Monday, September 22, 2008

The DNA Network

The DNA Network

Pitt research indicates new virus is culprit, not bystander, in deadly skin cancer [Think Gene]

Posted: 22 Sep 2008 06:46 PM CDT

Kevin: Our growing understanding that some cancers are viral in origin starts to make cancer seem a lot less mysterious. I’m optimistic about continued progress in this important area.

University of Pittsburgh scientists are uncovering more evidence that a virus they recently discovered is the cause of Merkel cell carcinoma, an aggressive and deadly form of skin cancer.

The findings, published in this week’s early online edition of the Proceedings of the National Academy of Sciences, put to rest the possibility that MCV infects tumors that already have formed. If that were the case, the virus would be a passenger rather than the driver of the disease.

Experiments in human tumors reveal that the cancer develops in two steps: during infection, the Merkel cell polyomavirus, or MCV, integrates into host cell DNA and produces viral proteins that promote cancer formation. Tumors occur when a mutation removes part of a viral protein needed for the virus to reproduce and infect other healthy cells, explained senior investigator, Patrick Moore, M.D., M.P.H, professor of microbiology and molecular genetics at the School of Medicine and director of the Molecular Virology Program at the University of Pittsburgh Cancer Institute. The virus then can spread only as the cancer cells themselves multiply.

Clearly, “MCV infects normal cells before they turn into cancer cells,” Dr. Moore noted. “The virus could not have infected a tumor afterwards because it can no longer replicate. It looks very much like MCV is the culprit that causes the disease.”

The researchers propose two possible reasons why these mutations develop: If viral replication continues, the immune system could recognize the intruder to eliminate diseased cells, or the viral replication itself will lead to the death of the cancer cells. Both of these possibilities provide promising leads to find better ways to kill Merkel cell cancer cells without harming healthy tissues.

Also, “this research shows evolution within tumors on a molecular level,” Dr. Moore pointed out. “You can see the specific molecular steps.” The team’s current work could account for known risk factors for Merkel cell carcinoma such as UV exposure and ionizing radiation, which damage DNA and can lead to the viral mutations.

Merkel cell cancers are rare, occurring in about 1,500 Americans annually. Half of patients who have advanced disease die within nine months of diagnosis, and two-thirds die within two years. The elderly and people with compromised immune systems are at greater risk of developing the cancer, which arises in skin nerve cells that respond to touch or pressure.

In a paper published in Science in January, Dr. Moore and his wife, Dr. Yuan Chang, who co-directs their lab, reported their identification of the virus and that it could be found in 80 percent of Merkel cell tumors. They cautioned that although up to 16 percent of the population carries MCV, very few will develop cancer.

There is no treatment for MCV infection right now, but identifying the agent and understanding how it triggers disease could lead to targeted interventions, Dr. Moore said.

Source: University of Pittsburgh Schools of the Health Sciences

The original paper: Clonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma. Huichen Feng, Masahiro Shuda, Yuan Chang, Patrick S. Moore. Science 22 February 2008:Vol. 319. no. 5866, pp. 1096 - 1100

The followup discussed here will be appearing in the upcoming early edition of the PNAS.

Do mosquitoes get the mumps?, part II [Discovering Biology in a Digital World]

Posted: 22 Sep 2008 05:00 PM CDT

Part II. What do mumps proteins do? And how do we find out?

This is the second in a five part series on an unexpected discovery of a paramyxovirus in mosquitoes, and a general method for finding interesting things.

I. The back story from the genome record
II. What do the mumps proteins do? And how do we find out?
III. Serendipity strikes when we Blink.
IV. Assembling the details of the case for a mosquito paramyxovirus
V. A general method for finding interesting things in GenBank

In Part I, we looked at the NCBI SeqViewer, and found a new way to check out a genome map, and learn more about individual genes and proteins.

When we look at proteins from the mumps virus what do we find?

Read the rest of this post... | Read the comments on this post...

Calling for Four Stone Hearth Anthropology Blog Carnival submissions [Yann Klimentidis' Weblog]

Posted: 22 Sep 2008 04:48 PM CDT

It's time for the 50th edition of the Four Stone Hearth Anthropology Blog Carnival, so please email your submissions to me at yannatunmdotedu.

The Fourth Stone Hearth is a blog carnival that specializes in anthropology in the widest (American) sense of that word. Here, anthropology is the study of humankind, throughout all times and places, focusing primarily on four lines of research:

  • archaeology
  • socio-cultural anthropology
  • bio-physical anthropology
  • linguistic anthropology

Each one of these subfields is a stone in our hearth.

You need not be a blogger that specializes in anthropology to host or participate, but the posts submitted should relate to some aspect of anthropology.

Blogging on Genetics and Society [Tomorrow's Table]

Posted: 22 Sep 2008 12:11 PM CDT

This week I begin teaching "Genetics and Society", a course I created with a colleague 10 years ago. The goals of the course are:

1. To provide non-science majors with the basic concepts of genetic and modern methods of biotechnology,
2. To educate students in the process of scientific discovery.
3. Empower students to evaluate for themselves the present and future impact of genetics on society.

The class includes student debates on one of 8 topics:

1. Rice genetically engineered to produce provitamin A should be widely and freely distributed in less developed countries.
2. All food containing genetically engineered ingredients should be labeled as "GMO", to indicate that they contain genetically modified organisms.
3. Cloning of human embryonic stem cells should be banned.
4. Genetic selection of "designer babies" to avoid genetic disorders in the human population should be banned.
5. All people convicted for any legal violation should be DNA fingerprinted.
6. Genetic engineering of animals to produce pharmaceuticals should be prohibited
7. The United States should prohibit the experimental release and commercialization of genetically engineered plants until further safety testing is done
8. Human germline gene therapy should be banned

Students will be graded on clarity of their presentation, the persuasiveness of their arguments, and their ability to identify and convey relevant scientific knowledge to the class.

You can download lectures and notes from the class website:

This year we will add something new: A blog! I will post questions from students on my blog, students will post questions and members of the blogosphere can answer.

As Sandra Porter said in a recent post "This is an entirely new way that scientists can help with science education. It doesn't involve any kind of traveling and many, many different scientists can participate, thus minimizing volunteer burn out. It also gives students a way to practice writing about what they do and interacting with the world. Plus, with digital documentation, you can show your future employers and teachers the kinds of things you've been doing."

The other advantage is that I will be so busy teaching that it is likely I wont be able to post on any other topic.

Does your science class have a blog? [Discovering Biology in a Digital World]

Posted: 22 Sep 2008 12:00 PM CDT

Wow! One of my commenters, Ms. Baker, suggested an entirely new way that scientists can help with science education. The only requirement is that a science class have their own blog.

So, if your science class has a blog, let me know, so I can share the URL and maybe recruit some scientists or at least graduate students, to take a look.

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The Cancer Genome Atlas Reports Molecular Characterization of Brain Tumors [Highlight HEALTH]

Posted: 22 Sep 2008 10:31 AM CDT

ResearchBlogging.orgA large-scale, multi-dimensional analysis of the genomic characteristics of glioblastoma, the most common primary brain tumor in adults, provides new insights into the roles of several genes and defines core biological pathways altered in tumor development [1]. The new Cancer Genome Atlas study, published in the September 4th advanced online edition of the journal Nature, also reveals a link between the DNA repair enzyme MGMT and a hypermutation phenotype, and has potential implications for the diagnosis and treatment of glioblastoma.

Glioblastoma is the most common and aggressive type of brain cancer. Patients newly diagnosed with glioblastoma have a median survival of approximately one year with generally poor response to therapy [2]. Gene expression profiling studies suggest multiple subtypes of glioblastoma that, when fully defined, may allow for more personalized therapeutic approaches [3-4].

The Cancer Genome Atlas (TCGA) is an integrated network of clinical sites, core resources and specialized genome characterization and genome sequencing centers that work together to accelerate our understanding of the molecular basis of cancer. The TCGA was launched in December 2005 as a pilot program to determine the feasibility of a large-scale effort to systematically explore genomic changes in all types of human cancer [5]. TCGA utilizes genome analysis technologies to catalog and discover major cancer causing genome alterations in large groups of human tumors through integrated multi-dimensional analyses. Glioblastoma is the first type of cancer to be studied in the TCGA pilot.

Investigators from seven cancer centers and research institutions across the U.S. integrated multiple types of data, including genetic mutations, gene expression, large-scale changes in chromosome number (amplification or deletion), epigenomics and clinical treatment. The scientists evaluated 206 biospecimens for DNA copy number, gene expression and DNA methylation (a chemical modification of DNA that reduces gene expression). Of these, 143 samples had matched normal peripheral blood DNA; 91 were selected for detection of somatic (meaning cells that differentiate into various tissues and organs, as opposed to germline cells (e.g. sperm and ova)) mutation in 601 selected genes. Eight genes were identified as significantly mutated, three of which were not previously reported for glioblastoma:

Researchers then mapped the sequencing data with additional genome characterization information onto major biological pathways and identified a highly interconnected network of alterations. By copy number data alone, three critical biological signaling pathways were identified: the Receptor Tyrosine Kinase/Ras/Phosphatidylinositol 3-Kinase pathway (a.k.a. RTK/Ras/PI3K pathway), which controls cell proliferation, cell survival and RNA translation; the p53 signaling pathway, which controls senescence (aging) and apoptosis (cell death); and the Retinoblastoma (RB) signaling pathway, which controls cell cycle progression and cell division. In a given tumor sample, it was likely that there was at least one aberrant gene from each of the three pathways. In fact, 74% of the samples had mutations in all three pathways, suggesting that deregulation of the three pathways is a requirement for glioblastoma pathogenesis.

Oncologists already know glioblastomas that have a methylated MGMT gene (DNA methylation reduces gene expression) respond better to temozolomide, an alkylating chemotherapy drug that is the current standard of care for glioblastoma patients. By integrating methylation data, somatic mutation data and clinical treatment data, scientists identified a relationship between MGMT methylation and a hypermutator phenotype described previously [6]. In patients with MGMT methylation, temozolomide treatment introduces a strong selective pressure to mutate genes that are essential for DNA repair. Thus, patients who initially respond to temozolomide may evolve not only treatment resistance but also a hypermutator phenotype (since DNA repair genes have been mutated). Future selective therapies may therefore require targeting both DNA-repair-deficient cells and an alkylating agent.

National Institutes of Health (NIH) Director Elias A. Zerhouni, M.D. said [7]:

These impressive results from TCGA provide the most comprehensive view to date of the complicated genomic landscape of this deadly cancer. The more we learn about the molecular basis of glioblastoma, the more swiftly we can develop better ways of helping patients with this terrible disease. Clearly, it is time to move ahead and apply the power of large-scale, genomic research to many other types of cancer.

The power of this study lies in the statistically robust number of samples evaluated, allowing for the identification of molecular subtypes that may otherwise be undetectable. Additionally, multiple technologies were employed to identify genomic copy number alterations, which were used to validate the results from any one platform. These approaches highlight the power of comprehensive integrative analyses.

This is an excellent example of how current genome characterization technologies can systematically explore the universe of genomic changes involved in cancer. The TCGA is also studying lung and ovarian cancer.


  1. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008 Sep 4. [Epub ahead of print] DOI: 10.1038/nature07385
    View abstract
  2. Mischel and Cloughesy. Targeted molecular therapy of GBM. Brain Pathol. 2003 Jan;13(1):52-61.
    View abstract
  3. Mischel et al. Molecular analysis of glioblastoma: pathway profiling and its implications for patient therapy. Cancer Biol Ther. 2003 May-Jun;2(3):242-7.
    View abstract
  4. Liang et al. Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme. Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5814-9. Epub 2005 Apr 12.
    View abstract
  5. NIH Launches Comprehensive Effort to Explore Cancer Genomics. National Cancer Institute Office of Media Relations press release. 2005 Dec 13.
  6. Cahill et al. Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res. 2007 Apr 1;13(7):2038-45.
    View abstract
  7. The Cancer Genome Atlas Reports First Results of Comprehensive Study of Brain Tumors: Large-Scale Effort Identifies New Genetic Mutations, Core Pathways. National Cancer Institute Office of Media Relations press release. 2008 Sept 4.
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Other Articles You May Like

Are Indians destined to be diabetic? [Yann Klimentidis' Weblog]

Posted: 22 Sep 2008 10:20 AM CDT

I came across this interesting commentary paper that discusses whether there any particularities about diabetes risk among Indians (in India that is; living in New Mexico forces me to make that clarification). It discusses diabetes from an evolutionary perspective, as well as the link between mitochondrial function and the etiology of diabetes.

Genetic Genealogy Article in the Houston Chronicle [The Genetic Genealogist]

Posted: 22 Sep 2008 06:29 AM CDT

Journalist Maggie Greenhouse writes an entertaining article about genetic genealogy entitled “Who Do You Think You Are? Company Can Help Trace Genetic Ancestry” (Houston Chronicle, Sept. 19, 2008) .  Much of the article is about Oxford Ancestors (OA), a genetic genealogy company based in England, but the article also mentions some companies in the United States:

“Houston is also home to Family Tree DNA, a company that offers the same services as Oxford Ancestors. Last year, Harvard professor Henry Louis Gates joined forces with Family Tree DNA to help African Americans looking for answers about their past. AfricanDNA, the company Gates launched in November 2007, offers both genetic testing and genealogical tracing services for African Americans.”

Interestingly, the article mentions that OA databases have DNA from approximately 30,000 people.  By the way, I also noticed that the OA website has been completely redesigned.  It was a much needed update and looks good

Melamine Scandal Widens [Sciencebase Science Blog]

Posted: 22 Sep 2008 02:15 AM CDT

chinese-babyFour infants in China have died and at least 53,000 are reportedly ill, many seriously so, having been fed milk powder contaminated with the industrial chemical melamine. A three-year old girl in Hong Kong is also ill, but has now been released from hospital, she was the first reported case outside mainland China. Major formula milk producer Nestle says none of its products in China has been contaminated with melamine, although the Hong Kong government says it has found the contaminant in the company’s milk formula.

I guess it’s no surprise that this scandal has emerged after, rather than before or during, the Olympic Games, but that is not something that would be peculiar to China. Governments the world over try to manage bad news and China certainly does not have a monopoly on cover-ups. If melamine is the primary contaminant, then regardless of claims that other compounds may be present, long-term use (six months or so) would be enough for this toxic compound to accumulate in an infant and lead to toxic effects such as kidney stones. The LD50, or acute toxic dose is not entirely relevant if an infant is being fed contaminated milk day after day. Incidentally, LD50 is a measurement per kilogram of body mass, so it is not higher for people than it is for rats, although it may be different because of differences in our body’s biochemistry.

I used to use an analytical instrument when I worked part-time in quality control in a milk-processing plant during my early post-student days. The machine could give you an almost instantaneous printout of fat, protein and sugar levels in the milk passing through the dairy. Those in QC also had to look at the milk for colour and quality and smell and taste it to check for taints (from pipe disinfectants, bacterial action, or contaminants). Indeed, one of the qualifications for the job was to have a palate sensitive enough to detect phenolic (smoky) compounds down to a few parts. It would usually have been quickly apparent if there was a problem with any incoming milk supply and I cannot see how others in the supply chain in China were not duplicitous in this conspiracy.

There could, of course, be other contaminants, I alluded to that in the original melamine in milk post. If someone is unscrupulous enough to add melamine to baby milk falsify protein levels, then there’s no reason why they would use expensive chemically pure material. This would answer partly one of the questions asked by a commenter on the original post. Apparently, th Chinese government reported findings 2565 ppm or 0.25% of melamine in Sanlu’s milk powder. The cost of melamine is relatively high, so what would be the economic justification for such an irresponsible act if it were only increasing the apparent protein level by 1.2%?

The melamine may have been obtained from low-quality sources that are themselves contaminated with other toxic compounds, or it may be high-quality melamine, but stolen to order at some point in the supply chain? It has been suggested that other contaminants may be urea and aminopterin, but I have not seen any official note on that anywhere.

Melamine decomposes on heating, so one commenter on the original post was curious as to how does
survive the
pasteurization and evaporation processes
how does melamine survive the pasteurization and evaporation processes without decomposition used to make milk powder from raw milk.

Apparently, melamine has been mentioned in dispatches across China for more than 15 years, why is it that a pet food scare in 2007, and now this infant formula milk scandal are the only times that the western media has covered the problem?

nissin-cha-cha-dessertIt is becoming apparent that contaminated baby formula is not the only problem. Milk, ice cream, yoghurt, confectionery such as chocolates, biscuits and sweets, as well as any foods containing milk from China have been banned from import into Singapore after the country’s agri-food and veterinary authority found melamine in imported samples. Similarly, Taiwanese authorities seized imported products after notification of contamination from Beijing earlier this month. Japan has recalled various products. Canada’s Food Inspection Agency has warned citizens not to eat a dessert - Nissin Cha Cha Dessert - imported from China that has been found to be contaminated with melamine. The authorities in the Philippines are currently testing.

It is curious, but perhaps not surprising, that the Chinese authorities say not a single hospitalisation case has any connection with contaminated milk. Fonterra, parent company of milk producer Sanlu which is at the centre of the scandal says the whole debacle is one of sabotage and that there is no point in the production process at which melamine could have been added. Fonterra chief executive Andrew Ferrier claims an unknown third party put the banned chemical melamine into raw milk supplied to Sanlu. However, the company new about the contamination on August 2, just ahead of the Olympic Games, and claims that Chinese regulations prevented it from going public at the time.

Melamine Scandal Widens

Comparing genetic admixture methods [Yann Klimentidis' Weblog]

Posted: 21 Sep 2008 11:05 PM CDT

Comparison of Statistical Methods for Estimating Genetic Admixture in a Lung Cancer Study of African Americans and Latinos.
Aldrich MC, Selvin S, Hansen HM, Barcellos LF, Wrensch MR, Sison JD, Quesenberry CP, Kittles RA, Silva G, Buffler PA, Seldin MF, Wiencke JK.
Am J Epidemiol. 2008 Sep 12. [Epub ahead of print]
Abstract: A variety of methods are available for estimating genetic admixture proportions in populations; however, few investigators have conducted detailed comparisons using empirical data. The authors characterized admixture proportions among self-identified African Americans (n = 535) and Latinos (n = 412) living in the San Francisco Bay Area who participated in a lung cancer case-control study (1998-2003). Individual estimates of genetic ancestry based on 184 informative markers were obtained from a Bayesian approach and 2 maximum likelihood approaches and were compared using descriptive statistics, Pearson correlation coefficients, and Bland-Altman plots. Case-control differences in individual admixture proportions were assessed using 2-sample t tests and logistic regression analysis. Results indicated that Bayesian and frequentist approaches to estimating admixture provide similar estimates and inferences. No difference was observed in admixture proportions between African-American cases and controls, but Latino cases and controls significantly differed according to Amerindian and European genetic ancestry. Differences in admixture proportions between Latino cases and controls were not unexpected, since cases were more likely to have been born in the United States. Genetic admixture proportions provide a quantitative measure of ancestry differences among Latinos that can be used in analyses of genetic risk factors.

Autumn Leaves [Sciencebase Science Blog]

Posted: 21 Sep 2008 06:00 PM CDT

autumn-lakeToday, is the first day of autumn, the fall, and Google is celebrating with a new leafy logo. But, why do leaves turn red in the fall? It’s all down to chemistry. Red pigments known as anthocyanins form in leaves from many plant and tree species at the same time as the green photosynthetic apparatus is dismantled by the plant during which nutrients containing nitrogen (N) and phosphorus (P) are re-absorbed by the plant from its leaves for winter storage. If these nutrients are not resorbed next year’s growth is inhibited. As the levels of green compounds in the leaf falls and anthocyanins rise so the leaves of many species change from verdant to rusty with a range of colours in between.

red-leavesFor more information on why leaves turn red in autumn, check out this page from Wisconsin University. Science Made Simple has a nice explanation too as does Dr David Wilkinson from Liverpool John Moore’s University, and the USDA.

Autumn Leaves is a jazz classic about the bittersweet symphony that’s life. My singing group Big Mouth cover it in a medley of standards. I’ve created a playlist of the other songs we cover, on Youtube, these are either original versions or, as Jon points out, oddities.

This is an updated post Sciencebase from November 2006.

Autumn Leaves

Do mosquitoes get the mumps?, part I [Discovering Biology in a Digital World]

Posted: 21 Sep 2008 04:03 PM CDT

Part I. The back story from the genome record

Together, these five posts describe the discovery of a novel paramyxovirus in the Aedes aegyptii genome and a new method for finding interesting anomalies in GenBank.

I. The back story from the genome record
II. What do the mumps proteins do? And how do we find out?
III. Serendipity strikes when we Blink.
IV. Assembling the details of the case for a mosquito paramyxovirus
V. A general method for finding interesting things in GenBank

Read the rest of this post... | Read the comments on this post...

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