If All Scientists Worked Like Dr. Kochi

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An article this week in The New York Times highlighted the work of Dr. Arata Kochi, the Japanese chief of the World Health Organization’s global malaria program.

Dr. Kochi is, by all accounts, exactly the kind of role model that scientists around the world should look up to. He doesn’t soften his stance on combatting the global health crisis of malaria when it comes to the interests of business.

    In January, he attacked the drug industry, naming 18 companies that were selling artemisinin in single-pill form, and giving them 90 days to stop. Monotherapy encourages resistance, and if artemisinin was lost, he said, “it will be at least 10 years before a drug that good is discovered — basically, we’re dead.”

    If the companies refused to conform, he said, he would disrupt sales of all their drugs by getting the W.H.O. to refuse to certify any drug they made for poor countries.

And this abrasive doctor is looking for results, not friends.
    For example, he wants to standardize mosquito nets so that, instead of a welter of competing styles that must be home-dunked in pesticide, a few makers of factory-coated nets, which kill insects for years longer, are left to compete on price. He dismisses “social marketing,” in which nets are branded and sold cheaply instead of being given away, as with an early Bush administration policy that flopped. And, despite the objections of environmentalists, he wants DDT sprayed inside huts to kill mosquitoes where they rest on walls as they wait for dark.
Dr. Kochi, it seems, is willing to ruffle feathers in order to accomplish his goal of reducing the scourge of malaria.

The question is, how many scientists are willing to ruffle feathers to get something meaningful accomplished? Would that extra risk be worth, say, losing your chance at tenure? Or losing your opportunity to move up to associate director of your company’s R&D department? How many scientists have lost their focus; become apathetic; become accustomed to accepting the status quo?

So with a gentle reminder from Dr. Kochi, maybe it’s time for some of us to focus more on getting results. After all, getting results is what really matters.

Epigenomics to Use Affymetrix Platform

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Epigenomics AG has announced that it will use Affymetrix microarray technology in its in-vitro diagnostic (IVD) tests for oncology and other indications. The Affymetrix technology, along with Epigenomics’ previously announced alliance with Qiagen for sample preparation, will allow for Epigenomics to provide a “complete platform” for its DNA methylation marker pathology tests.

The first use of the Affymetrix platform will be in Epigenomics’ Molecular Classification Test (MCT) for prostate cancer, which is scheduled to begin clinical trials for FDA approval next year. Link

Grand Rounds: The Latest in Medical Blogging

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Grand Rounds, a medical carnival dedicated to highlighting some of the choice pieces of medicine-related posts from around the blogosphere, has a new edition available at Medviews. This edition includes a number of science-related posts, as well as some great commentary and stories from nurses, doctors, and other frontliners in clinical medicine.

I would like to thank Dr. Stuart Henochowicz, this week’s host, for choosing to include my recent piece on the epigenetics of systemic lupus erythematatosis (SLE). This happens to be Epigenetics News’ first inclusion in a carnival, but hopefully not its last. Link

Epigenetic Map of Human Chromosomes 6, 20, and 22 Released

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Epigenomics AG and the Wellcome Trust Sanger Institute have released new data mapping the epigenetic state of human chromosomes 6, 20, and 22, providing the first tangible product of the Human Epigenome Project (HEP).

The analysis was completed using 43 human samples, and examined the methylation patterns in 12 different tissues. This was done in part to identify genes that are differentially methylated between DNA from various human tissues, which could affect gene expression.

Thus far, Epigenomics claims that the data is exciting because after examining over 2,500 different genomic loci, it found that “21 percent of all loci, or 17 percent of all genes on these chromosomes are differentially methylated in at least one of the examined tissue.” The company plans to publish details of these differentially methylated locations in the coming months.

The results of the whole chromosome analysis are patented. However, the methylation states of these three human chromosomes are available today through the Human Epigenome Project web site for use by non-commercial research groups. Link

The U.S. Population Cohort Project on Genes, Environment, and Disease, Draft Report: Part I

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This is part one of a series examining the draft report of the Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS) entitled “Policy Issues Associated with Undertaking a Large U.S. Population Cohort Project on Genes, Environment, and Disease.” The Committee is seeking comment from the public until July 31, 2006.

In May 2004, National Human Genome Research Institute Director Francis S. Collins made his case in Nature that the “time is right” for the Unites States to consider a prospective cohort study in which a large number of individuals within the U.S. would be monitored over time for the combination of genes and environment that may contribute to the causes of disease. In the article, Dr. Collins outlined a number of key characteristics that the study should have:

  • A large number of participants, at least several hundred thousand, should be enrolled. This would ensure an adequate sample size for common disorders, particularly for gene-environment interactions.
  • Minority groups should be intentionally over-sampled to permit meaningful inferences about these groups and for the study of health disparities.
  • A broad range of ages should be represented to provide information on disorders from infancy to old age, with over-sampling of age groups as needed.
  • A broad range of genetic backgrounds and environmental exposures should be included to provide enough variability to detect and compare associations and interactions.
  • Family-based recruitment, including multiple generations, should be used for at least part of the cohort to increase the power of genetic analyses.
  • A broad array of clinical and laboratory information, not limited to any single disease, should be collected at the beginning and at regular intervals thereafter.
  • Sophisticated dietary, lifestyle and environmental exposure assessments should be carried out, using both questionnaires and biological measures.
  • Biological specimens, including DNA, plasma and cells, should be collected and stored.
  • A highly sophisticated data-management system should be included.
  • Access to study data and biological materials should be free and open to allow research into many diseases by scientists in many sectors.
  • Investigations during the study should not be limited to hypotheses conceived at its inception.
  • Comprehensive community engagement should be a major feature in the design and implementation of the study.
  • A state-of-the-art consent process should be adopted to allow multiple uses of the data and regular feedback to participants about progress.

The implications of the project would be substantial, particularly for researchers in the U.S. As the report notes:
    In this report, SACGHS uses the term “project” to refer to an effort that would involve the longitudinal collection and storage of data and biological specimens from large numbers of people for the research use of multiple investigators and investigative teams.
In addition, the report expresses the concern of some investigators that such a large-scale project would undermine the ability of current investigators-both in the study of genes and environment and other area-to retain funding for their existing projects.

Overall, the report aims to focus only on “preliminary and intermediate questions, steps, and strategies in five areas that need to be addressed before considering the larger question of whether the United States should undertake such a project: research policy; research logistics; regulatory and ethical considerations; the public health implications of the project; and the social implications of the project.” As such, many of the specific details of the project, such as the type of data and specimens that would be collected, are left for future discussion.

Taking the Public’s View Into Consideration

One of the most widely discussed topics of the report is the strong recommendation that the public’s views and comments be taken into consideration before a funding decision is made for the project. The Committee makes only a very generalized recommendation for how these comments would be collected:

    The public’s willingness to participate in a large population project should be assessed before embarking on such an expensive endeavor. Willingness could be assessed through opinion polls, requests for comments posted on agency websites, or through other measures.
The Committee also expresses concern that “most members of the public will be unfamiliar with the concepts of a large population project,”so “concerted efforts must be made to educate, inform, and solicit feedback and input.”

Issues Related to Research Policy of the Project

There are several strategies that are proposed in the report for the undertaking of the project, and the Committee itself seems to be in debate over which approach would be best suited for its viability.

    …although a large cohort project may be needed to collect sufficient data to elucidate the contribution of genetic variation and environmental factors to common diseases, some believe it may not necessarily lead to a better understanding of common diseases or population health benefits if it does not include a carefully designed, hypothesis-driven, disease-specific component. Others believe that such a project cannot be hypothesis driven, but rather that it should be a viewed as a data and tissue resource for researchers to mine.
The next part of the series will delve into the recommendations the Committee makes to the Secretary into resolving these and other issues as the project moves towards a funding decision.

10 Best Things About Being an Undergraduate Researcher

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1. You get to do a lot of the work, and get none very little of the credit.
2. There’s no reason to worry about trying to get your papers in “high impact” journals.
3. Living from paycheck to paycheck is always exciting.
4. Undergraduates get to repeatedly run the same assays over and over again.
5. You get to offer up ideas on a project that someone else can take credit for later.
6. I’ve never had a job before where talking about sex passed as productivity.
7. Undergrads get to play stupid when they accidentally order $1,000 in primers, and nobody questions how it happened.
8. Working with a model organism that would love to sink its teeth into you.
9. You don’t have concerns about who will ever hire you after the hack job you just pulled on your latest study.
10. The big job perks: splashes of fixative and inhaling chloroform.

Hypermethylation of WRN Gene Promoter Linked to Human Cancer

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New research published in the Proceedings of the National Academy of Sciences suggests that increased methylation of the promoter sequence of the WRN gene is highly correlated with inactivation of the gene in human cancer cell lines.

    In this manuscript, we demonstrate that WRN undergoes CpG island promoter methylation-associated gene silencing in human cancer cells. The hypermethylation of the WRN promoter leads to its loss of expression and hypersensitivity to topoisomerase inhibitors and DNA-damaging agents. The epigenetic loss of WRN function can be rescued by the use of DNA-demethylating agents. Furthermore, the reintroduction of WRN into those transformed cell lines with WRN-deficiency due to hypermethylation provokes a reduction in colony formation and a decrease in growth of tumor xenografts, supporting the hypothesis that WRN has a tumor-suppressor role. The analysis of a large panel of human primary tumors (n = 630) shows that WRN CpG island hypermethylation is a common event in tumorigenesis. Most importantly, for colorectal cancer, the presence of aberrant methylation at the WRN promoter predicts improved survival in those patients treated with irinotecan, a topoisomerase inhibitor commonly used in this neoplasm. These findings underline the significance of WRN as a caretaker of our genome with tumor-suppressor activity and identify epigenetic silencing of WRN as a key step in cancer development that may have an important clinical influence on the treatment of these patients.

New Advances in Epigenetics and Cancer

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Therapeutics Daily provides a summary of several recent research articles published involving new discoveries into the epigenetic mechanisms that contribute to the onset and spread of certain cancers. In one study, researchers report that epigenetically silenced tumor suppressors overcome resistance to apoptosis induction by interferons. The other studies probe for new insights into the link between epigenetics and colorectal carcinomas as well as prostate cancer tumorigenesis. Link

Maternal vs. Paternal Imprinting: A Brief Review

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The July edition of Nature Reviews Genetics contains a brief article summarizing recent research into the question, “Do mothers and fathers imprint differently?”

    Two imprinting mechanisms have been described to date: one involves an imprinting control region (ICR) at the well-studied H19/Igf2 locus. On the maternal chromosome the ICR acts as an insulator to inhibit expression of Igf2, whereas DNA methylation of the ICR on the paternal allele spreads to and silences the H19 gene. The other mechanism involves an ICR that acts as a promoter for a paternally expressed non-coding RNA, first described at the Igf2r locus by Denise Barlow and colleagues. Kcnq1ot1 is the second example of a non-coding RNA with a direct role in the silencing of imprinted genes. The fact that the activity of the ICR in the first mechanism occurs on the maternal chromosome whereas in the second, described by Tilghman and colleagues, the activity applies to the paternal chromosome raises the possibility that the two mechanisms are gender-specific. Understanding how other clusters of imprinted genes are silenced should verify this interesting possibility.
The research paper from Mancini-DiNardo, D. et al. entitled “Elongation of the Kcnq1ot1 transcript is required for genomic imprinting of neighboring genes” appeared in volume 20 of Genes Development. (The research highlights from NRG are free to the public, registration required.) Link

The Epigenetics of Systemic Lupus Erythematosus (SLE)

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Systemic Lupus Erythematosus (SLE), which is the most common form of lupus, affects one out of every 285 Americans (Lupus Research Institute). Lupus is characterized as an autoimmune disorder, in which the immune system becomes hyperactive and produces antibodies that attack normal tissues and organs, such as the skin, brain, kidney, heart, lungs, and blood. Most people with lupus lapse between periods of illness, called flares, and periods of remission. Lupus can be a particularly debilitating disease, with symptoms that may include swollen and painful joints, severe fatigue, abnormal blood clotting, chest pain upon deep breathing, and seizures.

While these symptoms are treatable, and the majority of those who are affected by lupus are able to lead normal, healthy lives, the cause and development of SLE is poorly understood. The investigation of epigenetic mechanisms that may lead to development of lupus may be key to improved treatment options for those that suffer with this autoimmune inflammatory disease.

The June edition of the Journal of Immunology contains a brief review by Ballestar et al. on the research findings that point to an epigenetic “face” to the cause of SLE. For instance, drugs that demethylate T cells, such as 5-azacytidine, are used by researchers to induce lupus-like disease in mice. Additionally, demethylation of certain gene promoter and regulatory sequences contributes to aberrant overexpression of various genes. Both of these findings suggest that DNA methylation may play a role in the development of lupus.

Histone modifications may also play a role in the development of SLE. SLE Th cells show abnormal expression of certain gene products involved in regulation of the immune system, but these effects can be reversed with treatment using a histone deacetylase inhibitor. This finding provides evidence that histone modifications, another epigenetic alteration, could play a role in the development of lupus as well.

The authors of the paper make a strong recommendation for further research investigating the role that epigenetic alterations may play in developing lupus. “We truly believe,” the authors note, “that the future in the treatment of SLE depends greatly on the ability to revert epigenetic alterations…” Link

David Haig Talks Genomic Imprinting

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David Haig, associate professor of organismic and evolutionary biology at Harvard University, is interviewed in ten questions with Razib at Gene Expression. The interview covers a number of topics on genomic imprinting, as well as the role of epistasis in evolutionary processes, maternally- and paternally-expressed genes, and the potential effects of deleterious mutations on the human population. Link

New Genetics Carnival: Mendel’s Garden

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A new carnival devoted to covering the latest writing in the realm of genetics, Mendel’s Garden, has published its debut edition at The force that through…. Among the myriad of links included is one to a primer on a interference RNA (RNAi), including microRNA (miRNA), that may provide some helpful background information pertaining to the recent research implicating miRNA in the inhibition of a cancer gene in human cancer cells. Link

Links of Interest

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I’ve come across some interesting posts over the past few days, and thought I would share:

Retrospectacle, written by a PhD candidate in neuroscience at the University of Michigan, has a great primer on how to get into a good graduate school in the sciences. As an undergraduate who is planning to pursue graduate work after graduation, this speaks my language.

I was struck by the irony of the unforgettable story of a scientist watching a drug that he helped develop save his son’s life.

And finally, I couldn’t help but read through the New York TImes article, “The Student: Forgive Us Our Student Debts” [registration required].

microRNA Inhibits Cancer Gene in Human Cancer Cells

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The June edition of Cancer Cell offers new research from Peter A. Jones and colleagues that “demonstrates that agents known to regulate gene expression can also impact regulatory RNAs that may function as tumor suppressors in normal cells and proposes a novel strategy for treating human cancers.”

    DNA methylation and histone deacetylation are epigenetic processes involved in the regulation of gene expression. In the case of cancer, these processes are thought to turn off genes that may protect cells from abnormal cell growth. Drugs that inhibit DNA methylation and histone deacetylation, known as chromatin-modifying drugs, can reactivate genes that have been abnormally silenced in cancer cells. It is conceivable that these processes may also regulate expression of some RNAs.

    MicroRNA (miRNA) is small and noncoding RNA that can regulate gene expression by inhibiting protein translation. Recent research has implicated miRNAs in cancer development and has led to the observation that some miRNAs are reduced in various human cancers and may normally function as tumor suppressors. According to study author Dr. Peter A. Jones from the Norris Comprehensive Cancer Center at the University of Southern California in Los Angeles, “Although the biological importance of miRNA is becoming increasingly apparent, regulation of miRNA expression is not fully understood.”

    Dr. Jones and his colleagues examined whether miRNAs can be controlled by epigenetic alterations linked to chromatin remodeling. Cancer cells and normal cells were treated with chromatin-remodeling drugs to simultaneously inhibit DNA methylation and histone deacetylation. A subset of miRNAs was upregulated in the cancer cells but not the normal cells. Importantly, miR-127, which is downregulated in 75% of the human cancer cells tested, was highly induced after treatment with the chromatin-remodeling drugs. Induction of miR-127 resulted in downregulation of BCL6, a known proto-oncogene. Therefore, induction of miR-127 by treatment with chromatin-remodeling drugs may have an anticancer effect.

The study is significant in showing that miRNAs could be a novel therapeutic target for anticancer therapies. Link

Endocrine Disruptors and Epigenetics in an Evolutionary Perspective

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Evolutionary biologist David Crews and colleague John McLachlan have published an interesting paper in the endocrine disruptor supplement in the June edition of the journal Endocrinology entitled “Epigenetics, Evolution, Endocrine Disruption, Health, and Disease.” The paper takes a closer look at some of the key research findings made in the last year in the area of epigenetics and how epigenetic modifications passed on to multiple generations may “become incorporated into the genome and subject to selection.”

    It is well known that EDCs [endocrine-disrupting chemicals], and very likely endogenous hormones, can act on a gene’s developmental mechanisms, altering phenotype expression. We are now seeing that the mechanism of these phenotypic changes is probably epigenetic; in other words, they cause mitotically heritable changes in gene function without changing the DNA sequence, i.e without mutation. In fact, EDCs do not act on genes alone but on developmental mechanisms that integrate genetic and epigenetic interactions, resulting in the phenotype. Link