Science Weekly: Getting high and the threat of climate war

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Mind-altering drugs; War as a consequence of climate change; Why some areas of science are too difficult to explain through sound alone; plus, next month’s Guardian science book club

New Publication on Risk-Based Source Data Verification Approaches: Pros and Cons

Target Health is pleased to announce that Dr. Jules T. Mitchel is a co-author of an article entitled: “Risk-Based Source Data Verification Approaches: Pros and Cons,” published in the November issue of the DIA Jounal (pages 745-756). Our friend and colleague Vadim Tantsyura (Infinity Pharmaceuticals) is the lead author on this very important paper . We can also send you a .pdf version by request.

This paper evaluates the FDA supported risk-based approach to SDV and provides a proposal on how to modify the SDV process without undermining the validity and integrity of the trial data. It summarizes alternative approaches to 100% SDV and evaluates the advantages, disadvantages of risk-based SDV (rSDV). The regulatory, data quality and cost implications of each approach are considered. The economics of rSDV is discussed and the cost implications of rSDV are presented based on the results of exploratory analyses for four hypothetical trials in cardiology and oncology.

For more information about Target Health contact Warren Pearlson (212-681-2100 ext 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

Researchers Unlock a Secret of Bacteria’s Immune System

Structural overview of the T4 phage

A team of Universite Laval and Danisco researchers has unlocked a secret of bacteria’s immune system. The details of the discovery, which may eventually make it possible to prevent certain 1) ___ from developing resistance to antibiotics, are presented in the Nov. 4 issue of the journal Nature.

The team led by Professor Sylvain Moineau of Universite Laval’s Department of Biochemistry, Microbiology, and Bioinformatics showed that this mechanism, called CRISPR/Cas, works by selecting foreign DNA segments and inserting them into very specific locations in a bacterium’s 2) ___. These segments then serve as a kind of immune factor in fighting off future 3) ___ by cleaving incoming DNA.

The researchers demonstrated this mechanism using plasmids, DNA molecules that are regularly exchanged by bacteria. The plasmid used in the experiment, which contained a gene for antibiotic resistance, was inserted into bacteria used in making 4) ___, Streptococcus thermophilus. Some of the bacteria integrated the segments of DNA from the resistance gene into their genome, and subsequent attempts to reinsert the plasmid into these bacteria failed. “These bacteria had simply been immunized against acquiring the resistance gene, commented Professor Moineau. This phenomenon could explain, among other things, why some bacteria develop 5) ___ resistance while others don’t.”

The CRISPR/Cas immune system also protects bacteria from bacteriophages, a group of 6) ___ that specifically target bacteria. This makes Professor Moineau’s discovery particularly interesting for food and biotechnology sectors that use bacterial cultures, such as the yogurt, cheese, and probiotics industries. Bacterial culture contamination by 7) ___ is a serious concern with considerable financial implications for those industries.

ANSWERS: 1) bacteria; 2) genome; 3) invasions; 4) yogurt; 5) antibiotic; 6) viruses; 7) bacteriophages

From Neanderthals to Ozzy Osbourne…DNA Rocks

Ozzy Osbourne in 2010


Target Health Inc. attended the Tedmed conference in San Diego, the last week of October 2010, where on the last day of the conference, Ozzy and Sharon Osbourne discussed their decision to have their individual genomes mapped. The appearance of these two rock celebrities, caused a stir. Some attendees thought it made T less serious. Target Health Inc: “The more people who understand the importance of individually mapped genomes, the better, because genome mapping leads to personalized medicine, plus the cost of doing it, goes down.”

Last year, shortly after completing work on rock music legend Ozzy Osbourne’s memoir, I Am Ozzy, the Sunday Times (London) reporter Chris Ayres was sitting next to Knome CEO Jorge Conde at the TedMed conference in San Diego. As a result, John Michael “Ozzy” Osbourne, the former lead singer of Black Sabbath, has become the latest member of the celebrity genome club, joining Glenn Close, Archbishop Desmond Tutu, Jim Watson, Craig Venter, Henry ‘Skip’ Gates and others. On October 24, Osbourne penned an absorbing 3,500-word account in the Sunday Times Magazine of his reaction to being presented with his personal genome on a souped-up thumb drive.

Osbourne is a curious character for a genome sequencing project, but his lively musical career, characterized by controversial episodes involving the occasional decapitation of birds and bats onstage and the consumption of copious quantities of drugs and alcohol, made Ayres and others curious as to whether the secret of his extraordinary longevity lies in the sequence of his DNA.

The sequencing was conducted at St Louis-based Cofactor Genomics, performed on the Life Technologies SOLiD 4 platform, which also assisted in the early bioinformatic analysis. The final genomic interpretation and presentation was handled by Knome. Cofactor offers Life Technologies’ SOLiD 4 and Illumina’s GA IIx instruments, and is contemplating whether to acquire Illumina’s HiSeq 2000. Cofactor is preparing a major project with Sigma to sequence the genomes of several strains of rat and build a publicly available database of rat genomic variation.

As for Ozzy, Armstrong was approached by Life Technologies asking if he would be interested in “an amazing opportunity” that had come up. He was told that Life Technologies “needed this done right the first time.” Ozzy was not Cofactor’s first whole genome sequence, but it was Cofactor’s first serious use of the SOLiD 4 machine.

Cofactor generated 39 Gigabases of Osbourne’s sequence (13X coverage) over about three weeks using both long-insert mate pairs and fragment reads. (Human genomes are usually sequenced to 30X coverage, but Osbourne’s sequence was time sensitive.) About 70% of the DNA reads were mappable, which is considered very good.

BioScope was used to map Ozzy’s sequence reads to the human reference genome (HG18); the process took about 8-10 hours. From there, BAM files were created, which were then used for the tertiary analysis. The BAM file returned the SNPs and small indels. Knome took the assembled sequence and ran it through its internal analysis pipeline, producing a richly annotated genome and a set of interesting DNA variants to select for further analysis. Knome’s director of research, Nathan Pearson, then flew to the UK recently to deliver Osbourne’s results in person, but not before he had conferred with Osbourne’s wife, Sharon, a judge on America’s Got Talent.

Knome also found a novel variant in the ADH4 alcohol metabolizing gene, which might explain Osbourne’s legendary high tolerance for alcohol. Ironically, Osbourne is highly sensitive to caffeine, and has the genetic variant to prove it. Another interesting variant was in the COMT gene. Osbourne carries two versions of the gene that have been associated with “worrier” and “warrior” behavioral tendencies.

Another interesting tidbit was the ability to screen Osbourne’s genome for traces of Neanderthal DNA, following new evidence of ancient inter-breeding between humans and Neanderthals emerging from the Neanderthal genome study.

By sequencing his genome, it has been shown that Ozzy Osbourne is a descendant of Neanderthal man, according to researchers who have studied the singer’s DNA, as well as, sharing some DNA with the ancient Romans who were killed in Pompeii when Mount Vesuvius erupted in 79 AD. He is also a distant relative of outlaw Jesse James, the last Russian tsar Nicholas II and King George I.


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Genetic Elements That Influence The Risk Of Type 2 Diabetes

Previously known as adult-onset, or non-insulin dependent diabetes mellitus, type 2 diabetes usually appears after age 40, often in overweight, sedentary people. However, a growing number of younger people – and even children – are developing the disease.

Diabetes is a major cause of heart disease and stroke in U.S. adults, as well as the most common cause of blindness, kidney failure and amputations not related to trauma. Type 2 diabetes is characterized by the resistance of target tissues to respond to insulin, which controls glucose levels in the blood. This leads to gradual failure of insulin-secreting cells in the pancreatic islets.

Epigenomic research focuses on the mechanisms that regulate the expression of genes in the human genome. Genetic information is written in the chemical language of DNA, a long molecule of nucleic acid wound around specialized proteins called histones. Together, they constitute chromatin, the DNA-protein complex that forms chromosomes during cell division.

A study published in Cell Metabolism (2010;12:443-455) has captured the most comprehensive snapshot to date of DNA regions that regulate genes in human pancreatic islet cells, a subset of which produces insulin. The study highlights the importance of genome regulatory sequences in human health and disease, particularly type 2 diabetes, which affects more than 20 million people in the United States and 200 million people worldwide. According to National Human Genome Research Institute (NHGRI) Scientific Director Daniel Kastner, M.D., Ph.D. “Epigenomic studies are exciting new avenues for genomic analysis, providing the opportunity to peer deeper into genome function, and giving rise to new insights about our genome’s adaptability and potential.”

The study used DNA sequencing technology to search the chromatin of islet cells for specific histone modifications and other signals marking regulatory DNA. Computational analysis of the large amounts of DNA sequence data generated in this study identified different classes of regulatory DNA. Among the results, about 18,000 promoters were detected, which are regulatory sequences immediately adjacent to the start of genes. Promoters are like molecular on-off switches and more than one switch can control a gene. Several hundred of these were previously unknown and found to be highly active in the islet cells.

The study also identified at least 34,000 distal regulatory elements, so called because they are farther away from the genes. Many of these were bunched together, suggesting they may cooperate to form regulatory modules. These modules may be unique to islets and play an important role in the maintenance of blood glucose levels.

“Genome-wide association studies have told us there are genetic differences between type 2 diabetic and non-diabetic individuals in specific regions of the genome, but substantial efforts are required to understand how these differences contribute to disease,” said co-lead author Michael Stitzel, Ph.D., NHGRI postdoctoral fellow. “Defining regulatory elements in human islets is a critical first step to understanding the molecular and biological effects for some of the genetic variants statistically associated with type 2 diabetes.”

The study also found that 50 single nucleotide polymorphisms, or genetic variants, associated with islet-related traits or diseases are located within or very close to non-promoter regulatory elements. Variants associated with type 2 diabetes are present in six such elements that function to boost gene activity. These results suggest that regulatory elements may be a key component to understanding the molecular defects that contribute to type 2 diabetes.

Fructose-Rich Beverages and Risk of Gout in Women

Fructose-rich beverages such as sugar-sweetened soda and orange juice can increase serum uric acid levels and, thus, the risk of gout, but prospective data on the relationship are limited. As a result, a study published online in the Journal of the American medical Association (10 November 2010) was performed to examine the relationship between intake of fructose-rich beverages and fructose and the risk of incident gout among women.

The study analyzed data from 78,906 women who participated in the Nurses’ Health Study, a US prospective cohort study spanning 22 years (1984-2006). Study participants had no history of gout at the baseline visit and provided information on intake of beverages and fructose through validated food frequency questionnaires during the course of the study. The main outcome measure was incident cases that met the American College of Rheumatology survey criteria for gout.

During the 22 years of follow-up, 778 confirmed incident cases of gout were documented. Increasing intake of sugar-sweetened soda was independently associated with increasing risk of gout. Compared with consumption of less than 1 serving per month of sugar-sweetened soda, the multivariate relative risk of gout for 1 serving per day was 1.74 and for 2 or more servings per day was 2.39 (P<.001 for trend). The corresponding relative risks for orange juice were 1.41 and 2.42 (P = .02 for trend). The absolute risk differences corresponding to these relative risks were 36 and 68 cases per 100,000 person-years for sugar-sweetened soda and 14 and 47 cases per 100,000 person-years for orange juice, respectively. Diet soft drinks were not associated with the risk of gout (P = .27 for trend). Compared with the lowest quintile of fructose intake, the multivariate relative risk of gout in the top quintile was 1.62; P = .004 for trend).

According to the authors, consumption of fructose-rich beverages is associated with an increased risk of incident gout, although the contribution of these beverages to the risk of gout in the population is likely modest given the low incidence rate among women.


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Dietary Intervention in Infancy and Later Signs of Beta-Cell Autoimmunity

Early exposure to complex dietary proteins may increase the risk of beta-cell autoimmunity and type 1 diabetes in children with genetic susceptibility. As a result, a study published in the New England Journal of Medicine (2010;363:1900-1908) was performed to test the hypothesis that supplementing breast milk with highly hydrolyzed milk formula would decrease the cumulative incidence of diabetes-associated autoantibodies in such children.

For the study, 230 infants with HLA-conferred susceptibility to type 1 diabetes and at least one family member with type 1 diabetes was randomized to receive either a casein hydrolysate formula or a conventional, cow’s-milk-based formula (control) whenever breast milk was not available during the first 6 to 8 months of life. Autoantibodies to insulin, glutamic acid decarboxylase (GAD), the insulinoma-associated 2 molecule (IA-2), and zinc transporter 8 were analyzed with the use of radiobinding assays, and islet-cell antibodies were analyzed with the use of immunofluorescence, during a median observation period of 10 years (mean, 7.5). The children were monitored for incident type 1 diabetes until they were 10 years of age.

During the study, 16 children developed type 1 diabetes by age 10: seven in the hydrolysate group and nine in the control group. The data suggest that weaning to a highly hydrolyzed formula‚ as compared with a cow’s-milk-based formula‚ was associated with a decreased risk of positivity for at least one diabetes-associated autoantibody‚ as reflected by an unadjusted hazard ration with the highly hydrolyzed formula of 0.54 and by a hazard ratio after adjustment for the difference in the duration of exposure to the study formula of 0.51. The unadjusted hazard ratio for positivity for two or more autoantibodies was 0.52, and the adjusted hazard ratio was 0.47. The rate of reported adverse events was similar in the two groups.

According to the authors, dietary intervention during infancy appears to have a long-lasting effect on markers of beta-cell autoimmunity and that these markers that may reflect an autoimmune process leading to type 1 diabetes.

TARGET HEALTH excels in Regulatory Affairs and Public Policy issues. Each week we highlight new information in these challenging areas.

HHS Announces New Tobacco Strategy and Proposed New Warnings and Graphics For Cigarette Packs and Advertisements

Tobacco use is the leading cause of premature and preventable death in the United States, responsible for 443,000 deaths each year. Thirty percent of all cancer deaths are due to tobacco. Each day 1,200 lives of current and former smokers are lost prematurely due to tobacco-related diseases. Every day, almost 4,000 youth try a cigarette for the first time and 1,000 youth become regular, daily smokers.

The U.S. Department of Health and Human Services today unveiled a new comprehensive tobacco control strategy that includes proposed new bolder health warnings on cigarette packages and advertisements. Once final, these health warnings on cigarettes and in cigarette advertisements will be the most significant change in more than 25 years. These actions are part of a broader strategy that will help tobacco users quit and prevent children from starting.

The strategy includes a proposal issued by the FDA titled Required Warnings for Cigarette Packages and Advertisements. Specifically, the proposed rule details a requirement of the Family Smoking Prevention and Tobacco Control Act that nine new larger and more noticeable textual warning statements and color graphic images depicting the negative health consequences of smoking appear on cigarette packages and in cigarette advertisements. The public has an opportunity to comment on 36 proposed images through January 9, 2011.

By June 22, 2011, FDA will select the final nine graphic and textual warning statements after a comprehensive review of the relevant scientific literature, the public comments, and results from an 18,000 person study. Implementation of the final rule (September 22, 2012) will ultimately prohibit companies from manufacturing cigarettes without new graphic health warnings on their packages for sale or distribution in the United States. In addition, manufacturers, importers, distributors and retailers will no longer be allowed to advertise cigarettes without the new graphic health warnings in the United States. By October 22, 2012, manufacturers can no longer distribute cigarettes for sale in the United States that do not display the new graphic health warnings. 

The FDA action is part of a broad department-wide strategy that was announced by Assistant Secretary for Health Howard K. Koh, M.D., MPH. While progress has been made, smoking remains particularly high with low-income and within certain racial/ethnic groups and in certain populations, including people with mental illnesses and substance abuse disorders. Ending the Tobacco Epidemic: A Tobacco Control strategic Action Plan outlines specific, evidence-based actions that will help create a society free of tobacco-related death and disease. 

In addition to the announcements made today, other recent tobacco control and prevention efforts include:

  1. The Affordable Care Act is giving Americans in private and public health plans access to recommended preventive care, like tobacco use cessation, at no additional cost.
  2. The American Recovery and Reinvestment Act (ARRA) invested $225 million to support local, state and national efforts to promote comprehensive tobacco control and expand tobacco quitlines.
  3. The Prevent All Cigarette Trafficking Act (PACT) aims to stop the illegal sale of tobacco products over the Internet and through mail order, including the illegal sale to youth.
  4. The Family Smoking Prevention and Tobacco Control Act (FSPTCA) gives FDA the authority to regulate the manufacture, marketing and distribution of tobacco products. Significant progress has already been made by restricting the use of the terms “light,” “low,” and “mild,” banning characterizing fruit, candy, and spice, flavors from cigarettes, and putting in place restrictions on the sale and distribution of cigarettes and smokeless tobacco products to youth.
  5. The Children’s Health Insurance Program Reauthorization Act (CHIPRA) raised the federal cigarette tax by 62 cents per pack. Raising the price of tobacco products is a proven way to reduce tobacco use, especially among price-sensitive populations such as youth


For more information about our expertise in Medical Affairs, contact Dr. Mark L. Horn. For Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.