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Cancer and Myc

Saturday, January 26, 2008

Myc is a gene that has been studied for over 20 years and is found to be overexpressed in many human cancers. The protein it codes for (which for simplicity we'll also refer to as Myc) is a transcription factor, like members of the FoxO family, which means it can enable or disable the expression of many other genes. How many? The estimate is about 15% of all human genes. Since there are at least 20,000 genes, the number regulated by Myc is 3000 or more. That's a lot of leverage.

Obviously, Myc is essential for cell function or it wouldn't have so much influence. The biological functions Myc affects include cell proliferation, cell growth, apopotosis, cell differentiation, and stem-cell self-renewal. It is possible for a single transcription factor to have such varied effects because other transcription factors (coactivators or corepressors) must also be present in order to activate or repress the expression of some specific other gene. That is, the expression of any particular gene depends on the presence (or absence) of a particular set of transcription factors.

Since Myc affects the functions mentioned above, it's hardly surprising to find that Myc is overexpressed in many cancers. In such cases, the difference between a normal cell and a cancer cell is the overexpression of Myc in the latter and possibly the abnormal presence of other coactivators or corepressors. The result in a cancer cell is excessive proliferation and/or avoidance of cell death by apoptosis.

Surely you've wondered why development of cancer therapies has taken so long. A large part of the reason is that so many genes involved in cancer interact with so many other genes that have essential functions. So it's not possible to interfere with the cancer-related genes without disrupting vital biological functions elsewhere in the body.

The expression of Myc itself is triggered by signals that are usually external to the cell and normally serve to stimulate cell growth and proliferation when needed, as in lymphocyte production, normal growth, or wound healing. Such signals are called mitogens, because they can initiate mitosis. Wnt, Shh, and EGF are mitogens that can lead to Myc expression.

It is probably almost impossible to hope to combat cancer by directly affecting Myc or its related mitogens, because all of these have essential normal functions themselves. Instead, anti-cancer research needs to examine how Myc may be overexpressed or complemented in harmful ways by other transcription factors.

One promising line of research involves cancer stem cells – cells that, like normal stem cells, can proliferate and differentiate into other cell types, and that also carry cancer-causing mutations. There is now thought to be a "signature" consisting of 11 genes that may be characteristic of cancer stem cells. One of these genes has an effect on Myc:

Scientists Uncover Role Of Cancer Stem Cell Marker: Controlling Gene Expression (1/18/08)
Scientists at Jefferson's Kimmel Cancer Center in Philadelphia have made an extraordinary advance in the understanding of the function of a gene previously shown to be part of an 11-gene "signature" that can predict which tumors will be aggressive and likely to spread. The gene, USP22, encodes an enzyme that appears to be crucial for controlling large scale changes in gene expression, one of the hallmarks of cancer cells. ...

In one example, they looked at the relationship between MYC and USP22. MYC, which is among the most commonly overexpressed genes in cancer, encodes a protein that controls the expression of thousands of other genes. The scientists showed that USP22 is a critical partner of MYC and that by depleting cells of USP22, they could prevent MYC from working properly, stopping it from inducing the invasive growth of cancer cells.

It turns out that Myc affects not only 3000 or so ordinary genes, but also a number of DNA sequences that code for microRNA – and some of these microRNAs play an important role in suppressing cancer. In fact, Myc can stop the production of at least 13 microRNAs:

Silencing Small But Mighty Cancer Inhibitors (12/12/07)
Researchers from Johns Hopkins and the University of Pennsylvania have uncovered another reason why one of the most commonly activated proteins in cancer is in fact so dangerous. As reported in Nature Genetics recently, the Myc protein can stop the production of at least 13 microRNAs, small pieces of nucleic acid that help control which genes are turned on and off.

Furthermore, additional observations showed that some of these microRNAs have an inhibiting effect on cancer, a striking result in itself:
[I]n several instances, re-introducing repressed miRNAs into Myc-containing cancer cells suppressed tumor growth in mice, raising the possibility that a sort-of gene therapy approach could be effective therapy for treating certain cancers.

Since the microRNAs repressed by Myc affect many other genes, there could be thousands of other genes indirectly affected by Myc:
"This study expands our understanding of how Myc acts as such a potent cancer-promoting protein," says Mendell. "We already knew that it can directly regulate thousands of genes. Through its repertoire of miRNAs, Myc likely influences the expression of thousands of additional genes. Activation of Myc therefore profoundly changes the program of genes that are expressed in cancer cells."

More: Researchers zero in on the tiniest members in the war on cancer (12/13/07)

Myc is actually a member of a family of genes, the Myc family. Most members of the family have similar functions. Separate members undoubtedly appeared in the course of evolution from the duplication of earlier members and later mutation. One member, called N-myc, plays a role in both normal development of the retina, as well as cancers of the retina (retinoblastoma).

Recent research has shown that N-myc seems to be responsible for the surprising fact that the retinas in all vertebrates have about the same thickness, regardless of the size of the entire animal or its eyes:

Eye Cancer Gene's Role In Retinal Development Defined (1/18/08)
"A series of complex developmental processes must be carefully orchestrated for the eye to form correctly," said Michael Dyer, Ph.D., associate member in the St. Jude Department of Developmental Neurobiology. "One important aspect of this coordination is that retinal thickness be the same, irrespective of eye size. For example, the mouse eye is about 5,000 times smaller than that of the elephant eye, but the retinal thickness in these two species is comparable."

Working with mice, the researchers found that a gene called N-myc coordinates the growth of the retina and other eye structures to ensure the retina has the proper thickness necessary to convert light from the lens into nerve impulses that the brain transforms into images.

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Top science stories of 2007

Wednesday, January 23, 2008

Well, 2007 has been over for three weeks now. Must be time to look back and figure out what happened there. Overall, I'd say it was a good year, but not a great year. Let's have a look at what others picked for the "top" stories.

Science usually makes pretty good calls, as you'd expect. Since online access is by subscription only, here's my paraphrase of their list of top "breakthroughs":

  1. Recognizing human genetic variation – in other words, there's more diversity in human DNA than expected
  2. Making pluripotent stem cells by reprogramming
  3. Closing in on the origins of ultra-high-energy cosmic rays
  4. Determining the structure of a G protein-coupled receptor (for adrenaline)
  5. Investigating transition metal oxides as an alternative to silicon for electronics
  6. Exploring the prospects of materials exhibiting the quantum spin Hall effect for realization of spintronics
  7. Understanding how asymmetric division occurs in CD4 T cells
  8. Growing ability to synthesize complex pharmaceutical and electronic compounds
  9. Adding to the evidence that memory is an important ability for imagining future events and situations
  10. Proving that it is possible (for a computer) to never lose a game of checkers against a human (or another computer)

There are some surprising developments in this list – such as the extent of human genetic diversity or (especially) the apparent ease with which cells can be reprogrammed to behave like pluripotent stem cells. But what strikes me most about the list is that not much in it gives a sense of "closure" in the way that, say, determining the genetic code or proving the Poincaré conjecture (last year's top "breakthrough") was.

Instead, what we have are a number of developments that are merely the first steps towards much more impressive things to follow. We are just beginning to understand how genetic programs actually work, especially in disease conditions and in processes like metabolism and cell division. There will be much more meaningful developments with stem cells, protein structure determination, molecular synthesis, non-silicon electronics, spintronics, and nanoscale engineering.

I suppose this is why the items in the list are called "breakthroughs".

Here's a press release from the AAAS with a synopsis of their list: Human genetic variation -- Science's 'Breakthrough of the Year' (Physorg.com)

Many other lists of top stories could be found. Here are some of them, with my somewhat jaundiced opinion of most, as well as a bit of measured praise for the less awful.

2007: A year of stunning progress in the science of life (Guardian Unlimited)
Please read this one. It's not particularly lengthy, and it will be instructive to compare it with most of the other articles summarized below. It's lucid, and not larded with fluff.

In terms of what's actually noted as key advances, it covers genetics, synthetic biology, stem cells, cloning, and regenerative medicine. And despite the title, it also covers climate change and further improved evidence of dark matter.

Year in science review: Global warming, new species (USA Today)
The quality of this list is surprisingly good, considering the source. (Scientific American should be ashamed – fat chance.) Significant items include climate change (a perennial winner), stem cells, the extremely bright supernova SN 2006gy, and the Earthlike planet of Gliese 581. As a sop to the mass-market audience for "science" the list also includes dinosaurs, vanishing honeybees, and the discovery of many new biological species, alongside the looming extinction of others.

2007 News review (NewScientist)
The main list is sparingly presented in a few brief paragraphs. The selections are a bit odd (the dangers of noise pollution? really?). But in a sidebar there's a tidy list of links to separate additional articles, allowing you to easily avoid whatever you might regard as needless tedium. What I don't quite understand is the removal of, oh maybe 75% of science, to a separate article on 2007: The year in biology and medicine.

Top 25 Science Stories of 2007 (Scientific American)
Much of this list is in the nature of tabloid-style science "journalism" – all too pathetic a reminder of what is far too widely considered to be "newsworthy" in the realm of science. Not quite as bad as the printed birdcage liner found at a supermarket checkout station, but close. Daylight saving time redefined? Some guy with TB goes on a honeymoon to Europe? Poisoned pet food? Baseball jocks on steroids? Oh, please. They forgot to mention flying saucer or Yeti sightings – surely there must have been some.

See, the problem with this is that it tends to trivialize, by association, those few stories they included which were actually important, such as climate change, stem cells (the science, not the bogus controversy), and Earthlike extrasolar planets.

Top 10 Scientific Discoveries (Time)
Fortunately, this list is shorter than Scientific American's, so there's less tabloid-style dreck in it. And what there is of that isn't quite so egregious (dinosaurs, "kryptonite", an elderly clam). This makes for a somewhat higher percentage of actual science (stem cells, human genome, supernova SN 2006gy, extrasolar planets).

But here's the depressing thing about this list. Not so much the content, which doesn't quite treat the readership as unqualified imbeciles, but rather the presentation, which treats the readership as short-attention span consumer droids who will docilely plow through separate pages for each story, replete with stock photo imagery, brief text, and delightful time-wasting banner ads and "sponsored links".

Briefly noted: Here are some more specialized or other "best of 2007" lists that don't seem to require much further comment from me. Some are good; others are..., well, just other.

Sirtuin news

Monday, January 21, 2008

Back in November we had a series of posts about sirtuin proteins. This included an overview, with a particular focus on the relevance to calorie restriction and longevity, especially in light of recent research announcements at the time. This was followed by a couple of posts (here, here) on background history.

Now is a good time to return to that thread and continue the discussion of sirtuins, because of additional related research announcements, including especially this:

Sirtris Announces Positive Results with Proprietary Version of Resveratrol, SRT501, in a Phase 1b Type 2 Diabetes Clinical Study (1/7/08)
Sirtris Pharmaceuticals, Inc. ... announced today that the Company's first product to enter the clinic, SRT501, was found to be safe and well-tolerated, and was found to significantly lower glucose in an oral glucose tolerance test conducted as part of a 28 day Phase 1b clinical study in patients with Type 2 Diabetes.

This 28-day Phase 1b study was designed to assess the safety, tolerability and pharmacokinetics of once-daily, orally administered doses of either 2.5 g or 5 g of SRT501 in patients with Type 2 Diabetes who were naive to other diabetes drug treatments. Both doses of SRT501 were found to be safe and well-tolerated, and pharmacokinetics, a measure of drug levels in the blood, were identical at days one and 28, suggesting no drug accumulation. There were no serious adverse events and no dose-related adverse events. Importantly, SRT501 showed a statistically significant improvement in an oral glucose tolerance test on day 28 at two hours and a trend towards lower fasting plasma glucose levels.

SRT501 is also being tested in patients with Type 2 Diabetes in a Phase 1b BID (twice daily administration) study and in a Phase 2a study in combination with metformin, the current first-line therapy for Type 2 Diabetes. SIRT1 is the founding member of the human sirtuin family of enzymes which control the aging process. Specifically, SRT501 acts by increasing mitochondrial activity and therefore is targeted to address metabolic diseases, such as Type 2 Diabetes.

"This is the first time that a small molecule targeting sirtuins, the genes which control the aging process, has shown efficacy in a disease of aging," said Peter Elliott, Ph.D., Senior Vice President of Development at Sirtris.

OK, this is obviously a self-promotional PR piece from the drug developer. In particular, sirtuins aren't "the genes which control the aging process", merely some of them. However, if the claims hold up under further testing, especially the one stated in the last paragraph, this is an important validation of much prior research into the effect of sirtuins on longevity as a result of action in various cellular pathways. Our previous discussions reviewed some of this research conducted on model organisms like yeast and the nematode C. elegans.

More information: Resveratrol-like drug works in humans-Sirtris (1/7/08), Sirtris Anti-Aging Drug Generates Buzz, But May Already Be Old News (1/8/08)

This drug, SRT501, has been in human clinical trials for about a year and a half already. The initial trial (called "Phase 1") involved 85 healthy volunteers and began in June 2006 (see here). Results from that trial were reported in October 2006 (see here) and demonstrated that the drug was reasonably safe and well-tolerated.

SRT501 is a small molecule drug that achieves its effects by activating the mammalian SIRT1 NAD-dependent deacetylase enzyme, which has been investigated extensively for a decade (as discussed here). The drug is essentially just a proprietary formulation of resveratrol, the well-known component of red wine that has been shown to have lifespan-extending and anti-diabetes properties in several model organisms. (See here for an extended discussion, including reports of important research announced in late 2006.) SRT501, however, is a much more practical way to take advantage of resveratrol, compared to consumption of red wine, where hundreds or thousands of bottles of wine would be needed to achieve the same effect.

Perhaps the most important result shown by this newly reported result is that SRT501 actually seems to provide measurable beneficial effects of improved glucose tolerance and reduced blood glucose levels for humans with diabetes.

SIRT1 activators which are apparently much more powerful than SRT501 are under active investigation at Sirtris and in the laboratory of Sirtris co-founder David Sinclair. This has been documented in research that was published last November:

Sirtris unveils promising, novel SIRT1 activators for treating diseases of aging (11/28/07)
In November 2006, Sirtris scientists and Sirtris co-founder, Prof. David Sinclair from Harvard Medical School, published consecutive papers in the journals Cell and Nature showing that resveratrol, a SIRT1 activator found in red wine, could reduce the impact of a high fat diet, increase stamina two fold and significantly extend lifespan of mice. Unfortunately, it was estimated that a person would need to drink 1000 bottles of red wine to obtain an equivalent dose of resveratrol. Now, scientists at Sirtris have developed SIRT1 activating molecules that are chemically distinct from resveratrol and are 1000 times more potent.

"The new drug candidates represent a significant milestone because they are the first molecules that have been designed to act on genes that control the aging process. For this reason, we feel they have considerable potential to treat diseases of aging such as Type 2 Diabetes," said Christoph Westphal, M.D., Ph.D., Chief Executive Officer and Vice Chair of Sirtris Pharmaceuticals. "The breakthrough in potency we have achieved with the novel chemical entities (NCEs) means that we can obtain the health benefits of resveratrol with a considerably lower dose."

Here's a useful professional assessment of these results: Sirtuin activators as anti-diabetes drugs, and beyond (11/29/07) More: Sirtris Drug May Slow Aging, Create 'Armstrong' Cells (11/28/07)

Additional information:

Gene Believed To Promote Long Life Linked To Cholesterol Flushing (10/12/07)
Research conducted in part by sirtuin-research pioneer Leonard Guarente has established one mechanism through which SIRT1 provides health and longevity benefits. The mechanism promotes flushing harmful buildups of cholesterol in macrophage cells of the immune systems of mice. This mechanism could explain part of the health benefits of SIRT1-activators such as resveratrol and calorie restriction.

Red Wine Ingredient -- Resveratrol -- Fights Diabetes In Mice (10/4/07)
Chinese researchers have reported that relatively low doses of resveratrol can improve insulin sensitivity in mouse cells, and they believe this effect is due to SIRT1 activation by resveratrol. Additionally, the researchers found that SIRT1 levels are reduced in insulin-resistant cells, and that increased SIRT1 activity improved insulin sensitivity

Sirtris Pharmaceuticals – Treating Disease by Modulating Sirtuins
This is a brief overview of Sirtris Pharmaceuticals drug development focus.

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School of Business confirms recipe for herd behavior

Friday, January 18, 2008

Popular opinion not always so popular
Whether you're a voter choosing the next president, a manager making policy decisions or a consumer selecting a brand, it's likely your decision is influenced by the opinions of others.

But beware: Your estimate may well be based on a lone, repetitive voice that you've mistaken for a chorus, say researchers at the University of Michigan's Ross School of Business.

Professors Stephen Garcia and Norbert Schwarz say that much like the squeaky wheel that gets the grease, a single opinion repeated often enough has nearly as much influence as one expressed by several people.

"What we think others think greatly influences our own personal thoughts, feelings and behavior," said Garcia, adjunct assistant professor of management and organizations at the Ross School. "Quite obviously, an opinion is likely to be more widely shared the more different people express it. But surprisingly, hearing one person express an opinion repeatedly also leads to the conclusion that the opinion is more widespread relative to hearing the same opinion expressed only once."

Is there any doubt about the reasons this sort of thing is studied and taught in "business schools"?

Supernova Remnants Dance in the LMC

Thursday, January 17, 2008

Supernova Remnants Dance in the LMC

The Gemini South Multi-Object Spectograph (GMOS) recently captured a dramatic image of a vast cloud complex named DEM L316 located in the Large Magellanic Cloud. The peanut-shaped nebula appears to be a single object, but the latest research indicates that it is really comprised of two distinct gas and dust clouds formed by different types of supernova explosions.

The new image reveals the intricate tendrils of gas and dust located in the remnants of the stellar explosions that created the still-expanding cloud complex. The object was first recognized in the early 1970s as a supernova remnant, a type of object that is enriched with elements created in stellar explosions. The nebula was likely created a few tens of thousands of years ago by more than one type of supernova exploding in this region of the Large Magellanic Cloud.

DEM L316 – click for 1000×1000 image

Additional information: here

Physical sciences news, 12/24/07 - 12/30/07

Tuesday, January 1, 2008

High-energy galactic objects
Objects in our galaxy that are capable of generating hard X-rays or the even higher-energy gamma-rays are quite unusual, and therefore of significant scientific interest. A European ground-based observatory known as H. E. S. S. (High Energy Stereoscopic System) is capable of indirectly detecting TeV gamma-rays. One of the sources it has found, designated as HESS J1837-069, has also been detected by the Japanese Suzaku satellite X-ray observatory, and is suspected to be what is called a "pulsar wind nebula". A similar object, HESS J1614-518, which is the brightest extended TeV gamma-ray source discovered in the H. E. S. S. galactic plane survey, has also been observed as a weak X-ray source by Suzaku.

Mysterious Cosmic Powerhouses Explored
Discovery of Extended X-Ray emission from the unidentified TeV source HESS J1614-518 using the Suzaku Satellite
The INTEGRAL - HESS/MAGIC connection: a new class of cosmic high energy accelerators from keV to TeV

X-rays from rotating radio transients
Compact objects first known only by periodic short bursts of radio-frequency photons have been suspected to be rotating neutron stars and are called "rotating radio transients". Periodic X-ray bursts occurring much more frequently from one such object (J1819-1458) have been detected by the XMM-Newton satellite X-ray observatory, and they support the identification of the object as a neutron star.

XMM-Newton Detects Pulsed Heartbeat Of A Weird New Type Of Star
Pulsed Heartbeat Star
Discovery of Pulsations and a Possible Spectral Feature in the X-ray Emission from Rotating Radio Transient J1819-1458

Star formation
Yet another illustration of the value of observing astronomical objects in diverse portions of the spectrum comes from studies of a protostar known as HH-211. Radio-frequency observations show jets of matter emerging from the poles of the rotating protostar, while infrared observations show emissions from shocked molecular hydrogen in a region of gas surrounding the jets. The observations support the hypothesis that the jets carry off angular momentum, allowing gradual growth of the protostar.

Jets Are a Real Drag
Jets Spiral in 'Reverse Whirlpool' from Star
Submillimeter arcsecond-resolution mapping of the highly collimated protostellar jet HH 211

Extrasolar planets
The existence of most extrasolar planets detected so far has been deduced indirectly from perturbations in the movement of its parent star. But extrasolar planet HD 189733b has proven to be one of the most amenable extrasolar planets to direct observation. (For example, here.) Now it has actually been observed by reflected light from the stellar parent.

Polarization technique focuses limelight
Studying Planets With Sunglasses
First Reflected Light from an Exoplanet?

Nanoparticle medicine
In the last year or so there has been quite a flood of reports of the use of nanoparticles as medical diagnostic tools or mechanisms for combating cancer and infectious diseases by heating or delivery of drugs. The past week has brought two more examples, involving gold nanoparticles. In one example the nanoparticles bind specifically to tumor cells, where they can be observed using laser illumination. In a second example the nanoparticles bind to the parasite responsible for toxoplasmosis. The parasite is destroyed when the nanoparticles are heated using suitable illumination from a laser.

Gold Nanoparticle Probes May Allow Earlier Cancer Detection
'Golden Bullet' Shows Promise For Killing Common Parasite

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