Friday, May 16, 2008

The DNA Network

The DNA Network

Pam and Raoul to discuss Tomorrow's Table with Dr. Michio Kaku on Science Fatntastic [Tomorrow's Table]

Posted: 16 May 2008 07:30 PM CDT

Science Fantastic is a new live science radio talk show on 90 stations across the country. Pam and Raoul will be on at 3 pm PST to discuss Tomorrow's Table with the host Dr. Michio Kaku, theoretical physicist and best selling author of Physics of the Impossible.

Call us! Listeners are invited to call 1-800-449-8255 during the show to ask questions.

Check your local radio listings to find out on which radio station the show airs in your city. Some are shown here

WEST COAST AFFILIATES:

WA Seattle-Tacoma KGTK 920
WA Seattle-Tacoma KITZ 1400
CA Riverside-San Bernardino KMET 1490
NV Las Vegas KDOX 1280
CA Victor Valley KIXW 960
CA Palm Springs KPSI 920
CA Needles KTOX 1340

EAST COAST AFFILIATES:

PA Pittsburgh WBVP 1230
PA Pittsburgh WMBA 1460
MA Providence-Warwick-Pawtucket, RI WSAR 1480
VA Norfolk-Virginia Beach WBVA 1450
VA Norfolk-Virginia Beach WPMH 670
MA Worcester WCRN 830

How Genomic Medicine Is Changing the Management of Breast & Ovarian Cancer [A Forum for Improving Drug Safety]

Posted: 16 May 2008 05:07 PM CDT


Our friends at Helix Health, a medical practice with expertise in genomic medicine are hosting a free 90-minute webcast this Wednesday, May 21, 2008 from 1:00-2:30 PM EDT on: How Genomic Medicine Is Changing the Management of Breast & Ovarian Cancer. 

To register, point your browser here: http://event.netbriefings.com/event/helixhealth/register.html.

Join NPR's David Ewing Duncan, author Jessica Queller and a panel of medical and legal experts in a 90-minute webcast on genetic testing, genomic medicine and breast & ovarian cancer to learn some of the best practices in genomic medicine today from:

Steven A.R. Murphy, MD - Clinical Genetics Fellow at Yale School of Medicine, and Helix Health's Managing Partner will moderate the panel.

Barbra A. Ward, MD - Director, The Breast Center of Greenwich Hospital; the principal investigator of the STAR Trial at the Yale Cancer Center; prior director of the Yale Comprehensive Breast Care Center and currently a surgical oncologist affiliated with Yale-New Haven Health System.

Jessica Queller - author of Pretty Is What Changes, an account of her valiant decision to accept the results of genetic testing and her difficult decision to undergo a prophylactic double mastectomy. Television writer for Felicity, The Gilmore Girls and One Tree Hill. Writer/producer on Gossip Girl.

Jennifer Ibrahim, MD - clinical geneticist specializing in preconception genetics as well span as familial cancer syndromes.

David Ewing Duncan - bestselling author of Masterminds: Genius, DNA and the Quest to Rewrite Life; Chief Correspondent and co-host of National Public Radio's Biotech Nation"; Contributing Editor and Columnist, Portfolio; Ditto, Wired; Director, Center for Life Sciences Policy, UC Berkeley; author to articles and short stories, and a television, radio and film producer and correspondent.

Gary E. Marchant - Ph.D. J.D., Lincoln Professor of Emerging Technologies, Law & Ethics, Sandra Day O’Connor College of Law. Executive Director, Center for Law, Science & Technology, Professor, School of Life Sciences Arizona State University.

More information is available on the Helix Health website. http://www.helixhealth.org/. If you are unable to attend, a podcast of the session will soon be available. 

Transgenics. Pop Art. Government Anti-terrorism Thugs. A Complete Evening’s Entertainment! []

Posted: 16 May 2008 03:08 PM CDT

transgenicpop.jpg

The Critical Art Ensemble is doing a great job of tapping into the collective anxiety around GMOs. They had the idea, it seems of trying to remove the psychological tension around transgenic organisms by making “a participatory theater project that would get people hands-on involved in the production of these transgenic organisms.” All fine and good. Kinda fun, actually.

 

Then the government (we’d say idiotic government, but in the era of the Bush administration it’s an oxymoron…) caught wind. CAE founder Stephen Kurtz was subpoenaed under the Biological Weapons Anti-Terrorism Act, then indicted for mail fraud by a federal jury in 2004. Wow! Totally reminiscent of responses to Warhol’s silk screens or Stravinsky’s Rite of Spring! Who knew biotech could be so… edgy?

 

Happily, charges against Kurtz were recently dropped. But not after serious harassment and, undoubtedly, huge legal fees. The artists’ media may change, but apparently the suffering-for-art part hasn’t.

Uh oh! I’m about to get besieged by angry futurists! [Synthesis]

Posted: 16 May 2008 03:02 PM CDT

They’ve picked up on my futurist snark. I really do like futurists, I promise.

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More on America’s declining importance to the world [Synthesis]

Posted: 16 May 2008 02:50 PM CDT

Lately I’ve been hearing comments about things like declining research competitiveness, bright young Indians choosing to stay in India instead of come to the U.S. to seek their fortune, and comments about how even the research that is being done in American universities is increasingly being done by foreign students. Some international talent(which presumably has scores of advisors helping with these decisions) is even choosing to be paid in euros instead of dollars. The troubling thing about this is that instead of these comments coming from the more rabble-rousing section of the web, they’re coming from intelligent, well-read people with a worldly perspective. If you were looking for the proverbial “canary in a coal mine”, wouldn’t you think these people would be about the best you could find in that respect?

While I like to think that Steve’s post was particularly prescient, in fact if you were listening to the same sources he apparently has been, it’s blindingly obvious. I don’t claim to be anywhere as smart as the people I linked to above, but I don’t think you really need to be if you’re listening to the right people, and overwhelmingly they’re saying there’s a problem.

Of course, we didn’t get ourselves in this mess overnight (become a consumer instead of production , as Maitri so deftly puts it), and we won’t dig ourselves out of it overnight either. Let’s just hope that our years of neglect of the educational system turn out better than our years of neglect of the levee system.

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Let's stop stifling the careers of young scientists [adaptivecomplexity's column]

Posted: 16 May 2008 12:45 PM CDT

In today's issue of Science, AAAS CEO Alan Leshner argues that young scientists are getting a raw deal, and that the current system is stunting the growth and creativity of young scientists:

Heavy Heart [The Gene Sherpa: Personalized Medicine and You]

Posted: 16 May 2008 12:43 PM CDT

I vowed I would never post when family took precedence. I have to break that vow today. I wish I didn't but there is something so vitally important that I must share with you. Why is this important?...

[[ This is a content summary only. Visit my website for full links, other content, and more! ]]

Bill C-51: A Rant [Bayblab]

Posted: 16 May 2008 10:18 AM CDT

There's a whole lot of fear-mongering going on about Canadian Bill C-51, an amendment to the Food and Drugs Act. Facebook groups are popping up against the bill, protests are being organized and a website has been set up to organize the troops.

What C-51 is, quoting from the bill, is an attempt
to modernize the regulatory system for foods and therapeutic products, to strengthen the oversight of the benefits and risks of therapeutic products throughout their life cycle, to support effective compliance and enforcement actions and to enable a greater transparency and openness of the regulatory system.
In other words, it's an attempt to regulate therapeutic health products to ensure their safety and efficacy. Obviously, this has raised the ire of the natural products industry who has responded with 'news' pieces like this with alarming 'facts' such as "C-51 is outlawing herbs, supplements and vitamins", or "a mother giving an herb to her child, under the proposed new language, could be arrested for engaging in the sale of unregulated, unapproved 'therapeutic substances.'" (more on that one in a moment). This alarmism is stirred in with a nice painting of draconian enforcement and a dollop of Big Pharma conspiracy theory to make it an amusing, if typical, propaganda piece.

I'm obligated to point out that I am not a lawyer, but I've read the bill. It is NOT outlawing products, but rather bringing the natural health product industry up to a certain standard of testing. It's an attack on deceptive labeling, improper health claims and pseudoscience. No thug is going to kick down your door for serving dandelion greens at dinner. What is being outlawed is selling dandelion greens in a misleading way (eg. with untested health claims).

This brings us to the definition of 'sell', which is a major point for the alarmists. The amended act, if passed, will define sell as
offer for sale, expose for sale or have in possession for sale — or distribute to one or more persons, whether or not the distribution is made for consideration — and, in relation to a device, includes lease, offer for lease, expose for lease or have in possession for lease.
The phrase that the bill-opposers have latched onto is 'distribute to one or more persons'. They take that to mean that, to use the above example, serving dandelion greens for supper counts as 'selling'. While this interpretation of the new wording is technically true, one has to look at the contexts in which the word "sell" is used in the bill. Reading through it, it becomes clear that it's very specific things that run contrary to the proposed law. For example, 'selling' dandelion greens is only prohibited if they have a poisonous or harmful substance in or on it; if they are unfit for human consumption; are adulterated; are injurious to human health; or are processed, manufactured, stored, etc. in unsanitary conditions. That does NOT sound like draconian restrictions on what you can put on your table or give your family. It sounds like common sense. The bill goes further than that, prohibiting 'selling' "a food in a manner that is false, misleading or deceptive or is likely to create an erroneous impression regarding its character, value, quantity, composition, merit, safety or origin." For a therapeutic product, this is expanded to include "creat[ing] an erroneous impression regarding its benefits, risks, conditions of use." In other words, no false claims. So, to the people who oppose this language change, is it because you want to be free to distribute harmful goods, or because you're interested in making false or untested claims about your product?

Shawn Buckley, natural product lawyer, has weighed in with a 20 page review of C-51. (You may remember his name being thrown around by the pro-algae folks on the StemEnhance thread) He goes on to list a number of concerns. First on his list is that roughly 60% of of natural health product licenses are failing, meaning that with this amendment over 60% of the products on the market will become illegal and can be removed from the market by Health Canada. What is implied in this statement, is that 60% of the natural health products already on the market are not licensed. Nor does he state why these licenses are being denied. Is he seriously pushing for unlicensed health products - products that have failed to get government approval - to remain on shelves?

Buckley tries to portray the government as being bullies towards the natural health product industry. He points to language changes proposed by the act, such as replacing 'drug' with 'therapeutic product' and then asks "is the change of terminology directed at the Natural Health Product industry or are there other reasons?" My guess is that the answer is 'yes' and I would respond with the question 'So?' The changes in the act seem to have in mind the goal of bringing the natural product industry to a particular standard. The pharmaceutical industry is already regulated in terms of safety requirements, evidence-based results, etc. Obviously bringing drugs and natural products under the same 'therapeutic product' umbrella is designed to ensure that ALL of these products are safe, effective and work as advertised. As Buckley himself points out, the pharmaceutical industry already has a high compliance rate with Health Canada rulings, while 60% of natural products go to market having their licenses denied.

What is more concerning is the National Health Products Protection Association (NHPPA, of which Buckley is president) position. In the legal review of C-51, their goals are listed as a regulatory environment where, among other things, "NHPs [natural health products] are presumed to be safe. A NHP cannot be taken off of the market unless the Government can prove that it is unsafe." This is just a ridiculous attitude. If the default position for a natural product is 'safe', that means people have to start getting ill or dying before somebody steps in. The reality is that health products should be deemed safe before they go to market. Just because it's labeled natural doesn't make it safe. As I've pointed out before, several potent cancer drugs are natural products. Would the NHPPA have these, or any future similar discoveries given a blanket 'safe' label and start selling to people?

Therein is the lunacy of the natural product position: The want their products to be at once efficacious and totally harmless. For any product to be useful in some therapeutic way, it has to have a biological effect. If it has a biological effect, then you have to start thinking about how it works, safe doses, potential side-effects, etc. Now don't get me wrong, I don't think the bottle of vitamin C in the medicine cabinet is particularly dangerous (of course, anything is at a high enough dose), but natural health products include more than standard vitamin supplements with known tolerances. They include products that claim to mobilize stem cells, alter gut flora composition, and stimulate the immune system as well as non-standard megadoses of of common vitamins. All of these effects have the potential to cause adverse events. The default position is not 'totally harmless'.

Mr. Buckley does raise some interesting points about the use of the word 'government' in the bill, and how it may affect adoption of future regulations. In C-51, the definition of government includes international bodies and foreign governments and states that "A regulation may incorporate by reference documents produced by a person or body other than the Minister of the Canadian Food Inspection Agency including ... (c) a government." This sounds like the amended bill makes it easier to incorporate foreign policies into Canadian law. However, given Buckely's position with the NHPPA, I doubt the sovereignty of Canadian law is his primary concern.

Of course there will be people arguing that the government has no right to tell us what to put in our bodies. That's not what these changes are doing. It doesn't say you can't eat your dandelion greens, take your garlic supplement or multivitamin. It says that the products must be safe and that their sales and marketing can't be false, misleading or deceptive. You can eat your greens, but they can't be sold as age-reversing. You can take your garlic pills, but they can't be sold as cancer-curing. Unless, of course, there's evidence.

Is Organically grown food 40% more nutritious? [Tomorrow's Table]

Posted: 16 May 2008 09:42 AM CDT

There are many reasons to support organic farming- avoidance of synthetic pesticides and fertilizers means improved farmworker health, reduced energy use and cleaner streams- but more nutritious food is not one of them. In the New York Times article "Change We Can Stomach", Chef Dan Farber claims that organic fruit and vegetables contain 40% more nutrition than their chemical-fed counterparts". Although there is some data indicating that organically grown produce carry higher levels of antidoxidants, whether or not this translates into more nutritious food is unknown. The future of food production will increasingly rely on organic farming practices but not because it is more nutritious.

Stem Cell Research [Sciencebase Science Blog]

Posted: 16 May 2008 07:00 AM CDT

Embryonic stem cellsLots of visitors are hitting the Sciencebase site look for information on stem cell research. It is a subject I’ve written about before, both on this site and elsewhere, but I thought it might be useful, given that my alma mater is at the forefront of stem cell research in the UK, to provide a FAQ on the subject of stem cells. Just to be clear, usually when the media uses the phrase stem cells, they really mean human embryonic stem cells, but that occasionally takes print journalists over the wordcount, so it’s commonly abbreviated to stem cells, so for the sake of brevity, I’ll do the same here.

  • What are stem cells?

    Stem cells are primordial cells that can divide without limit and differentiate into the various types of cell used to build our livers, hearts, bones, brains, skin, and other organs, blood cells, nerves etc. More details.

  • Where are stem cells found?

    Pluripotent stem cells, which can form any cell type, can be harvested from human embryos that are just a few days old.

  • What do researchers do with harvested stem cells?

    Harvested pluripotent stem cells can be cultured in the laboratory to create “stem cell lines” for research and development.

  • What can be done with cultured stem cells?

    A cultured stem cell line can multiply indefinitely in the lab, so once produced researchers can use the same line without having to harvest new stem cells.

  • What might stem cells be used for?

    Cultured stem cell lines can be “engineered” to differentiate into specific cell types, which researchers are hoping can be transplanted into a patient to treat a wide range of problems, including cancer, spinal cord injury, stroke, burns, heart disease, diabetes, birth defects and neurodegenerative disorders, such as Parkinson’s and Alzheimer’s disease.

  • Have researchers cured diseases with stem cells?

    Not yet, stem cell research is little more than a decade old and is very much in the experimental stages. Legal, funding, and ethical issues in the US, UK and elsewhere have slowed stem cell advances during this time to some degree.

  • Aren’t bone marrow transplants using stem cells?

    The well-known bone marrow transplant uses the blood stem cells found in bone marrow and has been used to treat a range of diseases, such as leukaemia, for four decades.

  • Do embryos have to be used to harvest stem cells?

    Not necessarily, the umbilical cord is being researched as an alternative source of stem cells that would sidestep some of the ethical issues associated with embryonic stem cells. There is also research into using tissue-specific stem cells from adult donors.

    A much more detailed FAQ on stem cell research can be found on the ISSCR site.

    A post from David Bradley Science Writer

    Stem Cell Research

Around The Blogs [Bitesize Bio]

Posted: 16 May 2008 06:01 AM CDT

Time for our weekly look around the best of the blogs…

More on Google Reader. This article on the Bootstrapper blog, along with Bala’s article on Google Reader for Academics, will help you on your way to Google Reader mastery.

All our ideas in one basket. Mr Gunn at Synthesis commented on a very interesting project, that everyone can take part in, by the Institute of the Future. X2 is a hypothesis aggregator… users can enter any hypothesis they have about how things will pan out in the future, and other users rate the hypotheses. The result is a surprisingly interesting and convincing collection of ideas.

Phosphorylation is over-rated. Attila voices an interesting opinion on the importance of protein phosphorylation at PIMM.

How to succeed in science. This concise guide published in Nature Reviews Molecular Cell Biology by Jonathan Yewdell was highlighted at Medical Writing, Editing and Grantsmanship.

Dawkins on Evolutionary Biology. Razib at Gene Expression picked up this interview with Richard Dawkins by the people at 3Quarks.

Moving on from RNA. John Timmer at Arstechnica discusses two views on how life made the transition from membrane encased RNA catalysts to the three forms of life we know now.

…and finally…

Add one word - “Relatively”. Take a look at this crazy piece of creationism propaganda if you can stand it. Frank Sherwin MA (what does this mean, Master of Arts!?) argues that although we call bacteria “simple” organisms, they are in fact pretty complicated beasts, therefore they cannot be at the lower end of the evolutionary tree.

DNA Quote: Kevin Kelly on Zillionics [Eye on DNA]

Posted: 16 May 2008 03:04 AM CDT

zillionFrom Kevin Kelly’s The Technium:

When you reach the giga, peta, and exa orders of quantities, strange new powers emerge. You can do things at these scales that would have been impossible before. A zillion hyperlinks will give you information and behavior you could never expect from a hundred or thousand links. A trillion neurons give you a smartness a million won’t. A zillion data points will give you insight that a mere hundred thousand would never.

…Zillionics is a realm much more at home in biology—where there have been zillions of genes and organisms for a long time—than in our recent manufactured world. Living systems know how to handle zillionics. Our own methods of dealing with zillionic plentitude will mimic biology.

TED talks: statistics [Mailund on the Internet]

Posted: 16 May 2008 02:00 AM CDT

I wasn’t planning on covering statistics in my list of TED talks, but I saw a familiar face:

Table of contents for TED Talks

  1. TED talks: Biology
  2. TED talks: IT
  3. TED talks: Space
  4. TED talks: statistics

The Latest News About 23andMe [The Genetic Genealogist]

Posted: 16 May 2008 02:00 AM CDT

image For new readers of The Genetic Genealogist, 23andMe is a personal genomics company that offers a service to examine more than 600,000 SNPs throughout an individual’s genome. The information is then used to analyze ancestry (using Y-DNA and mtDNA) and to estimate propensity for disease. For much more info about 23andMe and similar companies, look under “Personal Genomics” on my Featured Articles page.

A Contest

Today, 23andMe announced on their blog - The Spittoon - the winner of the company’s first ‘Win Your Genome Contest’. The contest was to describe Lilly Mendel, a publicly available but anonymous profile at 23andMe - based upon her genetic information alone. The winner was Mike Cariaso, who previously created a program that analyzes 23andMe SNP data using the growing SNPedia database.

A New Partnership

In another announcement today, 23andMe released details of a partnership between the company and The Parkinson Institute to analyze the genomes of the Institute’s patients. Unlike the typical customer, the Institute’s patients will provide information about their “individual environmental exposures, family history, disease progression and treatment response.” The official press release is here, GenomeWeb News coverage is here, and there is a mention at Simon Lin’s blog Retail Genomics.

A Panel Discussion

Linda Avey, one of the founders of the company, recently participated in a panel discussion at the Cold Spring Harbor Biology of Genomes meeting. She was joined by representatives from two competitors, deCODEme and Navigenics. Daniel Macarthur at Genetic Future provides a fantastic and lengthy review and analysis of the discussion. A mention at Genome Technology Online laments the fact that the panel discussion was civil, even though it was a gathering of three competitors. The site also provides a summary of the meeting (subscription required).

A Controversy

Also in the news are reports that two states, California and New York, are evaluating whether personal genomics services offered by companies such as 23andMe and deCODEme are regulated by state laws, and if so, whether the companies are meeting those regulations. For more information, see “California, New York Officials Probing Gene-Testing Companies” at The Mercury News.

And Everything Else!

And lastly, here are a few newspaper articles or blog posts that mention the latest in personal genomics (note that these articles are provided so that you can perform your own analysis of personal genomic services - unfortunately, I haven’t evaluated these articles for accuracy):

Gene Genie #32 Call for Submissions [Highlight HEALTH]

Posted: 16 May 2008 01:00 AM CDT

Highlight HEALTH will be hosting the next edition of Gene Genie, edition 32, on Sunday, May 25th. As host, I invite you to send your submissions.

Gene Genie is a bi-weekly blog carnival of genes and genetic conditions.

Past editions can be found at the Gene Genie website.

Submit your article here or email them to me using the submission format below.

Submission Format:

Subject line: Gene Genie submission
Email body:
- Submitted Post Title
- Submitted Post URL

Send your submissions to me using the email address on the sidebar no later than Friday, May 23rd at 04:00:00 UTC (12:00pm CST).

Receive e-mail notification when Gene Genie #32 is published.

Let’s make this another great collection of the best posts pertaining to genes and genetic conditions. I look forward to your submissions!

Thank you for subscribing by RSS or email. I work hard to make the articles on Highlight HEALTH engaging and I truly appreciate your interest and readership!

This article was published on Highlight HEALTH.

Related articles

Small primate ancestors had a leg up [Think Gene]

Posted: 16 May 2008 12:48 AM CDT

Smaller primates expend no more energy climbing than they do walking, Duke University researchers have found. This surprising discovery may explain the evolutionary edge that encouraged the tiny ancestors of modern humans, apes and monkeys to climb into the trees about 65 million years ago and stay there.

The researchers compared the energy consumed by five different primate species while negotiating vertical and horizontal treadmills. Their work appears in the May 16 issue of the journal Science.

"We assumed it would be more energetically expensive for all of them to climb than to walk, so this finding was unexpected," said Jandy Hanna, a faculty member at the West Virginia School of Osteopathic Medicine in Lewisburg who was a Duke graduate student at the time of the study. "There's this longstanding assumption that it should cost more to go up," she added.

Hanna had to design and build a novel climbing treadmill — essentially a loop of rope around two pulleys — to measure the animals’ efforts. As the animals moved at their highest sustainable speed, sensors measured oxygen level changes within a chamber to derive the primates' energy consumption.

While climbing was not significantly more demanding for heftier primates than lighter ones, "the energetic cost of walking decreased with size," said Timothy Griffin, a medical instructor at the Duke Medical Center’s Orthopaedic Bioengineeing Laboratory. Consequently, species weighing more than half a kilogram (about 1 pound) may have more incentive to walk than to climb. But for those weighing less, "there was no difference," he added.

The common assumption is that a transition to life in the trees helped lead to modern primates and our own up-right, two-legged walking.

Scientists think our earliest primate ancestors, which were only the size of large rats, underwent a number of fundamental evolutionary changes as they adapted to moving and feeding on thin branches of trees 65 million years, said Daniel Schmitt, a Duke associate professor of biological anthropology and anatomy who was Hanna’s doctoral dissertation advisor. "Those changes included developing grasping hands with nails instead of claws," Schmitt said. "They were climbing up into the canopy and staying there. What we have shown is that they could have made this shift into a rich environment with insects and fruits without increased energetic cost."

The eight primates evaluated for energy consumption during climbing and walking were the slender loris (Loris tardigradus), fat-tailed dwarf lemur (Cheirogaleus medius), pygmy slow loris (Nycticebus pygmaeus), Bolivian squirrel monkey (Saimiri boliviensus) and mongoose lemur (Eulemur mongoz). The squirrel monkey studies were done at the University of South Alabama in Mobile, and the others at the Duke University Lemur Center.

Source: Duke University

The Energetic Cost of Climbing in Primates. Jandy B. Hanna, Daniel Schmitt, and Timothy M. Griffin. Science 16 May 2008: 898.

Full paper

Josh says:

This is really interesting, and I would like to see more of the physics of how and why this is possible. Unfortunately, the actual paper is very brief and doesn’t go into much detail other than discussing the oxygen consumption experiment they did and its outcome.

Off to give a talk at the Dept. of Biology [Mailund on the Internet]

Posted: 16 May 2008 12:43 AM CDT

In about an hour I’m off to give a short talk at the Dept. of Biology. I’m not really sure what the occation is — some yearly department meeting, I think — but I was asked to give one of the talks a few months ago. Don’t know why. I do not work in that department. I’m just very easy to talk into these things as long as the talk is far enough in the future that I can convince myself that at that time I wont be as busy as I am now. This is rarely the case, of course.

Immune cells kill foes by disrupting mitochondria 2 ways [Think Gene]

Posted: 16 May 2008 12:39 AM CDT

When killer T cells of the immune system encounter virus-infected or cancer cells, they unload a lethal mix of toxic proteins that trigger the target cells to self-destruct. A new study shows T cells can initiate cellular suicide, also known as programmed cell death or apoptosis, by a previously unrecognized pathway that starts with the destruction of a key enzyme in mitochondria, the power plant of the cell.

The study, from the lab of Judy Lieberman, a senior investigator at the Immune Disease Institute and Professor of Pediatrics at Harvard Medical School, reveals that T cells use both the novel pathway and the classical apoptotic pathway to interfere with mitochondrial function and induce cell death.

"This work gives us a new understanding of a major T cell defense pathway," Lieberman says. The results will appear in the May 16 issue of Cell.

The Lieberman lab studies cytotoxic T lymphocytes (CTLs), key cells in the immune defense against viral infection and cancer. When CTLs recognize an infected or transformed target cell, they release the contents of cytolytic granules onto the target cell. These granules contain serine proteases called Granzymes, which induce programmed cell death in the target cells. Two major Granzymes, A and B, account for most of the killing activity in granules.

Granzyme B triggers the classical programmed cell death pathway involving breakdown of the outer mitochondrial membrane, and the release of death-promoting proteins which activate the caspase protease cascade and result in massive DNA damage.

Previous work from the Liebeman lab showed that Granzyme A initiates cell death by a different biochemical pathway. That pathway involves the mitochondria, but does not result in mitochondrial membrane breakdown or caspase activation, and triggers a different type of DNA damage. The current study was aimed at understanding how Granzyme A kills cells.

To identify Granzyme A target proteins in mitochondria, Lieberman and colleagues used proteomics to look at the fate of a large number of mitochondrial proteins after Granzyme A exposure. One protein, NDUFS3, a subunit of the large multi-protein Complex I assembly that participates in energy generation for the cell, disappeared.

Further work established that when Granzyme A was released into a cell, it could enter the mitochondria where it degraded NDUFS3. Further, the investigators showed that loss of NDUFS3 caused mitochondria to produce damaging reactive oxygen, known to be essential for Granzyme A's deadly effects on cells. Destruction of NDUFS3 was sufficient to initiate the toxic effects of Granzyme A on human cells, they showed.

The new demonstrate that while both Granzymes target mitochondria, they do so in very different ways. Lieberman says she is not surprised that immune cells have multiple means of inducing mitochondrial-dependent cell death. "Many viruses and cancers have found ways to be resistant to the caspase-dependent apoptosis pathway triggered by Granzyme B, so it makes sense that immune cells would have a second, parallel pathway to cause cell death," she said.

Source: Harvard Medical School

Granzyme A Cleaves a Mitochondrial Complex I Protein to Initiate Caspase-Independent Cell Death. Denis Martinvalet, Derek M. Dykxhoorn, Roger Ferrini, and Judy Lieberman. Cell, Volume 133, Issue 4, 16 May 2008, Pages 681-69

Full Paper

Josh says:

It definitely makes sense that there is another apoptotic pathway that T cells take advantage of. NDUFS3 is one of the Fe-S clusters in NADH dehydrogenase, and is also called NADH-coenzyme Q reductase. Its degredation would disrupt the electron transport chain, which like the authors say, would probably cause a buildup of oxygen.

Embryonic pathway delivers stem cell traits [Think Gene]

Posted: 16 May 2008 12:21 AM CDT

Studies of how cancer cells spread have led to a surprising discovery about the creation of cells with adult stem cell characteristics, offering potentially major implications for regenerative medicine and for cancer treatment.

Some cancer cells acquire the ability to migrate through the body by re-activating biological programs that have lain dormant since the embryo stage, as the lab of Whitehead Member Robert Weinberg has helped to demonstrate in recent years. Now scientists in the Weinberg lab have shown that both normal and cancer cells that are induced to follow one of these pathways may gain properties of adult stem cells, including the ability to self-renew.

In a paper published online by Cell on May 15, former postdoctoral researcher Sendurai Mani and his colleagues demonstrated in mice and in human cells that cells that have undergone an "epithelial-to-mesenchymal" (EMT) transition acquire several important characteristics of stem cells. Conversely, the researchers also showed that naturally existing normal stem cells as well as tumor-seeding cancer stem cells show characteristics of the post-EMT cells, including the acquisition of mesenchymal cell traits, which are usually associated with connective tissue cells.

Epithelial cells, which make up most of the human body, bind together in sheet-like structures. In embryonic development, the EMT process breaks up cell-cell adhesion in the epithelial layer, and converts epithelial cells into more loosely associated mesenchymal cells. In the context of cancer development, some cancer cells within a primary cancer may undergo an EMT, migrate through the body to their end destination, and there resume their epithelial form through a reverse process (the mesenchymal-to-epithelial transition).

Mani and his colleagues have identified FOXC2, one of the key genes involved in invasion and metastasis. In addition, FOXC2 appears to program the metastatic ability of some breast cancers.

Mani knew that during embryonic development, FOXC2 expression is restricted to mesoderm and mesoderm-derived cells when they are in an undifferentiated state, and its expression disappears once these cells differentiate. Similarly, his experiments showed that epithelial cells that undergo EMT express FOXC2, but that expression is lost when they revert back to an epithelial state.

In collaboration with Andrea Richardson and Jeffery Kutok, pathologists at Boston's Brigham and Women's Hospital, Mani went on to study FOXC2 expression in normal human breast tissue. It turned out that such cells were located precisely where researchers expect to find mammary epithelial stem cells.

As he pondered these findings and the earlier results about FOXC2's role in metastasis, Mani wondered: Just what were these cells generated by EMT that expressed FOXC2″

Were they simply fibroblasts, the most common cells in normal connective tissue” Or were they actually stem cells”

"I asked Mai-Jing Liao, another postdoc in the Weinberg lab, to check whether the cells generated by EMT would have any stem cell properties," recalls Mani, now an assistant professor in the department of molecular pathology at the University of Texas's M. D. Anderson Cancer Center in Houston. "He said, 'You must be out of your mind, but it won't take more than half an hour to check.'"

Much to Liao's surprise, when he examined cells that had undergo an EMT, his tests did highlight surface proteins that are key markers for stem cells.

The researchers found that the cells that underwent the EMT process were mesenchymal-like in appearance and demonstrated stem-cell surface markers. The cells also displayed an increased ability to grow in suspension, forming structures called mammospheres—another trait of mammary stem cells. Some cells in the resulting mammospheres showed, in turn, stem cell markers, indicating they could differentiate into two kinds of mammary cells. And cells in the mammospheres retained their stem cell properties even after the EMT induction process was stopped.

Furthermore, when the Weinberg lab scientists isolated stem-cell-like cells from cultured human mammary epithelial cells or from mouse breast tissue, their properties were very similar to the EMT-induced cells. Working with Kornelia Polyak of Dana-Farber Cancer Institute and Harvard Medical School, Mani found that this was also true with normal and tumor cells obtained from human patients.

"This for us is a very exciting discovery, not only because of its unexpectedness but because it offers a route by which one could in principle generate unlimited numbers of stem cells committed to create a specific cell type," says Weinberg, who is also a professor of biology at Massachusetts Institute of Technology. "One could imagine, for example, that if one takes skin cells and induces them to undergo an EMT, they could become skin stem cells."

Importantly, the researchers also demonstrated that inducing the EMT process can produce cells with many characteristics of cancer stem cells. (Beginning in 2003, scientists in various labs have identified these self-renewing, tumor-seeding cells in a number of solid tumors.)

This finding could help to answer a key question about metastasis: When tumor cells spread into different sites, how do they multiply enough to form a dangerous new tumor”

"If you take a population of human cancer cells that normally form a tumor very inefficiently and induce an EMT, their tumor-initiating abilities increase by about a hundred-fold, so that it takes about 10,000 cells rather than a million cells to form a tumor," says Wenjun Guo, co-lead author on the paper and postdoctoral researcher in the Weinberg lab. "This suggests cancer stem cells are using pre-existing normal stem cell machinery to propagate their own self-renewal and therefore their tumor-initiating ability."

Mani is continuing his research on the EMT/cancer stem cell connection and its role in cancer metastasis at the M. D. Anderson Cancer Center. Researchers in the Weinberg lab will investigate the EMT process with other cell lines. They also will attempt to give final proof in mice that the process creates completely defined stem cells, by taking cells from mouse mammary fat pads, inducing an EMT for some of the cells, returning the resulting cells to the fat pad, and seeing if they can regenerate the mammary gland.

Source: Whitehead Institute for Biomedical Research

"The epithelial-mesenchymal transition generates cells with properties of stem cells". Sendurai A. Mani, Wenjun Guo, Mai-Jing Liao, Elinor Ng Eaton, Ayyakkannu Ayyanan, Alicia Zhou, Mary Brooks, Ferenc Reinhard, Cheng Cheng Zhang, Michail Shipitsin, Lauren L. Campbell, Kornelia Polyak, Cathrin Brisken, Jing Yang, Robert A. Weinberg. Cell, online publication May 15, Print Edition, Volume 133 (4)

Full paper

Josh says:

Perhaps it’s just me, but this seems somewhat obvious. While people used to think cancer was differentiated cells that somehow dedifferentiated, it’s now commonly believed that the cancer cells were always stem cells and were not differentiated. At the EMT, the mesenchymal cells form that give rise to all the mesoderm, and by definition they would be stem cells. The authors seemed surprise by this, but I just always assumed this would be true. Does anyone else feel this way or have any other insight?

Deriving information from structured data [business|bytes|genes|molecules]

Posted: 16 May 2008 12:13 AM CDT

On net@nite I heard that Dipity, a great site for mashing up timelines uses Freebase as one of its information sources. An excellent example is this timeline for Marillion embedded below

Earlier today, on Friendfeed, Alex Iskold described an “aha” moment for Powerset, which I have been quite underwhelmed by thus far (although it has a gorgeous UI). When I browsed over to the search link, it seemed to be that the reason the results appeared as they did were because they came from Freebase, whose structure made the query very powerful. Wonder if others think that’s the primary reason as well? The Wikipedia results for the query were not that impressive.

So what do these results tell us? Well, perhaps there is value in taking data and adding structure the way Freebase and dbpedia are doing. The ability to generate different representations, etc is quite powerful. I can already envision what Pierre might do with some of these tools and the work he has been doing with Freebase and Wikipedia.

These examples are somewhat trivial, but it is not difficult to imagine more interesting scenarios, perhaps to represent protein interactions, or trying to find non-obvious relationships and linkages. Will be interesting to see what kinds of applications are developed on the backs of these data platforms

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What Makes Cells Tick? Reverse Engineering Biological Cycles [adaptivecomplexity's column]

Posted: 15 May 2008 11:05 PM CDT

Physics can explain the cycle of the earth around the sun, but what drives cellular cycles? Two of the most important cycles in cells are the series of events that take place when cells divide, and circadian rhythms - the cycle of day-night events that even bacteria participate in.

Unlike a planet, a cell's cycle can't be described by simple physical laws, nor does it have a CPU like a computer to keep time and and control the order of events. So how do cells control their cycles? Researchers have been trying to reverse engineer cell cycles, and two recent successes give a fascinating molecular view of what's going on.

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A lack of discrimination [genomeboy.com]

Posted: 15 May 2008 09:53 PM CDT

Michael Kinsley is a smart man and a terrific writer. But I think he’s dead wrong about GINA when he writes:

Is it unfair that Yo-Yo Ma can play cello better than I can? Or that people hire Frank Gehry instead of me when they want a beautiful building, or that Warren Buffett is a better stock picker? Sure, it’s unfair. And it’s unfair in precisely the same way the results of a genetic test are: my lack of talent at playing the cello is something I was born with and beyond my control.

This is a non-sequitur. What’s unfair is when people are tested for diseases by their employers without their consent. What’s unfair is when soldiers are kicked to the curb by the military because their ailments are deemed pre-existing. And I think he’s wrong about insurance, too:

The very appealing notion that genetic discrimination is unfair looks especially odd in the context of insurance. The idea of insurance is to protect against the unexpected or unlikely. Forbidding insurers to take predictable risks into account when choosing whom to insure and how much to charge is asking them to behave irrationally and make bets they are sure to lose. Not insuring people who are likely to get cancer, or charging them more, isn’t evil. It’s rational behavior. Of course, we outlaw a lot of behavior that would be rational if it weren’t against the law. But the skeptics who say this is a step on the way to universal health care actually understate the case. To truly apply the appealing principle that people should not be discriminated against because of their genes would be a leveling experiment, like something out of Stalinist Russia or China’s Cultural Revolution.

Then I will sing “L’Internationale” at the top of my lungs. This is another specious argument. Most people in this country are not subect to medical underwriting–they are already treated blindly by their insurers*. Michael Kinsley has Parkinson’s disease. Should he be denied health insurance or employment? I don’t think so. Maybe it would be rational, but would it be right?

The question comes down to this: What kind of society do we want to live in?

*Yes, I know, this excludes the 45 million without health insurance at all.

My view–and Bob Cook-Deegan’s–can now be found here.

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