Science Weekly: Our evolutionary agony aunt, and hiding from aliens

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Our evolutionary agony aunt dishes out some relationship advice, why Earth is hiding from aliens, and ginger dinosaurs

Science Weekly Extra: Kennedy v coal baron

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A debate on mountaintop mining between Bobby Kennedy Jr and Don Blankenship of Massey Energy

Target Health Europe

Target Health is pleased to announce that Carsten Junge Pedersen will be representing Target Health in Europe, doing Business Development and Data Management services for European clients. This service will include promotion of Target Health’s Data Management, Clinical Trial Software and CRO services. Carsten is certified in Nursing from Copenhagen and Business Computing from New Zealand. Carsten worked in Data Management for Novo Nordisk, and participated in Change Management programs and in a business reengineering project as Manager for Data Management in AstraZeneca Denmark. As Director for Data Management at Ferring Pharmaceuticals, Carsten was been involved in CDISC implementation project lead in a DM process development project.

Contact Carsten at:
Baneledet 8
DK-2830 Virum
Denmark
Mobile: +45 4166 9000

For more information about Target Health and our software tools for paperless clinical trials, please contact Dr. Jules T. Mitchel (212-681-2100 ext 0) or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health at www.targethealth.com

Made-to-Order Heart Cells

Last month, Madison, WI-based Cellular Dynamics International (CDI) began shipping heart cells derived from a person’s own 1) ___ cells. The cells could be useful to researchers studying everything from the toxicity of new or existing drugs to the electrodynamics of both healthy and diseased cardiac cells. CDI’s scientists create their 2) ___ cells–called iCell Cardiomyocytes–by taking cells from a person’s own blood (or other tissue) and chemically reversing them back to a pluripotent state. This means they are able to grow or can be programmed to grow into any cell in the 3) ___. The science comes from the lab of CDI cofounder and stem-cell pioneer James Thomson of the University of Wisconsin. In 2007, his lab published a study that detailed how to reverse virtually any human cell back to an undifferentiated state known as an induced pluripotent stem 4) ___, or IPS cell. “One of the biggest advantages of these cells is we can make them in quantity and on demand,” says CDI CEO Robert Paley. “Before, you had to get heart cells from a cadaver, so there was a limited supply.” Now, a customer receives all of the different types of heart cells in a vial about the size of the tip of a little finger; some of the 1.5 million to 5 million heart cells in the vial can be induced to pulse when placed in a petri 5) ___. CDI designed the cardiac cells primarily to aid drug discovery and to help predict the efficacy and toxicity of different drugs. Other tests might include screens to determine if there are differences in how various ethnicities and other genetic subpopulations respond to drugs – such populations can be at higher risk for side effects from drugs, and at a higher risk for the drugs simply not working. Some researchers also plan to see how cells derived from patients with different types of heart disease respond to particular 6) ___. The cells provided by CDI also offer a ready supply for scientists conducting basic research in how cardiac cells function. But they do not come cheap. Paley says they cost about $1,000 for a vial, compared to about $800 for cells from 7) ___, though the latter are not as readily available, and they don’t beat in a petri dish, limiting researchers’ ability to study the electrodynamics of heart cells. IPS-derived cells also have the potential to become a powerful predictive tool when combined with 8) ___ profiling that identifies genetic predispositions to adverse reactions to drugs. Cells derived from people with DNA markers giving them a high risk for side effects from a drug can be tested to determine if the risk is real before they ever take the medication. The cells also allow researchers to test cells from the same stem-cell stock over time as they develop drugs, which can take years. Researchers also can check drugs on cells from different types of patients to see if there are different reactions, and study why some cells become 9) ___. IPS cells are genetically and immunologically compatible with the person who provided the original cells. This means that cardiac and other cells produced from IPS cells won’t be rejected by a person’s 10) ___ system, always a possibility with cells that come from donors, animals, or cadavers. Because of this, IPS-derived cells for the heart and other tissue may one day be a perfect genetic 11) ___ for effecting repairs to damaged tissue in the heart and elsewhere, though IPS-derived cells cannot yet be used as spare parts. However, personalized drug testing has the potential to become a powerful predictive tool combining genetic profiling with cell-toxicity screening. It could help determine adverse reactions to drugs in genetically high-risk individuals before they ever take a given drug. This technique is a game changer and is going to dramatically change biology and drug 12) ___.”              Source: MIT Technology Review

ANSWERS: 1) stem; 2) heart; 3) body; 4) cell; 5) dish; 6) drugs; 7) cadavers; 8) genetic; 9) diseased; 10) immune; 11) match; 12) development

Schizophrenia

The search for potential genetic and environmental causes of schizophrenia began not long after Eugen Bleuler coined the name of the disease in 1908. In the first decades of the 20th century, twin and adoption studies began to consistently point to an inherited component in the susceptibility to the disease. In the decades before the molecular era, the twin data implied that it was a multigenic disease, with multiple genes of modest or small effect. That general sense of a multifactorial etiology became apparent at a time during which evidence for an environmental component came with surprising difficulty. That evidence emerged slowly from careful epidemiologic studies of second-trimester influenza infections, and from the consequences of deliberate starvation of the Dutch population by the Nazis during the winter of 1944. After both events, women who endured these conditions during their second trimesters had more babies who grew up to have schizophrenia. Researchers have also observed that obstetric and perinatal problems are associated with the disease, and they now generally accept that physical problems during pregnancy can increase the likelihood of schizophrenia. As the molecular era began in the middle of the 20th century, researchers confirmed the likely multigenic nature of schizophrenia’s etiology. Researchers began applying the first human molecular genetic maps to schizophrenia soon after such maps became available in the 1980s. They have since linked certain chromosomal regions more or less consistently to schizophrenia in different studies, and some genes in those regions appear to be associated with susceptibility. One recent report indicates a specific gene-environment interaction in schizophrenia, in which traumatic brain injury was more likely to be associated with schizophrenia in patients with a family history of that disorder. The second half of the 20th century also saw the development of biochemical hypotheses for schizophrenia. The most prominent was the dopamine hypothesis that Carlsson and Lindqvist originally put forth in 1963; it was based on the biochemical effects of treatment with the first antipsychotic drugs, which had been introduced only in 1952. The overall picture for schizophrenia is now quite promising. The genes associated with schizophrenia vulnerability are also related to treatment in the case of dopamine receptors. This suggests that treatments might be tailored to the susceptibility variants, and that the tailored treatments would be more effective in patients who had the specific variants. It also suggests that new treatment approaches might be developed from translational research based on the more recently developed gene-disease associations. Finally, it invites research on prevention based on precautionary care of women through deterrence of viral infections during pregnancy, and improvements in obstetric delivery. Click here for a database of all published studies on gene associations with schizophrenia.

Virus-Like Particle Vaccine Protects Monkeys From Chikungunya Virus

Chikungunya (in the Makonde language “that which bends up”) virus (CHIKV) is an mosquito-borne virus, of the genus Alphavirus , that has infected millions of people in Africa and Asia. CHIKV is transmitted to humans by virus-carrying Aedes mosquitoes. CHIKV manifests itself with an acute febrile phase of the illness lasting only two to five days, followed by a prolonged arthralgic disease that affects the joints of the extremities. The pain associated with CHIKV infection of the joints persists for weeks or months, or in some cases years. According to an article published in the online version of Nature Medicine (28 January 2010), experimental vaccine developed using non-infectious virus-like particles (VLP) has protected macaques and mice against CHIKV. The vaccine was developed because there is no vaccine or treatment for CHIKV. To develop the vaccine, scientists in NIAID’s Vaccine Research Center (VRC) identified the proteins that give rise to chikungunya VLPs. The VLPs mimic actual virus particles but cannot cause infection, so they can be used safely as a vaccine to elicit immune responses. The researchers immunized rhesus macaques with the VLPs, waited 15 weeks before exposing the animals to chikungunya virus, and observed that the vaccine provided complete protection from infection. When the group found that antibodies were responsible for immune protection, they transferred antibody-containing serum from the vaccinated macaques to mice with deficient immune systems. The mice then were exposed to a lethal dose of chikungunya virus, but the immune serum protected them from infection. There are two VLP vaccines for other diseases approved by the FDA: one for hepatitis B and one for human papillomavirus. This study marks the first time that scientists have used VLPs in a vaccine to protect against chikungunya virus. The group plans to determine whether VLPs will work against other alphaviruses, such as Western and Eastern equine encephalitis virus found in the United States and o’nyong-nyong virus found in Africa.

COPD, Even When Mild, Limits Heart Function

One in five Americans over the age of 45 have COPD (chronic obstructive pulmonary disease), but as many as half of them may not even be aware of it. COPD is the fourth leading cause of death in the US, and it is strongly associated with smoking. COPD often involves destruction of lung tissue, called emphysema, as well as narrowed airways, persistent cough, and mucus production, known as chronic obstructive bronchitis. These abnormalities impair the flow of air in the lungs and make breathing more difficult. Although damage to the airways from COPD is not fully reversible, treatments can substantially improve a patient’s daily life. According to new findings published online in the New England Journal of Medicine (21 January 2010), COPD diminishes the heart’s ability to pump effectively even when the disease has no or mild symptoms. While it is well known that severe cases of COPD have harmful effects on the heart by decreasing its ability to pump blood effectively, the new results suggest that these changes can occur in mild cases and even before symptoms appear. Using breathing tests and imaging studies of the chest, the study measured heart and lung structure and function in 2,816 generally healthy adults (average age of 61 years). Study participants were part of the MESA Lung Study, an extension of the Multi-Ethnic Study of Atherosclerosis (MESA), a large, NHLBI-supported study focused on finding early signs of heart, lung, and blood diseases before symptoms appear. Sensitive magnetic resonance imaging (MRI) and computed tomography (CT) scans uncovered mild abnormalities in heart and lung function in many participants. They discovered that the link between lung and heart function was strongest in current smokers, who are at risk for both diseases, and especially in those with emphysema. The findings also appeared, to a lesser extent, in people with mild COPD who had never smoked. The larger MESA project involves more than 6,000 middle-aged and older men and women from six urban communities across the United States. Participants in MESA come from diverse races and ethnic groups, including African Americans, Latinos, Asians and whites. They have been tracked since enrollment began in 2000. Because the MESA study population is ethnically mixed and covers a broad age range of apparently healthy people, the results of this study may be widely applicable to the general U.S. population.

Newly Identified Genes Influence Insulin And Glucose Regulation

 

About 24 million people in the US have diabetes and worldwide, the number is about 285 million. Diabetes is the main cause of kidney failure, limb amputations, and new onset blindness in adults and is a major cause of heart disease and stroke. Type 2 diabetes, which accounts for up to 95% of all diabetes cases, becomes more common with increasing age. It is strongly associated with obesity, inactivity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, and racial or ethnic background. The prevalence of diagnosed diabetes has more than doubled in the last 30 years, due in large part to the upsurge in obesity. According to an article published online in Nature Genetics (17 January 2010), 13 new genetic variants have been found that influence blood glucose regulation, insulin resistance, and the function of insulin-secreting beta cells in populations of European descent. Five of the newly discovered variants increase the risk of developing type 2 diabetes. The results of two studies, conducted by the Meta-Analyses of Glucose and Insulin Related Traits Consortium (MAGIC), provide important clues about the role of beta cells in the development of type 2 diabetes. In one paper, the MAGIC investigators set out to find genes that influence metabolic traits, including fasting glucose and insulin levels and measures of beta cell function and insulin resistance. About 2.5 million genetic variants were analyzed in 21 genome-wide association studies (GWAS) that had enrolled 46,186 individuals who did not have diabetes and had been tested for measures of glucose and insulin regulation. GWAS look for common genetic associations by scanning the DNA of thousands of individuals, thus increasing the chances of finding subtle associations of genetic variants with specific diseases or traits. The most common variation is a change in a single nucleotide polymorphism (SNP), or single base pair change, in one of the building blocks of DNA. The initial analysis yielded 25 candidate SNPs that were further tested in genetic samples from about 77,000 additional individuals. This step led to 16 SNPs that were clearly associated with fasting glucose and beta cell function and two SNPs associated with fasting insulin and insulin resistance. The investigators then asked whether any of the SNPs raise type 2 diabetes risk by comparing gene variants from thousands of people with and without type 2 diabetes. Among the five variants that raise type 2 diabetes risk, one of the more intriguing SNPs is in the region of ADCY5, which influences fasting and postprandial glucose levels. Another is in FADS1, which is linked with fasting glucose as well as lipid traits. None of the variants found were associated with type 1 diabetes, an autoimmune disease that has been traced mainly to genes that regulate immune function. As the hallmarks of type 2 diabetes are insulin resistance and impaired beta cell function, the authors were intrigued to find that most of the newly found variants influence insulin secretion rather than insulin resistance. Only one variant, near IGF1, is associated with insulin resistance. Beta cell impairment may therefore play a larger role in type 2 diabetes than previously recognized. Also, the environment may contribute to insulin resistance more than it does to insulin secretion. Learning how the genes influence cell signaling and development, glucose sensing, and hormonal regulation will assist the development of targeted methods to prevent and treat diabetes. In the second paper, MAGIC researchers evaluated genetic associations with glucose levels 2 hours after an oral glucose challenge in a subset of 15,234 participants. They found that a genetic variant in the gene GIPR, which codes for the receptor of gastric inhibitory polypeptide, a beta cell regulating hormone, influences blood glucose levels after a glucose challenge, or sugary meal. Individuals with the risk variant have reduced beta cell function. The discovery highlights the role of incretin hormones, which are released from endocrine cells in the gut. This finding adds to a growing body of evidence implicating the incretin pathways in type 2 diabetes risk and that these pathways, which stimulate insulin secretion in response to digestion of food, may offer a potential avenue for therapeutic intervention.

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients performing all FDA submissions. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available.

Critical Path Initiative

The “Critical Path” is the scientific process through which a potential human drug, biological product, or medical device is transformed from a discovery or “proof of concept” into a medical product. It consists of scientific tests and tools used to predict whether a product candidate will be safe and effective, to assess how prototypes interact with the human body, and to guide the sponsor in choosing an appropriate dose and regimen or device size and/or placement. It consists of scientific tools to manufacture the product at commercial scale and assess the quality of the manufactured product. In order to bring a product to market successfully and efficiently, product sponsors need scientifically sound approaches to these challenges.

Critical path tools are scientific or technical methods used to:

  1. Predict whether a product candidate will be safe and effective, so the sponsor can decide which candidates to move to each successively more rigorous phase of testing,
  2. Assess whether a product candidate is safe and effective, once the potential product is moved into human testing, or
  3. Manufacture large amounts of the product, and assess the quality of the finished product. 

Examples include:

  1. Animal models of human disease – used to predict whether potential products will ameliorate the target condition and/or be toxic to humans.
  2. “Biomarkers” – physiologic indicators (e.g., blood protein levels) that can be used to measure the progress of a disease or the effects of a treatment, often long before other indications are apparent in a patient.
  3. Clinical trial designs – the scientific protocols that reliably assess the effects of a potential product on humans.
  4. Quality assessment technologies – used to analyze product quality (e.g., durability of devices, stability of drugs).

 

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

 

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