, even if only a single cell is affected to begin with. Clearly, it is in the best interest of the individual, and perhaps the whole species, for cells to have good mechanisms for dealing with the problems caused by DNA damage.

Apart from dealing with the original causes of DNA damage, cells have basically two ways of coping with damage after it occurs.

One sort of mechanism involves being able to detect the presence of DNA damage, and to initiate measures that limit or stop the cell's ability to proliferate, or even cause the cell to die. P53 is perhaps the best known protein involved in this type of mechanism. Compromised p53 production is found in more than half of all cancers. If a gene, in the same cell, that codes for a protein needed to implement one of these mechanisms has been damaged previously, the probability of cancerous proliferation will rise. Mechanisms of this kind are complex. There's a lot that can go wrong, and that's one reason cancer is as common as it is.

The other sort of mechanism is actual DNA repair. It's not so draconian. Such mechanisms attempt to actually correct the DNA damage, returning the DNA to its state before the damage occured. That's great. If it actually works, the cell can survive unharmed, and not pose any extra risk of becoming cancerous.

There are a variety of kinds of DNA damage, and hence a variety of repair mechanisms are needed. Individual bases attached to the nucleic acid backbone can be modified or deleted. The base sequence can be altered by faulty copying. The backbone itself can be broken or warped, preventing expression of some genes. Entire chromosomes, which carry DNA in a compact, packaged form, can be broken or improperly duplicated.

It's easier to recognize that damage has occurred than it is to repair it. Here the distinction between DNA mutations and other kinds of damage becomes relevant. A mutation exists when a base pair on the two strands of DNA is replaced with a different but otherwise normal base pair (i. e. adenine-thymine or guanine-cytosine). The resulting DNA is still technically undamaged, although the protein resulting from a gene with a mutation may not work as well as the unmodified version. In such a case, it is difficult or impossible for the problem to be recognized by DNA repair mechanisms. And it the problem can't be recognized, it certainly can't be repaired.

However, with most DNA damage, one or both strands of the DNA molecule is/are either distorted or broken. In that case, the DNA cannot be properly transcribed into RNA, or the DNA cannot be copied during cell division (or both). But for the same reason that these copying problems occur, it is also possible for appropriate enzymes to recognize that things are not right, and to activate a suitable repair mechanism (even if the repair cannot always succeed).

If, on the other hand, the damage is not repairable, other pathways can be activated to cause cell senescence or apoptosis. This more drastic situation may lead to cancer if there is already a problem with the senescence or apoptosis pathways. However, the research we're about to mention doesn't deal with this case. It's about problems in the repair mechanisms, due to DNA damage or mutations affecting those mechanisms, that lead to repair failure and that, consequently, lead to cancerous cell behavior.

The nature of repairable damage is varied, and the details of repair are quite technical, so we won't go into that here. Suffice it to say that there are effective damage repair mechanisms. What's not clear is whether malfunctions in those mechanisms (resulting from previous uncorrected errors or mutations) frequently result in cancer.

Researchers investigated genes that code for proteins involved in DNA repair. After statistical analysis of many relevant studies they found only two with a significant correlation to cancer:

Few DNA Repair Genes Maintain Association With Cancer In Field Synopsis (12/31/08)

Variants of numerous DNA repair genes initially appeared to be statistically significantly associated with cancer risk in epidemiological studies. When the data from individual studies are pooled, however, few DNA repair gene variants appear truly associated with increased cancer risk, according to a new field synopsis. ...

In the current study, John P. Ioannidis, M.D., of the University of Ioannina School of Medicine in Greece, and colleagues identified 241 previously reported associations between gene variants and the risk of cancer. The team pooled the data from 1,087 data sets and reexamined these associations.

Initially 31 of the 241 associations appeared to be statistically significantly associated with cancer risk in the meta-analysis. However, only two remained statistically significant after the researchers adjusted for multiple comparisons. An XRCC1 allele (-77 T>C) and an allele of ERCC2 (codon 751) were associated with lung cancer risk.

The conclusion of the meta-analysis is that either there's a problem with the way in which candidate genes were selected, or else problems in DNA repair mechanisms do not by themselves play a big role in carcinogenesis.

"The lack of many signals with strong credibility that emerged from our analysis, despite an enormous amount of work in this area over the years, needs careful consideration," the authors write. "The ability of the candidate gene approach to identify genetic risk factors may have been overestimated. Alternatively, the importance of the DNA repair pathway may have been exaggerated. However, there is increasing recognition that genetic risks of cancer conferred by single variants are almost always very modest. This means that even if the DNA repair pathway is essential for carcinogenesis, extremely large-scale evidence would be necessary to establish with high confidence the presence of specific associations."

Even though it seems that genomic studies have failed to turn up important oncogenes among genes that are involved in DNA repair, there is practical significance in these research findings.

For one thing, we should not expect to find useful biomarkers of cancer risk among alleles of DNA repair genes. Likewise, it's probably not worth exploring gene therapy approaches to compensating for malfunctioning DNA repair genes. Instead, what's more likely to succeed is a focus on alleles of genes involved in detection of DNA damage or of genes involved in senescence or apoptosis pathways.

Still, DNA repair genes remain very important. In many types of current cancer therapy, such as chemotherapy or radiotherapy, the intent is explicitly to cause DNA damage in order to bring about senescence or apoptosis. A problem with DNA repair in cancer cells cuts both ways. On one hand, faulty DNA repair leaves more errors uncorrected, exposing the cells to senescence or apoptosis as long as those pathways remain intact. That's good. But on the other hand, it can allow new errors to accumulate, making the cells more vulnerable to compromise of the senescence and apoptosis pathways, hence more likely to proliferate. That's bad.

Perhaps this ambivalence of DNA repair in the cancer process explains the apparent lack of strong correlation between faulty DNA repair and cancer.

Here's another way to think about the "right" way for an organism to defend itself from cancer. Cancer is a problem that's of concern only to multicellular organisms – communities of cells. While the integrity of each cell is certainly important, it's even more important to protect the whole community. A suitable analogy might be that it's more important to the community to have a good fire department as the last line of defense, than to rely on effective sprinkler systems to put out small fires in every separate location. If the fire department itself is compromised, and unable to combat a spreading conflagration, the community as a whole is in serious danger.

Here's the research abstract:

A Field Synopsis on Low-Penetrance Variants in DNA Repair Genes and Cancer Susceptibility

We have conducted meta-analyses of 241 associations between variants in DNA repair genes and cancer and have found sparse association signals with strong epidemiological credibility. This synopsis offers a model to survey the current status and gaps in evidence in the field of DNA repair genes and cancer susceptibility, may indicate potential pleiotropic activity of genes and gene pathways, and may offer mechanistic insights in carcinogenesis.

Update, 1/25/09: There's a significant follow-up on all this here.

Tags: cancer, DNA damage, DNA repair

Theory vs. observation

I wrote the following for another context, but I think it might be of interest here.

What it's all about is a debate between people with two different views of how the scientific process operates. One group claims that science is based, first, on careful observation of the world, followed by construction of a theory to account for the data. The other group claims that theories and hypotheses are constructed first, followed by collection of data to provide evidence or refutation for the theory or hypothesis.

My opinion's different from that of either group...

Science relies on both observation and theory. Neither alone is sufficient, but the mixture that any particular science or scientist uses can vary a lot from case to case. Kind of like blind men describing the elephant.

It's an iterative process. Scientists use theory to guide observation, and observation to guide theory. In working on any particular problem, one can enter at different phases of the process. Sometimes one starts with puzzling observations in need of a better theory. (Quote: "The most exciting phrase to hear in science, the one that heralds new discoveries, is not 'Eureka!' but 'That's funny...'" -- Isaac Asimov) And sometimes one starts with theoretical ideas in need of observational support.

Which comes first, theory or observation? That's a less important question than may be apparent. As noted, any particular individual enters the process at a specific point, which may more heavily involve theory or observation. In either case, it's always (nowadays) true that every investigator is standing "on the shoulders of giants". (A large topic in itself. The metaphor, supposedly, is due to Newton. Famous book on the subject by Robert K. Merton. Basic idea: there are antecedents to everything, including the metaphor.)

But which is the absolute first? Sure, it has to be observation, but only in a somewhat trivial sense, in that all "knowledge" ultimately comes in through the physical senses. Or you could say that it's "only a theory" that your observations have a direct relationship to reality. Now we're in the territory of epistemology, which is generally not the concern of working scientists.

However, when one is thinking about the philosophy of science, one has to take into account the idea that theory determines what can be observed, and in fact what the "meaning" of observations can be. This leads into the realm of Thomas Kuhn and "paradigms" that control what is observed and how it is interpreted. This can be, and has been, taken to the extreme relativist position that science is meaningful only in terms of somewhat arbitrary cultural constructs. Almost all working scientists, of course, think that's going way too far.

Nevertheless, there are plenty of cases where theory has run far ahead of observation. Example just in physics include quantum mechanics, the big bang theory, cosmic inflation, and black holes. Indeed, the gold standard of theory is to make correct predictions of observations that have NOT already been made. A theory that merely accommodates existing observations is suspect of being fudged to fit the facts. Yet that's the right way to go in some cases, where the theory has "free parameters", like the Standard Model of particle physics. (Physicists still want to find a theory that predicts the parameters, and that goal remains quite elusive.) Climate models are the same way. They are adjusted to fit what has been observed in the past, with the hope that forward predictions will also be correct.

And that brings us back to relativity, in the Einsteinian, not cultural, sense (which have very little to do with each other).

The foundation of special relativity is Einstein's rather unorthodox (at the time) idea that the speed of light is the same in all reference frames. If one takes that to be axiomatic, then some quite surprising consequences inevitably follow, such as the equivalence of mass and energy (E=mc²). Nobody was expecting that, or had any observations to even suggest it. Two of Einstein's (five) amazing papers of 1905 resulted from following the axiom to its logical conclusion.

Now, one might think that the Michelson-Morley experiment of 1887 gave the observational basis for Einstein's special theory. But the evidence for this is very unclear. Einstein himself was quite vague about the issue. Pais' biography devotes more than 10 pages to the topic. One thing is clear: Einstein didn't cite the experiment in his 1905 paper, even though it would have bolstered his case. But at various times he acknowledged having been aware of it in 1905. In any event, the experiment doesn't seem to have been anything like the key motivation for special relativity.

General relativity (1916) is an even more interesting case. One of the foundations of GR was special relativity, of course. Another key insight was Einstein's "equivalence principle", which posited that the behavior of a moving object in a gravitational field was the same as the observed behavior of the object in a reference frame that is accelerating with respect to the object.

Again, Einstein took theoretical principles as axioms. He worked for about 10 years to figure out what the consequences had to be. While some observation obviously supported his principles, there was no other observational input after making them axioms. Interestingly, Einstein was not a strong mathematician, which may be why it took him 10 years after 1905 to come up with GR. He had to rely on a friend, Marcel Grossman, who was much better at math. (Of course, what they needed was very cutting edge math at the time.) Einstein also obtained the help of other eminent mathematicians, like Tullio Levi-Civita.

Out of this collaboration emerged the theoretical idea that gravity should not be regarded as a traditional Newtonian force, but instead as a phenomenon due to curvature of space itself. There was nothing particularly observational about this idea. It was simply a beautiful theoretical idea. Indeed, people still have a tough time conceptualizing what it means for space to be curved. Just as people have a hard time conceptualizing the 4 dimensions of spacetime. These kinds of ideas simply do NOT come out of everyday observation.

The story gets even better. Einstein and his collaborators decided that the right equation to describe gravity should have certain very technical, theoretical properties. The equation had to have a "covariant tensor" form. It should describe the geometry of space in terms of a mathematical construct called a "metric". And in the boundary case where no gravitational mass is present, the metric should be, specifically, the "Lorentz metric" used for spacetime in special relativity. From these theoretical considerations, rather than from any specific observations, the collaborators came up with a tensor equation, which is the essential part of GR.

From that equation it was possible to predict that light has to bend in the presence of (large) masses. Nobody had ever observed that, or even suspected it. Not only was the fact of bending correct, but the equation even correctly predicted the amount of bending. This is why Eddington's measurement in 1919 of the bending of light during a solar eclipse caused quite a sensation, including headlines in the NYT. It's part of the reason Einstein acquired his "genius" reputation. (Few ordinary people knew anything about the 1905 papers.)

And the story goes on. Einstein was, in fact, misled by observations to modify his GR equation. He inserted into it what he called a "cosmological constant", so that the equation would predict what observations at the time (around 1920) seemed to indicate - namely that the universe was not collapsing under the force of gravity, but appeared to be static. At times, it is actually better to rely on theory than observation.

Subsequent observations by Hubble (later 1920s) indicated that the universe was in fact expanding. (Even those observations turned out to be quite inaccurate, though qualitatively correct.) So Einstein tossed out the cosmological constant in disgust. That was (apparently) a mistake, as in 1997 new observations indicated that the universe was not only expanding, but actually doing so at an accelerated rate. The cosmological constant - if chosen correctly - in fact predicts that.

Now, the actual value of the constant does depend on observations. It has to have the value that gives the correct amount of observed acceleration. All attempts to use theory to compute this value a priori have been miserable failures... so far.

And that view of the cosmological constant depends on other theoretical assumptions (such as the near perfect flatness of spacetime due to inflation) which have conceptual appeal, but (at least until fairly recently) little independent observational support. Indeed, much of modern cosmology itself depends largely on theoretical assumptions (isotropy and homogeneity) that observationally are only approximations, and could be substantially wrong.

Bottom line: theory and observation in the scientific process cannot be separated. It's kind of like trying to imagine one hand clapping.

Tags: relativity, scientific method

Sugar can be addictive

And you may well have noticed this addictive characteristic if you overindulged in sugar over the recent holidays. Turns out, the neurotransmitter dopamine plays a big role here. There's a lot of research on dopamine coming out these days. The research discussed here is just one example.

We last dealt with dopamine back in November: here. One could paraphrase the conclusions of that research as suggesting that genetic problems with a dopamine receptor lead to reduced sensitivity to dopamine, which leads to stronger than normal craving for food, leading to overeating and obesity.

The research in question here looks at a special case of this in an animal model, involving rats and sugar. In this case, reduced sensitivity to dopamine isn't a consequence of a variant allele for a dopamine receptor. Instead, it seems to result from excessive intake of the addictive substance (sugar), resulting in fewer brain receptors for dopamine.

Sugar Can Be Addictive: Animal Studies Show Sugar Dependence (12/10/08)

"We have the first set of comprehensive studies showing the strong suggestion of sugar addiction in rats and a mechanism that might underlie it," [principal investigator Bart] Hoebel said. The findings eventually could have implications for the treatment of humans with eating disorders, he said.

Lab animals, in Hoebel's experiments, that were denied sugar for a prolonged period after learning to binge worked harder to get it when it was reintroduced to them. They consumed more sugar than they ever had before, suggesting craving and relapse behavior. Their motivation for sugar had grown. "In this case, abstinence makes the heart grow fonder," Hoebel said.

The rats drank more alcohol than normal after their sugar supply was cut off, showing that the bingeing behavior had forged changes in brain function. These functions served as "gateways" to other paths of destructive behavior, such as increased alcohol intake. And, after receiving a dose of amphetamine normally so minimal it has no effect, they became significantly hyperactive. The increased sensitivity to the psychostimulant is a long-lasting brain effect that can be a component of addiction, Hoebel said.

The research investigated the physiological changes responsible for this addictive behavior:

Hoebel has shown that rats eating large amounts of sugar when hungry, a phenomenon he describes as sugar-bingeing, undergo neurochemical changes in the brain that appear to mimic those produced by substances of abuse, including cocaine, morphine and nicotine. Sugar induces behavioral changes, too. "In certain models, sugar-bingeing causes long-lasting effects in the brain and increases the inclination to take other drugs of abuse, such as alcohol," Hoebel said.

Hoebel and his team also have found that a chemical known as dopamine is released in a region of the brain known as the nucleus accumbens when hungry rats drink a sugar solution. This chemical signal is thought to trigger motivation and, eventually with repetition, addiction. ...

Hungry rats that binge on sugar provoke a surge of dopamine in their brains. After a month, the structure of the brains of these rats adapts to increased dopamine levels, showing fewer of a certain type of dopamine receptor than they used to have and more opioid receptors. These dopamine and opioid systems are involved in motivation and reward, systems that control wanting and liking something. Similar changes also are seen in the brains of rats on cocaine and heroin.

It's interesting that overstimulating with an addictive substance (sugar) not only reduces the number of dopamine receptors but also increases the number of opioid receptors. What's not so clear is the relationship between the dopamine and opioid systems. Having more opioid receptors would appear to increase cravings for substances that stimulate them, which is the opposite of what happens with dopamine receptors. Hypothetically, perhaps, opioid stimulation is able to substitute for reduced dopamine sensitivity.

Research in this area may have even wider implications than behavior linked to overconsumption, as there is other recent research that suggests addictive behavior related to other kinds of stimulation, such as gambling and risk-taking.

Watch for a lot more discussion of this line of inquiry.

Tags: dopamine, addiction

Top science stories of 2008

Popular interest in science news just isn't what it used to be. That's a sad but apparent fact. However, one reason that some people will always be interested in science news is that it satisfies a deep-rooted need for novelty. We get bored with the same old, same old after awhile. Our brains even tend automatically to tune out stimuli that don't ever change, or that change very little.

Science, on the other hand, keeps on providing a steady stream of genuinely new, and sometimes even surprising, information. This was just as true in 2008 as ever. It's a fact that could be lost sight of amidst all the other chaos of the year. As we review this year's noteworthy events in science, take note of how often the interest of the story resides in the novelty of the information.

Last year we did a summary of the news summaries. It was fun, so let's do it again.

As usual, Science magazine again provides the most intelligent selection of significant developments (December 19 issue).

The number 1 story (in their opinion) was reprogramming cells from one type to another. This research was announced in August and published a little later (October 2) in Nature. I was plannning to write about it – haven't yet – may still do so.

Here's how Science describes it:

Reprogramming Cells

By inserting genes that turn back a cell's developmental clock, researchers are gaining insights into disease and the biology of how a cell decides its fate.

This year, scientists achieved a long-sought feat of cellular alchemy. They took skin cells from patients suffering from a variety of diseases and reprogrammed them into stem cells. The transformed cells grow and divide in the laboratory, giving researchers new tools to study the cellular processes that underlie the patients' diseases. The achievement could also be an important step on a long path to treating diseases with a patient's own cells.

And here's the whole Top 10 list:

1. Reprogramming cells
   
2. Direct visual observation of extrasolar planets
   
3. Identification of specific genetic abnormalities in cancer cells
   
4. New class of high-temperature superconductors
   
5. Clarification of how proteins bind to their targets
   
6. Discovery of a new, cheaper catalyst for splitting water into hydrogen and oxygen
   
7. Real-time imaging of zebrafish embryonic development
   
8. Discovery that cells of "brown" fat are more closely related to muscle cells than to cells of "white" fat
   
9. Computation using quantum chromodynamics of correct (to within 5%) mass of a proton
   
10. Much faster and cheaper genome sequencing technologies
    

References:

• Science's Breakthrough Of The Year: Cellular Reprogramming – 12/18/08 press release
  
• Special Online Collection: Breakthrough of the Year 2008 – package of related articles
  
• Breakthrough of the Year: The Runners-up
  

Could this list have been better? Yes. It doesn't mention anything in astrophysics or cosmology, where there was actually quite a lot happening in the areas of dark matter, dark energy, star and galaxy formation simulations, gamma-ray astronomy, high-energy cosmic rays, and more.

Several other print and/or online publications attempted to come up with similar lists. Here are some of the better ones:

News 2008 (Nature)

Nature's list of important stories gets a lower rating because their criterion was "newsworthiness" or something like that, perhaps in terms of social or political impact, rather than scientific significance. Polar bears? Eh. In terms of actual science the list includes genome sequencing, synthetic genomes, Arctic sea ice, and pluripotent stem cells (a year late).

2008: Science News of the Year (Science News)

A little disappointing, because it covers so many stories. But from another point of view, that's the biggest strength, if you have patience to go through longish lists in 13 different categories.

Top 100 Stories of 2008 (Discover)

This traditionally long list (couldn't they at least have separated out the best 20 or so?) is substantially improved this year by organization into categories. But then they spoil it and lose mucho points for referring to the Higgs particle as the "God particle". Ugh.

The Year in Science (MSNBC)

Good job by Alan Boyle. Intelligent choices, not too long, not too short. Nice mix of scientific results and political/social implications. Now we just need to convince Alan and other American science writers to stop using the name of a long-dead baseball jock in connection with an important neurological disease (ALS).

Year in science: Dig into DNA, out-of-this-world discoveries (USA Today)

Workman-like effort from Dan Vergano. This is the one to read if you want brevity. Genome mapping, extrasolar planets, ancient DNA.

Top Ten Physics Stories of 2008 (American Institute of Physics)

Pretty fair list, albeit in just one area of science. Covers superconductivity, quark physics, gamma-ray bursts, cosmic rays, and low-temperature physics.

The best of 2008 (Physics World)

Another decent physics list. Drawback is organization by month, which doesn't map well to topic areas – notable ones being superconductivity, graphene, quantum computing, and dark matter. Somehow they managed to miss the proton mass calculation, and anything in astrophysics except for dark matter.

Biggest Science Stories: Bloggers' Picks for 2008 (National Geographic)

Interesting concept: the magazine chooses bloggers to discuss the most important stories in several areas – anthropology, paleontology, energy, archaeology, psychology, and environment.

Lists of lists:

• TOP TEN (and more, or less) Lists - or, How’d we miss the squid with elbows story….??? (Knight Science Journalism Tracker) – Kudos to Mr. Petit for a good job, and he lists some klunkers, so I don't have to
  
• Top 10s.... wish list
  

Unimpressive lists:

• News review 2008: The year in science (New Scientist) – The lede says it all about this one: "It was a year when everything seemed to fall apart."; however, New Scientist redeems itself with a slew of independent articles reviewing many areas (see below)
  
• Top 5 Amazing Astronomy Discoveries in 2008 (Space.com) – Weak and hypey, but somewhat makes up for neglect of astronomical topics on other lists
  
• Time Top 10 Scientific Discoveries (Time) – Forgettable picks in another icky "slide show"
  
• The Year in Medicine 2008 (Time) – Long list of 37 items (I think), but double-bad organization (alphabetical as a "slide show") makes it a royal pain to peruse
  
• The top science stories of 2008 (Christian Science Monitor) – Correctly describes itself as a "small sample"
  
• The 10 Biggest Science Stories of 2008 (Scientific American) – Sad, so sad; the "slide show" format only deepens the pain
  
• Science year in review: 2008 (ABC (Australia) Science) – Mostly gee-whiz stuff
  
• The top 10 news stories of 2008 (Cosmos) – Spunky little publication, but if this is the "top 10", science is in really deep do-do; also loses points for using the verb "baffle"
  
• Top Innovations of 2008 (The Scientist) – All about biological laboratory equipment and technology, which is understandable for a trade magazine
  

New Scientist did offer up a number of collections of its own favorite articles in various topic areas. You get to separate the wheat from the chaff.

It's unfortunate how little coverage there is in this, and most other non-professional media, of significant stories about cell and molecular biology, where scientific activity is frenetic.

• Your amazing brain: Top 10 articles from 2008
  
• Cosmology: Top 10 articles from 2008
  
• Top 10 environment articles in 2008
  
• Genetics: Top 10 articles from 2008
  
• Darwin's dangerous idea: Top 10 evolution articles
  
• Most extreme news stories of 2008
  
• A year in the quantum world
  
• 2008: A good year for Neanderthals
  
• Nanotechnology's biggest stories of 2008
  
• Green fuel technologies pick up speed in 2008
  
• 2008: The year in the solar system
  
• 2008: The year in astronomy
  

Chinese food, umami, autism, schizophrenia, and cancer

There's a fascinating interrelationship among the things mentioned in the title – and it takes us through equally fascinating topics in molecular cell biology and neurobiology.

No, Chinese food has not been found to cause the listed maladies – although with the additives that the People's Republic of China seems to be allowing in many of its food products these days (e. g. melamine), who knows for sure?

So what's the connection? Try monosodium glutamate (MSG). That, of course, is the sodium salt of glutamic acid (which itself is often referred to as "glutamate"). MSG is a rather well known food additive which at one time was very commonly used in Chinese food for its ability to "enhance" flavor. Technically, the form of glutamate responsible for flavor is the ionic form rather than the sodium salt – the former being what is found in aqueous solution rather than the latter dry crystalline form.

MSG became notorious some time ago when Chinese food became popular in western countries, because it was at first unfamiliar and also tended to cause headaches or at least a peculiar lightheaded sensation after eating food to which it had been added. Consequently, most Chinese restaurants, at least in the U. S., now carefully inform customers that their food "contains no MSG".

Nevertheless, it's impossible to escape glutamate, because glutamic acid is one of the 20 amino acids that make up all proteins. It's essential to life as we know it, and so in fact it can't be avoided.

It also happens to be one of the most important neurotransmitters, and in that role is absolutely essential to the function of animal nervous systems. This role of glutamate is the key part of the story here.

As a flavor, glutamate is responsible for the much hyped "fifth taste" known in Japanese as umami. The first four basic tastes are sweetness, bitterness, sourness, and saltiness. Each of these is detected by specialized receptors on human tongues. Like the others, umami is also detected by its own receptor, but what's actually being detected is the amino acid glutamate present in all protein-containing foods, especially meats, cheese, and soy products.

Although the flavor is enjoyable, it's as a neurotransmitter that glutamate is important for the present story. As a neurotransmitter, glutamate is excitatory. In fact, it's the most abundant excitatory neurotransmmitter in mammalian nervous system. An electrical impulse traveling down a neuron's axon triggers the release of glutamate at the presynaptic side of glutamate synapses. When this glutamate is picked up by receptors at the other side (the postsynaptic side) of the synapse it contributes to possible excitation of the postsynaptic neuron. This is the basic mechanism by which signals are transmitted through an animal's nerves. (But there are other neurotransmitters besides glutamate that may be involved.)

However, this excitatory behavior can get out of hand, and when it does glutamate can have a toxic effect, called excitotoxicity. This can kill neurons and cause disease conditions such as autism, schizophrenia, and epilepsy.

Since glutamate is both essential but also (in excessive amounts) potentially toxic, an elaborate negative feedback system has evolved to keep glutamate production and release under careful control. It is when this feedback system fails somehow that neurological diseases develop. A typical cause of failure is mutation of genes that produce proteins essential to the feedback system.

So what are some of these genes/proteins? The first of these is the metabatropic glutamate receptor, mGluR for short. This is a receptor found on the surface of an axon, close to a glutamate synapse. When glutamate outside the neuron binds to such a receptor, it acts to tamp down the exited state of the neuron that led to release of glutamate in the first place. This process is called autocrine signaling, meaning that it involves a cell releasing a signaling molecule that can trigger a receptor on the same cell to modify cell behavior. This is the start of the negative feedback loop.

One source of failure is in mutation of mGluR itself, if this mutation causes further steps in the feedback loop to fail. What are some of these further steps? The first and possibly most important involves a protein enzyme with the charming name of PI3K. That's short for "Phosphoinositide 3-kinase", and we should be grateful for not having to write it out in full every time.

PI3K is a kinase, which means its enzymatic action is to cause phosphorylation of other proteins. A sequence of phosphorylating kinsaes constitutes a signal cascade or "pathway".

PI3K is the start of a pathway that plays a huge role in cell survival and proliferation – among other things. Clearly, it's an important protein.

The next step in the pathway is another kinsase called AKT. It's actually, in humans, a small family of proteins, Akt1, Akt2, and Akt3. Akt1 is the main player. One of its main jobs is cell survival, as an inhibitor of apoptosis. There are many reasons, both good and bad, for a cell to die by apoptosis. Akt1 is there to prevent the bad reasons for being responsible for too much cell death.

However, in cells that have become cancerous, one or another member of the AKT family typically functions only too well, resulting in the uncontrolled proliferation of cells that is the hallmark of cancer. In fact, an AKT kinase is hyperactive in the majority of human cancers. These molecules have been called perhaps the most frequently activated type of oncoprotein. (Reference: here.) Not only is AKT, in one form or another, involved in a majority of cancers, in many types of cancer, some form of AKT is a key factor. For instance, in melanoma, the interaction of Akt3 and another important cancer-related protein, c-Raf, is involved in 60-70% of melanoma-related tumors. (Reference: here.)

Not too long ago we discussed several other kinases (mTOR and MAP kinases), as well as PI3K and AKT, that play a role in cancer.

Its significant involvement in cancer is far from the only reason AKT is interesting, though. It is a versatile kinase involved in multiple pathways. In particular, it also participates in the negative feedback loop for glutamate because it deactivates a FoxO transcription factor. (For many details on that topic, see here.)

Now we're really getting into the heart of the story on the negative glutamate feedback loop. Recent research on fruit fly motor neurons, which we're about to refer to, suggests (among other things) that an AKT kinase inhibits a FoxO transcription factor that otherwise would stimulate glutamate release.

In a nutshell, the autocrine stimulation of the mGluR glutamate receptor activates PI3K, which activates an AKT kinase, which then inhibits a transcription factor, thereby inhibiting further glutamate release. This negative feedback loop keeps motor neurons from becoming overactive.

Here's a picture of what's going on:



Any mutation of the signaling kinases involved in this feedback loop would, of course, destabilize the control mechanism, but would likely cause other pathology as well, because of the involvment of PI3K, AKT, and FoxO in many other important cellular processes. However, if it was the mGluR glutamate receptor that was affected by a mutation, the main consequence would be some neurological pathology such as epilepsy.

A further reasonable speculation would be that mutations affecting mGluR in other types of neurons could cause other neurological problems, such as autism or schizophrenia. The present research does not actually deal with this more general case. However, other research has implicated PI3K and mGluRs in epilepsy, neurofibromatosis (a type of non-cancerous tumor), autism, schizophrenia, and other neurological disorders in humans.

Here's the research and its abstract:

A PI3-Kinase–Mediated Negative Feedback Regulates Neuronal Excitability

Use-dependent downregulation of neuronal activity (negative feedback) can act as a homeostatic mechanism to maintain neuronal activity at a particular specified value. Disruption of this negative feedback might lead to neurological pathologies, such as epilepsy, but the precise mechanisms by which this feedback can occur remain incompletely understood. At one glutamatergic synapse, the Drosophila neuromuscular junction, a mutation in the group II metabotropic glutamate receptor gene (DmGluRA) increased motor neuron excitability by disrupting an autocrine, glutamate-mediated negative feedback. We show that DmGluRA mutations increase neuronal excitability by preventing PI3 kinase (PI3K) activation and consequently hyperactivating the transcription factor Foxo. Furthermore, glutamate application increases levels of phospho-Akt, a product of PI3K signaling, within motor nerve terminals in a DmGluRA-dependent manner. Finally, we show that PI3K increases both axon diameter and synapse number via the Tor/S6 kinase pathway, but not Foxo. In humans, PI3K and group II mGluRs are implicated in epilepsy, neurofibromatosis, autism, schizophrenia, and other neurological disorders; however, neither the link between group II mGluRs and PI3K, nor the role of PI3K-dependent regulation of Foxo in the control of neuronal excitability, had been previously reported. Our work suggests that some of the deficits in these neurological disorders might result from disruption of glutamate-mediated homeostasis of neuronal excitability.

Further reading:

Possible Clues To Root Of Epilepsy, Autism, Schizophrenia (12/9/08) – press release

Eric Howlett, Curtis Chun-Jen Lin, William Lavery, Michael Stern (2008). A PI3-Kinase–Mediated Negative Feedback Regulates Neuronal Excitability PLoS Genetics, 4 (11) DOI: 10.1371/journal.pgen.1000277

Tags: autism, schizophrenia, epilepsy

A Sparkling Spray of Stars

A Sparkling Spray of Stars (12/16/08)

NGC 2264 lies about 2600 light-years from Earth in the obscure constellation of Monoceros, the Unicorn, not far from the more familiar figure of Orion, the Hunter. The image shows a region of space about 30 light-years across. ...

Much of the image appears red because the huge gas clouds are glowing under the intense ultra-violet light coming from the energetic hot young stars. The stars themselves appear blue as they are hotter, younger and more massive than our own Sun. Some of this blue light is scattered by dust, as can be seen occurring in the upper part of the image.

This intriguing region is an ideal laboratory for studying how stars form. The entire area shown here is just a small part of a vast cloud of molecular gas that is in the process of forming the next generation of stars. Besides the feast of objects in this picture there are many interesting objects hidden behind the murk of the nebulosity. In the region between the tip of the Cone Nebula and the brightest star at the top of the picture there are several stellar birthing grounds where young stars are forming. There is even evidence of the intense stellar winds from these youthful embryos blasting out from the hidden stars in the making.

NGC 2264 – click for 1280×1465 image

Peroxisome proliferator-activated receptors and your ticker

Everyone knows by now that having diabetes raises the risk for heart disease in various forms. Wouldn't it be interesting to understand the biological reasons for this connection? Well, it turns out that various factors seem to be relevant, and one of them involves a variety of paths that all pass through the territory of a rather interesting protein called PPAR-γ.

Not only is PPAR-γ implicated in processes related to both diabetes and heart disease, but it turns out that some drugs used to control diabetes also affect the risk of heart disease – because of PPAR-γ.

We'll begin the discussion by looking at recent research on how PPAR-γ affects heart function.

First, of course, we should explain what a peroxisome proliferator-activated receptor is. The name is somewhat off-putting, and nowadays most people just write PPAR. It's also a bit of a historical artifact, in that this class of proteins was first investigated in connections with peroxisomes, which are cellular organelles that participate in the metabolism of fatty acids. That's an important clue right there, because if we are dealing with fat metabolism, there may well be connections with conditions such as obesity and cardiovascular disease.

It turns out that is only a part of what PPARs are connected with.

A PPAR is not a cell surface receptor. Instead it is a nuclear receptor, meaning that it's a protein found in the interior of cells that (like a surface receptor) is activated when it connects with hormones and similar molecules. Such molecules that bind to a receptor are called ligands.

Initially, the ligands in question were known to cause proliferation of peroxisomes, but now many other kinds of ligands that activate PPARs have been identified.

Once a PPAR has been activated it can affect the expression of many different genes, because it acts as a transcription factor.

Three important PPARs are known: PPAR-α, PPAR-β (also called PPAR-δ), and PPAR-γ. It's the last of these we'll be concerned with here. In fact, PPAR-γ seems to affect many cellular processes related to metabolism and other things. Recent research that we may discuss another time (see here) has shown that there are about 5300 sites in the DNA of a fat cell that PPAR-γ can bind to, and hence potentially affect the expression of nearby genes. So it's not surprising that PPAR-γ is involved in quite a lot of cellular business.

Incidentally, all three PPARs are produced from the same gene, with the variant forms being due to alternative splicing.

The research we want to highlight here deals with how PPAR-γ is linked with the daily rise and fall of heart rate and blood pressure. Such things that are part of the normal circadian rhythm, in animals, are usually regulated from the central nervous system. But that doesn't seem to be the only regulator:

What Makes The Heart 'Tick-tock' (12/2/08)

Researchers have new evidence to show that the heart beats to its own drummer, according to a report in the December issue of the journal Cell Metabolism. They've uncovered some of the molecular circuitry within the cardiovascular system itself that controls the daily rise and fall of blood pressure and heart rate. The findings might also explain why commonly used diabetes drugs come with cardiovascular benefits, according to the researchers.

"This is the first study to demonstrate that a peripheral clock plays a role in the circadian rhythm of blood pressure and heart rate," said Tianxin Yang of the University of Utah and Salt Lake Veterans Affairs Medical Center.

While much progress has been made over the years in understanding the body's master clock in the brain, the new study offers one of the first glimpses into the biological function of peripheral clocks in maintaining the circadian rhythms of tissues throughout the body, the researchers said.

There has already been reason to suspect that PPAR-γ is involved in this:

Earlier studies suggested a role for the nuclear receptor called peroxisome proliferator-activated receptor-γ (PPAR-γ) in clock function. PPAR-γ is perhaps best known as the molecular target for a class of widely prescribed and effective diabetes drugs called thiazolidinediones (TZDs), including rosiglitazone (trade name Avandia) and pioglitazone (trade name Actos). Those diabetes drugs are known to come with a side benefit: they have protective effects on the cardiovascular system.

The new research shows that the circadian variation in heart rate and blood pressure is disrupted simply by eliminating PPAR-γ from cardiovascular cells. The elimination was effected by working with two strains of mice in which suitable genes had been knocked out:

The researchers found that both knockout strains showed a significant reduction of circadian variations in blood pressure and heart rate. .... The mice also showed declines in variation of norepinephrine/epinephrine in their urine—a measure of activity of the sympathetic nervous system, which plays a key role in heart rate and blood pressure.

The animals had impairments in the rhythmicity of the major clock genes, including Bmal1, a transcription factor that controls the activity of other core clock components, they report. By treating the mice with the diabetes drug rosiglitazone, they were able to increase the activity of Bmal1 in the animals' aortas, the largest artery of the body that issues blood from the heart, and further study showed that the core clock gene is directly controlled by PPAR-γ.

What, more precisely, is the role of PPAR-γ in affecting rhythmicity? Apparently the effect is indirect, due to its abillity to activate Bmal1, which is known to be an important clock protein. This is indicated because rosiglitazone seems to be able to compensate for missing PPAR-γ.

Interestingly, other recent research has shown that the sirtuin protein SIRT1 also affects Bmal1. (See here.) this may be significant, since SIRT1 has gene-silencing effects that depend on nutritional factors.

What other processes is PPAR-γ involved with? Better-known than its effect on cardiovascular circadian rhythm is its role in fatty acid storage and glucose metabolism, and hence its connection with diabetes. But we'll have to look at that another time.

Further reading:

Protein Found to Set the Heart's Cadence (12/2/08) – Science News article

Tags: circadian rhythm

Recommended older posts

Is DNA Repair A Substitute For Sex?

The amino acid chirality mystery

Black holes exist

TOR signaling and cancer

Induced Pluripotent Stem Cells II

Consciousness, free will, etc.

More about alternative energy

Memory and BDNF

A couple of things about memory

Cheating

Embryonic stem cells and Klf4

Alternative energy sources

Induced pluripotent stem cells

MicroRNA and cancer

Human gene count drops again

Cancer and Myc

Top science stories of 2007

Economics 101

FoxO transcription factors

P53, a versatile gene

Ultra-high energy cosmic rays

The discovery of sirtuins, part 2

The discovery of sirtuins, part 1

Sirtuin proteins

Religion and war

HDAC drugs for autoimmune diseases

A fear of pheromones

Dwarf galaxies

Digital storage technology

Resveratrol

Adiponectin

Beyond Einstein redux

Petascale computing and beyond

Memory and long-term potentiation

Inflammation, IL-6, NF-κB, and disease

Update on mirror neurons

Stress and weight gain

Origins of brains as sensory organs

Health benefits of omega-3 fatty acids

Axions

Histone deacetylase enzymes

Metering gene expression

How cells can cheat death

RNA tails and gene expression

Skip Buying Extra Stuff And Take A Vacation Instead

Modular arithmetic

Groups and rings

MicroRNA

Diophantine equations

Cytokine storms

Numbers - rational and irrational, real and imaginary

A brief history of algebra

T cells

Gamma-ray burst surprises in 2006

Art, fractal and otherwise

Clues to the origins of life

RNA activation of genes

Stuff I forgot to mention about memory

Alternative splicing

Improving your memory

Beyond Einstein

Inflation and the cosmic microwave background

Why blue-eyed men prefer blue-eyed women - but not vice versa

Big bang theory saved

Fertile women dress to impress

Thanks for the memories

Women become sexually aroused as quickly as men

Self-resurrecting bacteria

The Poincaré conjecture II

The Poincaré conjecture I

Longevity genes and cancer

Unsolved problems in mathematics

Is the singularity near?

The wind from a black hole

Reversing the cell division cycle

Quadratic forms

Mirror neurons

Cancer genes tender their secrets

The Literary Animal