Brain Plays Key Role In Diabetes Therapy

One of the complexities of understanding diabetes (recent discussion here) is that the body's reaction to insulin is rather variable. If too little insulin is available, glucose is not well absorbed from the bloodstream. Too much glucose in the blood (hyperglycemia) can lead to serious complications such as cardiovascular disease, nerve damage, kidney failure, and glaucoma. On the other hand, too much insulin can cause the body to become resistant to insulin's effects, which again leads to hyperglycemia.

So the body needs to need to be regulate insulin levels fairly closely. It now appears that the brain is part of a properly functioning insulin reglatory system.

Brain Plays Key Role In Diabetes Therapy

[T]he researchers examined the brain's effect on insulin sensitivity in rats with diabetes due to a lack of so-called pancreatic beta cells, which normally secrete insulin. The rats' condition mimics type I, or juvenile, diabetes, a form of the disease that begins in childhood most often due to autoimmune destruction of cells in the pancreas, which leave the organ unable to produce insulin.

The researchers infused the brains of the diabetic rats with a chemical that limits the function of an enzyme involved in the normal insulin response before injecting the animals with the hormone. Without the normal brain response to insulin, the hormone therapy's efficacy for reducing blood sugar fell by about 35%, Schwartz said. Furthermore, they found that gene therapy interventions designed to increase the brain's insulin response heightened the animals' response to therapy about 2-fold.

Tags: diabetes, insulin, medicine

Hubble panoramic view of Orion Nebula

Hubble panoramic view of Orion Nebula reveals thousands of stars (1/11/06)

In one of the most detailed astronomical images ever produced, the NASA/ESA Hubble Space Telescope is offering an unprecedented look at the Orion Nebula. This turbulent star-formation region is one of astronomy’s most dramatic and photogenic celestial objects.

The crisp image reveals a tapestry of star formation, from the dense pillars of gas and dust that may be the homes of fledgling stars to the hot, young, massive stars that have emerged from their gas-and-dust cocoons and are shaping the nebula with their powerful ultraviolet light.

Orion Nebula - click for 1280×1280 image

The stem cell research scandal

With relatively few exceptions, most of the major news in science, including genuine breakthroughs, gets little coverage in the media. Some topics, of course, do make news -- things like major space missions, health crises (AIDS, avian flu), and politically controversial topics (evolution, climate change, stem cells).

But scientific scandals involving faked research hardly ever fail to draw attention, especially when related to topics already in the news -- like stem cells. Is it possible that the relative rarity of such events (think of "man bites dog") has something to do with all the commotion? Major scandals don't seem to come up as often as once a year, worldwide.

In any case, one does not want to excuse scientific malfeasance. It's bad for everyone concerned. It hurts the reputations of most parties that are involved, and the reputation of science itself. And science is an area of human activity in which reputation is of rather more than averaage importance.

However, major scandals also tend to evoke somewhat melodramatic overreaction. I think the following is in that category:

Scandal over Stem-Cell Research / A hospitable environment for scientific fraud

It's an opinion piece by Spyros Andreopoulos, who is credited as "director emeritus of the Office of Communication and Public Affairs at the Stanford University School of Medicine". Some of his other writings tend to train their critical focus on scientists and scientific institutions. This, for example, argues that "We need to improve scientists' understanding of the public." That's certainly a reasonable point, but not one to get into right now.

The scientific enterprise as a whole needs critique just as much as individual scientific research. But one may also disagree about the details, so let's look at Andreopoulos' take on the stem cell scandal.

South Korean scientist Dr. Hwang Woo Suk has been regarded as one of the most brilliant researchers in his field. So why would he concoct an elaborate hoax in the pages of Nature, as his critics claim, that he had cloned a dog, and written in Science that he had created human embryonic stem cells matched to patients who might benefit from them?

Since the time that was published, the dog cloning claim has been verified as correct, but of course all the other claims have been shown to be faked. So the important questions include why the fakery was perpetrated.

Perhaps the answer is nothing more than ego. But another explanation could be the culture of science itself, which puts a premium on originality, on being first to make a scientific discovery. Being second, or third, hardly counts at all.

Stop right there. In a causal sense, Andreopoulos is most likely correct with respect to Hwang Woo Suk and the rather small number of others who have been responsible for similarly egregious instances of fakery.

But consider what he's saying, which is that a very competitive and intellectually challenging profession puts great pressure on individuals to succeed and even excel to the limits of their ability -- and sometimes beyond. This isn't any different from other professions like law, politics, journalism, medicine, and (especially?) business. Fraud and scandal are no strangers to any of those other professions either. I would dare to say that the levels of fraud found in science are a lot lower than in any other of those professions.

Competitiveness and striving are part of human nature, and affect large percentages of individuals in almost any type of endeavor. But there also would seem to be some positive correlation between the prestige of a profession and the degree of competitiveness one finds in it. This is understandable -- the larger the rewards, the harder people will work for them. That does produce undesirable side-effects. Occasional breaches of ethics -- and sometimes outright fraud -- are one kind. A different kind is the toll on the quality of life experienced by people who are caught up in the rat race to succeed.

Yet competitiveness within a profession has its positive effects as well. One is obviously the fact that honors and rewards (in whatever form -- wealth, power, self-esteem, or even a more active sex life) motivate people to produce the best results they can. Science certainly can't do without such motivating factors any more than the other prestige professions.

But there's also another positive effect, which benefits the scientific endeavor itself as much as those who win in competition. Science, more than most professions, needs to have a way to rate individuals in terms of the reliability and authority of their accomplishments. Reputation is all-important in science. In any given field, it is vital to recognize the individuals who have the most correct and accurate grasp of reality. And so science provides honors and rewards to identify the best and brighetest. These rewards come in a variety of forms -- academic tenure at top institutions, publication in the most prestigious journals, top scores in citation indexes, membership in National Academies and the like, conference speaking invitations, prizes and awards (including Nobels and numerous ones less famous). Most everyone in any given field knows, by such tokens, who the "alphas" are, since these awards are visible to anyone who's paying any attention at all.

Of course, this is elitism. It offends our egalitarian sensibilities. But science simply can't do without such things. Life is too short to read anything but the best of the literature in any particular field. Nobody can read it all. There need to be indicia of what's best. These reputational rewards which are part of the social system of science are the scientific community's method of voting for those of its members who seem most deserving of attention -- and, of course, future research grants.

It's not a perfect system. But nothing's perfect in human social arrangements. Votes are not at all weighted equally. Those who have already achieved the hightest rankings have the most heavily weighted votes. But would any other system work much better? In an egalitarian system, how would you identify people not among your immediate acquaintances who are the most deserving of having their papers read? Or most deserving of very scarce research funds? Or who run the research group that you most want to join because it has the best success prospects. These are not trivial matters.

So the bottom line is, there are limited quantities of rewards available, it's a zero-sum game, hence people compete fiercely. How could it be any other way?

It's always possible there could be another way, or at least improvements. And it would be nice if sociologists of science would apply scientific method to the fullest extent in order to determine, first, how the reward systems of science actually operate, and, second, where and how some mechanisms are "better" (in some sense) than others. With such actual information, we'd then be in a better position to make decisions about improvements.

But we've drifted quite a way from Andreopoulos' article. Let's get back to that. He has further remarks on why fakery occurs:

The causes of fakery in science are a matter of debate. Its incidence, whether episodic or widespread, could be due to individual aberrations. In "The Great Betrayal: Fraud in Science," author Horace Freeland Judson blames it on inadequate mentoring of scientists, veneration of a high volume of published research, chases for grants and glory and political pressures for practical results.

These are valid points, but in light of what I wrote above, I think that they miss the forest for the trees. Competitiveness is both inevitable and beneficial. Ideas for remediation ought to be aimed at detecting and controlling fraud and abuses rather than reigning in competition.

In a quite different sphere, that of business, competition is regarded as an almost unalloyed virtue -- provided that fraud and abuses are controlled. Anti-competitive phenomena such as monopolies and cartels are seen as undesirable (at best) or evil (except by would-be monopolists themselves). Mechanisms apart from free markets themselves -- such as government regulation -- for controlling fraud and abuse are also regarded as necessary evils (at best). But even the most ardent libertarians realize that fraud is a significant enough problem that we need a legal system to control it.

I'm not the world's most ardent libertarian, but I don't think it's a big stretch to take a similar attitude in science for controlling fraud and abuse. Respect and encourage competition, but have "appropriate" control mechanisms in place. That would limit the debate somewhat to identifying such mechanisms.

What does Andreopoulos suggest?

[A]nother probable cause contributing to lapses in individual behavior could be the scientific journals themselves. I have long suspected that the insidious rise of publication costs and fierce competition among journals may have contributed a hospitable environment for fraud.

He then devotes most of the remainder of his essay to dissecting the problem with journals and offering advice to journal editors and publishers on how to reform themselves.

I'm going to mostly skip over that for a simple reason: There is a tectonic shift underway in the journal publishing business. At the same time as publication costs and prices are ballooning -- to the point where academic libraries must continually cut back on their subscriptions -- technology is threatening to transform the whole academic publishing business beyond recognition. We now have "open access" journals like those of the Public Library of Science. In physics (and allied fields like mathematics and computer science) we have arXiv.org. And we have the elephant in the room -- Google (and a few similar efforts), with things like Google Scholar and Google Book Search.

In 10 years, the journal publishing business most probably won't look anything like it does now, so trying to "reform" it is very much trying to aim at a fast-moving target. On the other hand, some of the new electronic forms of publishing, such as arXiv, have much lower standards of peer review than present journals. That's certainly a worrisome matter as far as fraud is concerned.

So, to finally return to the consideration of dealing with fraud, do I have any recommendations (not that anyone's probably going to pay much attention)?

What I would say is this: At the grave risk of seeming too complacent, I think science's fraud control system is already pretty good, in spite of this nasty stem cell scandal. Human social systems are nothing if not imperfect. A great deal of "scientific method" consists of social mechanisms for controlling imperfections (of which ordinary fraud is only one kind) in human acquisition and cataloging of reliable knowledge about the real world. The method fails to the extent that any errors creep in, regardless of whether they are due to fraud or simply sloppy technique. It's amusing how even careless or fraudulent practices have occasionally managed to yield good science. One example is Robert Millikan's measurement of the electron's charge. Another is Edwin Hubble's measurement of the Hubble constant that describes the expansion of the universe. Because of erroneous assumptions about the intrinsic brightness of certains types of stars, which Hubble used to estimate distances, the value he originally estimated for the Hubble constant was off by a factor of seven. Even though it was decades before the value of this constant was better known, the general conclusions about the evolution of the universe were pretty much on target.

There are several reasons that science is pretty effective at self-correction. One of these lies in the very competitiveness of the process. In addition to encouraging fraud, which it can do, it is even more effective at rooting out fraud for the same reasons. For better or worse, one of the best ways for a scientist to compete is to demonstrate that some other scientist is wrong. And the more well-known and influential a scientist is, the more points can be gained by successfully discovering an error in his/her work. This can be very confusing to outside observers. A big news story may come out one month that receives attention in the popular press. And then a few months later someone comes along with evidence that the earlier results are wrong. (This happens a lot with research in health and medicine, to say nothing of the social science, but no branch of science is immune.)

It's instructive to look at how rapidly self-correction actually happens. Hwang Woo Suk's first paper found to be fraudulent was published in March 2004, and the second more important (but faked) paper in May 2005. The first public reports of problems appeared in November 2005. Hwang resigned his university post on December 23, 2005, and finally on January 10, 2006 it was announced that both the 2004 and 2005 stem cell papers were based on fabricated data. Although it took more than a year and a half for doubts to be raised, less than two months elapsed before the case was effectively closed. Hwang has admitted that mistakes were made, but not accepted full guilt. (Criminal charges may still be filed.)

Compare that with how slowly scandals in other fields are resolved. Take business for example, say the Enron and Worldcom scandals. Controversy swirled around Enron for months before it declared bankruptcy in late 2001. Top offcials of Enron (Kenneth Lay and Jeffrey Skilling) still haven't admitted guilt and have not yet gone on trial for their (alleged) malfeasance. The Worldcom case was similar. It declared bankruptcy in July 2002 after the company had been under suspicion of inflating its assets for a year and a half. The company's CEO (Bernard Ebbers) never admitted guilt, but was finally convicted of fraud, and sentenced to prison in July 2005.

Or how about politics. The Watergate scandal dragged on for two years from the break-in to Nixon's resignation. It was constantly in the news. All that time most of the guilty parties continued to protest their innocence. Today we have the Abramoff and DeLay scandals (among others) with the same pattern. Hardly anyone but the lowlier figures admit guilt. Resistance to release of relevant information is found at every turn. Only lengthy judicial processes have much chance of sorthing it all out. But religion seems to provide the worst example -- the Catholic Church and its pedophile priests. The Church has known about child sexual abuse incidents for at least two decades, and done little more (before public exposure) than move the perpetrators around. One Cardinal of the Church (Bernard Law), in particular, was notorious for negligence in taking action. Although he resigned as Cardinal in December 2002, the Church subsequently rewarded him with cushy appointments in the Vatican.

It's clear enough why the wheels of justice turn pretty slowly in business and political scandals. In the case of business, the people immersed in scandal are generally quite wealthy and able to drag things out with talented teams of lawyers. In politics, those involved in a scandal generally have friends (and quite possibily accomplices) in very high places, who can directly affect law enforcement and legal proceedings, as well as the release of crucial information. Scientists charged with malfeasance generally have none of these advantages, so once wrongdoing is suspected, justice can move swiftly to investigation, verification, and correction.

So let's get back to science. Another social mechanism it uses to deter fraud is the way young scientists are socialized. Basically, they are on probation from the time they enter graduate school until they receive academic tenure -- if they ever do. Until a young scientist manages to establish a good reputation, the onus is always on him or her to establish credibility and rigorously justify his/her research results. Young scientists have very little power compared to senior scientists (like Hwang). They just don't have the means to coerce others to help fabricate results. And in the present time, most science is very much a team effort.

Not to seem too idealistic about it, but if that weren't enough, the culture of science continually reinforces the idea that science is all about the search for truth. Fraud is simply antithetical to that ideal. In contrast, the culture of business and politics is much more about misleading marketing and cunning propaganda and what one can get away with rather than what is true. That's just the obvious (but sad) fact of the matter. And in contrast to science, business and politics (and law and other professions) have a culture where it's much more every man or woman for themselves, rather than a team effort.

We shouldn't be complacent about scientific quality, ever. I don't want to whitewash the situation. Maybe the take-away from all this is that we could certainly try to understand the sociology of science better. What factors make it work as well as it seems to actually do? What factors effectively deter deviance from the norms of good scientific content? What factors, on the other hand, induce deviance and abuse and fraud.

So maybe part of the answer is more systematic application of science to itself.

Tags: stem cell scandal, scientific scandals, sociology of science

The Cancer Genome Atlas

The recent article here on current research into cancer noted in passing a new initiative of the NIH to produce an atlas of the whole "cancer genome".

NIH Launches Effort to Explore Cancer Genomics

The National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both part of the National Institutes of Health (NIH), today launched a comprehensive effort to accelerate our understanding of the molecular basis of cancer through the application of genome analysis technologies, especially large-scale genome sequencing. The overall effort, called The Cancer Genome Atlas (TCGA), will begin with a pilot project to determine the feasibility of a full-scale effort to systematically explore the universe of genomic changes involved in all types of human cancer.

Although the focus of the project is on cancer, it is actually much more ambitious than the original Human Genome Project, because cancer actually represents at least 200 distinct diseases, and the individual cells within a single tumor can have a variety of different mutations in their genes.

Cancer is now understood to include more than 200 different diseases. In all forms of cancer, genomic changes -- often specific to a particular type or stage of cancer -- cause disruptions within cellular pathways that result in uncontrolled cell growth. TCGA will delve more deeply into the genetic origins leading to this complex set of diseases, and, in doing so, will create new discoveries and tools that will provide the basis for a new generation of cancer therapies, diagnostics, and preventive strategies.

What this means is that the DNA of many individual cells will need to be sequenced. However, the problem can be somewhat simplified by being selective about what genes will be sequenced. In addition, the pilot phase of the project will concentrate on a limited number of types of cancer. Since a common characteristic of most cancers is that some normal DNA repair functions are disabled, the genome of a cancer cell is said to be "unstable", and gene mutations may accumulate rapidly. The pilot phase will therefore search for types of cancer that have the least amount of variability in its cells.

Although the task of building The Cancer Genome Atlas is daunting, one has to recall the experience of the original Human Genome Project. That project was completed sooner than expected and at less expense, because the technology of DNA sequencing advanced much more rapidly than expected. This occurred in large part because of the entry by J. Craig Venter's Celera Genomics with a parallel project to sequence the genome, in competition with the government's original project. There's no reason to think that sequencing technologies can't continue to improve rapidly to cope with the complexity of the task.

The ultimate rationale for the project, of course, is the hope that by knowing as much as possible about the kinds of genetic abnormalities which lead to cancer it will be possible to compensate for or counteract these abnormalities. Already the knowledge in a few cases of how particular cancers develop has made it possible to create drugs which interfere with the effects of the abnormalities, and thereby halt or even reverse the progress of the cancer. For example:

Genetic mutations linked to breast cancer, colon cancer, melanoma, and other cancers already have led to diagnostic tests that can point to the most effective intervention. Recent discoveries in cancer genomics have helped to identify several treatments that work by targeting cancer cells with a specific genetic change, such as Gleevec®, a drug for chronic myeloid leukemia and gastrointestinal stromal tumors, and Herceptin®, a drug for one form of breast cancer.

Take CML as an example. It involves a fairly dramatic defect in which parts of two genes from separate chromosomes become combined, and the gene that results produces a hybrid protein (called bcr-abl) which is a very active "tyrosine kinase". That's a type of enzyme which acts on cellular receptor proteins to promote cell division, and the resulting excessive cell division yields CML. Gleevec, which has the scientific name imatinib, is a molecule which binds to the bcr-abl protein and blocks its kinase activity. It turns out that imatinib does not interfere harmfully with normal tyrosine kinases, and so it has no detrimental effects on noncancerous cells lacking the abnormal bcr-abl protein.

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Additional links on the Cancer Genome Atlas:

The Cancer Genome Atlas - project home page

NIH Launches Cancer Genome Project - Washington Post

New Genome Project to Focus on Genetic Links in Cancers - New York Times

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Tags: cancer, cancer genome atlas, medicine, biotechnology

High-fat diet and type 2 diabetes

Diabetes (which appears in several different forms) has been a difficult disease to understand in detail. The main diagnostic indication of diabetes is poor regulation of levels of glucose in the blood -- either too much glucose (hyperglycemia) or too little (hypoglycemia). From these conditions (if not treated) follow various other seriously harmful effects, including arterial disease, nerve damage, kidney failure, damage to the eyes, and gangrene in the extremities.

Insulin is the hormone which is most responsible for proper regulation of glucose levels. The body produces insulin only in the beta cells of the pancreas. Its primary function is to get glucose out of the blood by causing it to be taken up by cells, where the glucose is either stored or used for energy production.

This process can fail in two different ways. In the first case, a persistent excess of glucose can cause overproduction of insulin by the beta cells if those cells themselves are undamaged. This in turn leads to insulin resistance, in which other body cells do not take up glucose properly even in the presence of insulin. A common cause of this is excessive amounts of carbohydrates in a person's diet.

In the second case, not enough isulin is proudced, either because the beta cells have been damaged or else because they are inhibited in some way. One way that beta cells can actually be destroyed is in an autoimmune condition. Typically, but not necessarily, this occurs before adulthood, and so this has been called juvenile onset diabetes or (more commonly now) type 1 diabetes.

Diabetes that occurs (usually in adulthood) without major damage to beta cells is referred to as type 2 diabetes (formerly called adult onset diabetes). If this type isn't the result of insulin resistance (the first case above), it is due to underproduction of insulin in the beta cells. This circumstance has been the hardest to understand. Sometimes it appears to be genetic, but may also be triggered by obesity and/or a high-fat diet. New research is beginning to illuminate how this comes about.

Researchers Discover Mechanistic Link Between High-Fat Diet and Type 2 Diabetes

Howard Hughes Medical Institute researchers have discovered a molecular link between a high-fat, Western-style diet, and the onset of type 2 diabetes. In studies in mice, the scientists showed that a high-fat diet interferes with a genetic mechanism they discovered that promotes insulin production, resulting in the classic signs of type 2 diabetes.

In an article published in the December 29, 2005, issue of the journal Cell , the researchers report that knocking out a single gene encoding the enzyme GnT-4a glycosyltransferase (GnT-4a) disrupts insulin production. Importantly, the scientists showed that a high-fat diet suppresses the activity of GnT-4a and leads to type 2 diabetes due to failure of the pancreatic beta cells.

The enzyme GnT-4a was suspected of being involved in the problem because it is highly expressed in the pancreas. The same enzyme is also found in mice, so researchers studied mice in which the gene for GnT-4a was disabled.

The studies showed that GnT-4a has an important effect on another protein, called Glut-2, which is important in beta cells. Glut-2 normally occurs on the surface of a beta cell, and it enables the cell to sense the amount of glucose in the blood. The cell produces insulin in proportion to the blood glucose level. What GnT-4a does is to attach a sugar-like molecule called a glycan to Glut-2 -- a process called glycosylation. If there's not enough GnT-4a, the process doesn't occur, and Glut-2 is unable to situate on the beta cell membrane, which makes the cell unresponsive to glucose, which inhibits insulin production. It was already known that a deficiency of Glut-2 on beta cell surfaces occurs in patients with type 2 diabetes.

This fact alone indicates why diabetes can be a genetic condition: If both parents have diabetes as a result of defective GnT-4a genes, their offspring may have the same problem. (It would be a recessive trait.)

But what was really interesting was that the researchers found that when mice with normal GnT-4a genes were fed a high-fat diet, the levels of GnT-4a enzyme were also decreased. Somehow a high-fat diet inhibits the expression of GnT-4a genes, but the exact mechanism is still not clear.

As far as obesity is concerned, it's often the result of a diet that is too high in fat, but it's not clear whether obesity per se also affects GnT-4a. So it seems still undetermined whether the association of obesity with diabetes is because the two conditions have a common cause (too much fat), or whether something extra is going on.

But in any case, there's now more evidence that high-fat diets are not a good thing.

Tags: diabetes, health, medicine, insulin

Cartwheel galaxy

Cartwheel Galaxy Makes Waves in New NASA Image

A new image from NASA's Galaxy Evolution Explorer completes a multi-wavelength, neon-colored portrait of the enormous Cartwheel galaxy after a smaller galaxy plunged through it, triggering ripples of sudden, brief star formation.

Cartwheel galaxy - click for 600×600 image

More information: here, here

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

Stellar Snowflake Cluster

Stellar Snowflake Cluster

Newborn stars, hidden behind thick dust, are revealed in this image of a section of the Christmas Tree Cluster from NASA's Spitzer Space Telescope, created in joint effort between Spitzer's Infrared Array Camera (IRAC) and Multiband Imaging Photometer (MIPS) instruments.

The newly revealed infant stars appear as pink and red specks toward the center of the combined IRAC-MIPS image (left panel). The stars appear to have formed in regularly spaced intervals along linear structures in a configuration that resembles the spokes of a wheel or the pattern of a snowflake. Hence, astronomers have nicknamed this the "Snowflake Cluster."

NGC 2264 – click for 516×715 image

More information:

Spitzer Spots Stellar Snowflake on the 'Christmas Tree Cluster'
Spitzer Unveils Infant Stars in the Christmas Tree Cluster

Young stellar clusters

The Cosmic Christmas Ghost (12/25/05)

ESO PR Photo 42a/05 shows the area surrounding the stellar cluster NGC 2467, located in the southern constellation of Puppis ("The Stern"). With an age of a few million years at most, it is a very active stellar nursery, where new stars are born continuously from large clouds of dust and gas.

The image, looking like a colourful cosmic ghost or a gigantic celestial Mandrill [1] , contains the open clusters Haffner 18 (centre) and Haffner 19 (middle right: it is located inside the smaller pink region - the lower eye of the Mandrill), as well as vast areas of ionised gas.

The bright star at the centre of the largest pink region on the bottom of the image is HD 64315, a massive young star that is helping shaping the structure of the whole nebular region.

NGC 2467 - click for 1280×1280 image

Top science news stories of 2005

This is the time of year that everyone in the news business offers an opinion on the top stories of the year, so we're not going to be any different.

Science Magazine selected "Evolution in Action" as the year's top story.

Equipped with genome data and field observations of organisms from microbes to mammals, biologists made huge strides toward understanding the mechanisms by which living creatures evolve.

To round out the top 10, the runners-up were:

• 2. Planetary probes - missions to Mars, Saturn and its moons, and others
  
• 3. Plant development - molecular biology of flowers
  
• 4. Violent neutron stars - magnetars and short-duration gamma-ray bursts
  
• 5. Genetics of brain disease - schizophrenia, Tourette syndrome, dyslexia
  
• 6. Earth's differentiation - meaningful differences between earthly and extraterrestrial rocks
  
• 7. Potassium channels - molecular structure of an essential component of nerve and muscle cells
  
• 8. Climate change - a crescendo of evidence that it's real
  
• 9. Systems biology - understanding cells as complex systems
  
• 10. ITER - a site for the International Thermonuclear Experimental Reactor is finally chosen
  

We don't disagree with these choices, but our own list is mostly different, if only because it's limited to stories we have written about (or plan to soon). In the following list, there are references to some (but not all) of our relevant articles.

1. Accelerating progress on cancer - here, here, here, here
   
2. Climate change is real - here, here
   
3. Gamma-ray bursts - here
   
4. Dark matter and dark energy - here, here, here, here, here
   
5. Gene expression and epigenetics - here, here, here
   
6. Star formation - here, here
   
7. Video conferencing - here
   
8. Quantum computing - article coming real soon now
   

Other lists of top science stories for 2005

Top Science Stories of 2005 - Scientific American

Review of the year - Physics World

The Top Physics Stories for 2005 - Physics New Update

NewScientist.com's top 10 news stories of 2005

2005: The year in astronomy - New Scientist

2005: The year in the solar system - New Scientist

2005: The year in biology and medicine - New Scientist

Most Overlooked Science and Tech Stories of 2005 - by RJ Eskow - also here

What is your dangerous idea?

Edge has posted its Annual Question for 2006. This year it's a real doozy: What is your dangerous idea?

The history of science is replete with discoveries that were considered socially, morally, or emotionally dangerous in their time; the Copernican and Darwinian revolutions are the most obvious. What is your dangerous idea? An idea you think about (not necessarily one you originated) that is dangerous not because it is assumed to be false, but because it might be true?

John Brockman -- founder of Edge, literary agent par excellence for science writing, and agent provocateur working on behalf of what he calls the Third Culture -- provides background about Edge and the Annual Question at this article on the Huffington Post. (There are many interesting replies to this article.)

There are 117 essays written in answer to this question, by such people as Steven Pinker (whom Brockman thanks for suggesting the question), George and Freeman Dyson, Brian Greene, Martin Rees, Leonard Susskind, Craig Venter, Richard Dawkins, Daniel Dennett, Ray Kurzweil, Lynn Margulis, Lee Smolin, Jaron Lanier, Stewart Brand, Rudy Rucker, Gregory Benford, and... well you get the idea. Quite a roster. Interested yet?

It's simply impossible to pick out the most interesting ideas from the list, let alone to discuss adequately even a few of them right here, right now. Instead, of course, these questions will form inspiration for thought all year, and beyond. (Even if -- or because -- most of the essays leave plenty of room for disagreement.) As Brockman aptly puts it, quoting Ernst Mayr (shortly before his death), "It's a conversation."

An idea may be considered dangerous for several reasons. It may be an idea that one agrees with, and which one considers to be capable of having seriously destabilizing effects on the world. Or it may be an idea that one disagrees with -- but expects the same sort of effect. So one should not assume that any of the ideas suggested are actually favored by the suggester. It could be either way, though most people can't help tipping their hands.

Many who responded discussed ideas with which they themselves are closely identified. But by asking for ideas that are "dangerous", Brockman challenges everyone to contemplate ideas that are dangerous precisely because one fears they might be true -- whether or not one wants them to be true.

Putting the question this way is especially important for a simple reason: It forces thinkers to consider ideas seriously even though the truth of those ideas might be contrary to what one has invested heavily in.

This is how science should work. We should not stint on thinking about those very possibilities that contradict our favorite beliefs. At least, the thinking process will better equip us to better defend and substantiate those beliefs. We must be careful not to hold a belief simply because we want it to be true.

I expect to examine many of these ideas here over the coming months. This is more than just a little food for thought. It's a substantial smörgasbord.

Just to give a taste of how this can go, here's one comment that struck me, from Haim Harari:

When, in the past two years, Edge asked for brilliant ideas you believe in but cannot prove, or for proposing new exciting laws, most answers related to science and technology. When the question is now about dangerous ideas, almost all answers touch on issues of politics and society and not on the "hard sciences". Perhaps science is not so dangerous, after all.

Perhaps it's not the science and technology we humans produce that is the greatest threat to our continued existence. Maybe it's us. We're our own worst threat. We have met the enemy, and it is us.

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Already (and unsurprisingly) there have appeared discussions of Edge's question for 2006. Here are a few of them:

Not Even Wrong: What is Your Dangerous Idea?

Cosmic Variance: Dangerous, stupid, or simply dishonest?

Luboš Motl's Reference Frame: Dangerous ideas

The Slimmer List of Edge Dangerous Ideas

Other reports:

Gene discoveries highlight dangers facing society

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Tags: dangerous question