Science Weekly: Elon Musk’s mission to Mars

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A tour of Elon Musk’s rocket factory; grow your own underpants; an emotional robot; plus, how to tan your bum

Dr. Mitchel to Present at ACRP Panel at NYU Medical Center

Target Health Inc. is pleased to announce that Dr. Jules T. Mitchel will be participating in a panel entitled “IT (Information Technology) Compliant Centers; Part 11 Compliant, EMR, eCRF.” at the ACRP New York Metropolitan Chapter Fall 2010 Symposium entitled, “Site Excellence in Clinical Research.” This two-day event will take place on Friday September 24th and Saturday September 25th at New York University Medical Center. Dr. Mitchel’s topic will be “The Integration of Electronic Data Capture (EDC) with the Electronic Clinical Trial Record (eCTR) and Electronic Medical Record (EMR).” Other panel members include:

1. Victoria Spendel – Cincinnati Children’s Hospital Medical Center
2. Lisa Weiss – Shire Pharmaceuticals
3. Jaimie Lucove – Allscripts

Please let us know if you will be attending.

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.

New Method for Regenerating Heart Muscle by Direct Reprogramming

In heart disease, cardiac 1) ___ gradually dies off and, with little or no way to regenerate those cells, that can ultimately lead the heart to fail. But scientists reporting in the August 6th issue of Cell, might have found a way to fix those losses. They’ve devised a three-ingredient molecular cocktail that transforms fibroblasts – structural 2) ___ that the heart is chock full of – directly into beating heart cells.

“In the cardiac field, we’ve been trying for over 20 years to figure out how to convert non-muscle cells into 3) ___ muscle,” said Deepak Srivastava of the University of California, San Francisco. “Now we’ve found a way to change fibroblasts – which make up 50% of all heart cells – into new cardiomyocytes.” Researchers had been searching for a master regulator of cardiac muscle – a single ingredient that could drive the formation of 4) ___ muscle. That kind of master had been found for skeletal muscle in the 1980s, but finding the same for the heart turned out to be a bigger challenge.

More recently, Srivastava and his colleagues were inspired by the discovery that fibroblasts could be reprogrammed with a combination of factors into cells that look and act a lot like embryonic stem cells, so-called induced 5) ___ stem (iPS) cells. Perhaps they could find a cocktail that would reprogram fibroblasts into cardiac muscle, without having to revert to a stem cell state in the process. The researchers started with 14 factors known to play a role in heart 6) ___. That fairly complex cocktail showed small but sure signs of working. They then whittled that down, removing factors one by one, until they found three factors that did the trick.

In fact, a minimal cocktail was a lot more efficient in producing new cardiac muscle cells than the more comprehensive one they started with. Unlike iPS reprogramming, which is very inefficient, researchers got 20 percent of fibroblasts to turn to cardiomyocytes. By comparison, the iPS cocktail successfully transforms just 0.1% of 7) ___.

The initial reprogramming happens within three days. After that, the cells gradually take on the characteristics of cardiac muscle over the course of several weeks, as they turn into fully reprogrammed, beating heart cells. The same three factors could also transform fibroblasts taken from skin. When fibroblasts treated with the three factors were transplanted back into mouse hearts just one day later, they still differentiated into cardiac muscle. This knowledge gives researchers encouragement that cells sitting in the heart could be 8) ___ without taking them out.

The current recipe for cardiac muscle relies on inserting three genes encoding transcription factors into heart cells with a virus. Ultimately, this method could be replaced with one using small molecules or other secreted 9) ___. Those could perhaps be placed into a stent inserted into the heart, where they could drive the growth of new heart muscle. This is the long term goal of these regenerative medical researchers.

The researchers demonstrated that the fibroblasts in their study didn’t first have to return to a stem cell state. Rather, they hopped directly from one adult identity to another. That could be an advantage over using iPS or embryonic stem cells to regenerate heart cells. In the case of 10) ___ cells, it’s a problem if there are stray cells that haven’t fully differentiated. They might have the ability to turn into an unwanted cell type; they could grow into a tumor or a cell that just doesn’t belong.

And there is another plus: heart muscle cells derived from stem cells for some reason don’t mature into cells with the electrical activity characteristic of true adult cardiac muscle. The new method, on the other hand, produces cells that look and act like bona fide 11) ___ ventricular muscle cells. Now, the search is on for small molecules that could mimic the effects of the new cocktail and serve as heart-regenerating 12) ___ — an approach that has worked for iPS cells.

ANSWERS: 1) muscle; 2) cells; 3) cardiac; 4) heart; 5) pluripotent; 6) development; 7) fibroblasts; 8) reprogrammed; 9) proteins; 10) stem; 11) adult; 12) drugs

John Snow’s “Grand Experiment” 1855

For 14 weeks in the late summer of 1853, London suffered one of its worst cholera outbreaks. The leading voices in medicine believed the disease emanated from the foul gasses of London’s polluted streets. John Snow, a prominent anesthesiologist, was convinced otherwise. With this map of South London, Snow believed he could prove that cholera was transmitted through drinking water. But while he would later become known as the father of modern epidemiology, his peers of the time rejected his theory. Now, some contemporary medical historians are agreeing that Snow may not have had an ironclad case.

Map of London 1855

Snow estimated 315 deaths per 10,000 houses for Southwark compared to only 37 for Lambeth – a seemingly closed case. But Snow based his numbers on a parliamentary report that didn’t have house-to-house resolution he required. Even Snow himself later admitted that he didn’t have that data to fully show the relationship between cholera and water supply. As such, his peers went unconvinced. “The grand experiment promised in the map was a failure,” says Tom Koch, author of the forthcoming Disease Maps: Epidemics on the Ground (where the map will be featured).

#1 – The colors represent the territories of two companies that piped drinking water to South London. The Lambeth Company (red) drew its water from upstream in a relatively clean area of the Thames. The Southwark and Vauxhaul Company (blue, now faded to green) had its intakes in the polluted waters downstream at Battersea Park. Snow suspected that Southwark was piping cholera into people’s homes.

#2 – This purple (now faded to brown) area came to be known as “the grand experiment.” It produced the perfect condition for an environmental study. The pipes in the area were so intermingled that Snow had a near random sampling of neighbors, virtually identical in every way except for their source of water. To show that the disease was carried through the tap, “all that [I] required was to learn the supply of water to each individual house where a fatal attack of cholera might occur,” Snow wrote in his book On the Mode of Communication of Cholera, where the map was originally published in 1855.

Additional contributions to medicine by Dr. Snow:

  1. Snow’s views in an 1853 oration of cholera and epidemic diseases in general, showed early understanding and promotion of infectious disease epidemiology
  2. John Snow in 1847 published a book on the use of ether as an anesthetic agent in surgical operations. While his fame in anesthesiology derived from his extensive work with chloroform, he also was a pioneer in the use of ether.
  3. Dr. Snow was prominent as an anesthesiologist. He administered chloroform to the Queen on two occasions.
    1. Birth of Prince Leopold
    2. Birth of Princess Beatrice

Genomic Mapping Study Finds Largest Set Of Genes Related To Major Risk Factor For Heart Disease

Genome-wide association studies, or GWAS, analyze DNA across populations to pinpoint hard-to-find genetic hotspots for common diseases that are thought to have many causes, both genetic and environmental.

According to a study published in Nature (2010;466:707-713), based on the results from the scanning of genomes of more than 100,000 people from all over the world, the largest set of genes underlying high cholesterol and high triglycerides have been discovered. High cholesterol and high triglycerides are the major risk factors for coronary heart disease, the nation’s number one killer. Because high blood cholesterol and triglycerides on their own do not cause symptoms, doctors routinely do blood tests to assess individual risk. However, they do not know how much risk of developing cardiovascular disease is inherited. Taken together, the gene variants explain between a quarter and a third of the inherited portions of blood cholesterol and triglyceride.

Previous gene-scanning approaches have turned up hints about the nature of inherited heart disease risk. However, the new results pinpoint research directions to elucidate the molecular and cellular mechanisms by which genetic variants contribute to disease. The study identified 95 genetic variants – arrangements of the nucleic acids in DNA that differ among people – which contribute to changes in blood cholesterol and triglyceride levels. Of the genetic variants, 59 had not been known and thus provide new clues for developing effective medicines to combat heart disease.

A significant insight from this research is that many of the variants show up in the DNA of people of widely diverse backgrounds. That is because the study scoured the DNA from people participating in large, population-based heart disease studies, reflecting people of European, Eastern and Southern Asian, and African-American descent.

Together, research participants from NHLBI study populations contributed about half of the 100,000 genomes scanned. Among the NIH population-based studies involved in the research were the Framingham Heart Study; the Atherosclerosis Risk in Communities Study; the Cardiovascular Health Study; the SardiNIA Study; the Ages, Gene, Environment Study; the InCHIANTI Study; the Family Heart Study; the NHLBI Candidate Gene Association Resource Program; the NIH Pharmacogenetics Research Network; the deCODE MI Study; and the Women’s Genome Health Study.

Mature Egg Cells Generated From Early Ovarian Follicles Technique Successful In Mice May Offer Women New Options For Fertility Treatment

Target Health is pleased to announce that it was actively involved in 3 NDA approvals in the area of infertility.

Immature egg cells are encased in structures known as ovarian follicles. At birth, most women have about 400,000 small, or primordial, follicles. Most of them remain dormant, with about 1,000 primordial follicles activated per month. After reaching the reproductive years, about 20-30 medium-size follicles are present at the beginning of the menstrual cycle, and, typically, only one follicle develops further and gives rise to the mature egg.

Current infertility treatment techniques stimulate immature eggs so they develop to the stage at which the eggs can be fertilized. However, these techniques work only on eggs at a comparatively late stage of development. These later-stage eggs are few in number and much more difficult to recover than the early-stage eggs used in a study reported in the Proceedings of the National Academy of Sciences (2010;107: E92-E93). In the study, for the first time, activated mouse egg cells at the earliest stage of their development have been brought to maturity. The eggs then were fertilized and transferred into female mice, which carried them to term. To make the findings even more dramatic, the authors replicated the finding by also bringing human eggs to maturity in the laboratory. However, the human eggs were not fertilized. The technique is still in its early stages, has not been sufficiently studied for human use and will require several more years of study.

According to the authors, one day this technique could be used to treat female infertility, particularly forms of infertility in which the supply of available eggs is diminished or limited. Similarly, the technique could be combined with efforts to bank the ovarian tissue of women in need of cancer therapy that might cause infertility.

An enzyme known as phosphatase and tensin homolog (PTEN) keeps the early follicles dormant until they are ready to be activated. In the study, the authors bathed one of each pair of ovaries from three-day-old mice in a substance that erases the braking effect of PTEN together with a second substance, 740Y-P, to activate dormant follicles. After two days, early signs of activation were observed in most follicles in the treated ovaries.

The authors then transplanted pairs of ovaries into adult mice and gave the animals daily injections of follicle stimulating hormone (FSH). Although FSH spurs activated egg cells to mature, it cannot activate dormant follicles. After two weeks, the ovaries treated with the PTEN blocker and 740Y-P were visibly larger and more than three times heavier than the untreated ovaries. The treated ovaries also had up to six times more follicles in advanced stages of development than did the untreated ovaries, and a greater percentage of the treated ovaries contained egg cells that had reached maturity. The researchers then collected and fertilized the mature egg cells from the treated ovaries. From 118 two-cell embryos transferred into host mothers, 20 healthy mouse pups were born.

The authors examined the same technique using primordial follicle-rich ovarian cortical tissues removed during the treatment of women with ovarian cancer. After treating sections of tissue with the same PTEN-blocking substance for 24 hours, the authors transplanted the ovarian tissue into mice and gave the animals FSH injections every two days to stimulate egg development. The sections of transplanted tissue each contained more than 50 primordial follicles. While 96% of follicles in the tissue had been dormant at the time it was transplanted, the authors found that after six months, 89% of ovarian follicles in the treated tissue had begun to mature, compared with 40% in the untreated tissue. In addition, four times as many follicles had matured to advanced stages in the treated tissue. The authors also confirmed the treated tissue contained 27 mature egg cells, compared with one in the untreated tissue.

According to the authors, the technique for stimulating dormant ovarian follicles ultimately could be used in treating infertility resulting from a reduced number of follicles, such as primary ovarian insufficiency (POI), a disorder in which women have only a small number of follicles, which often fail to reach maturity. Similarly, for cancer patients about to undergo procedures that eliminate fertility, primordial follicles could be removed and frozen, then reactivated at a time when the woman is ready to have children.

Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema

Target Health is very pleased to announce that it was the US FDA agent for this program and took a major role for the questionnaire validation

Hereditary angioedema (HAE) is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms and Icatibant is a selective bradykinin B2 receptor antagonist. The results of two double-blind, randomized, multicenter trials of icatibant in patients with HAE presenting with cutaneous or abdominal attacks was published in the New England Journal of Medicine (2010; 363:532-541). In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms.

A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported.

In patients with hereditary angioedema having acute attacks, a significant benefit was found for icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. According to the authors, the early use of rescue medication may have obscured the benefit of icatibant in the placebo trial.

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

“Meaningful Regulations”

The Department of Health and Human Services has just promulgated the Electronic Health Record (EHR) “Meaningful Use” requirements for 2011 & 2012. These are the requirements that must be met by providers to qualify for incentive payments awarded those who adopt compliant EHR systems.

These incentives are significant. Up to $44,000 are available through Medicare and $63,750 through Medicaid. In the words of Blumenthal & Tavenner, writing in the New England Journal of Medicine (5 August 2010), these incentives offer the health care community a “transformational opportunity to break through the barriers to progress.”

Historically, adoption of electronic records has been slow, a fact perplexing to many medical and political leaders. Acceptance has been hampered by (among other problems) cumbersome systems (poor design), high expense, inadequate support, and concerns with both routine practice downtime for training and maintenance and unanticipated downtime for system “crashes.”

Happily, there was ample opportunity for comment on the proposed requirements (initially released in January 2010). The Department listened, leading to flexibility in the final approach that had been missing in the original proposal. There are now a set of core requirements, all of which must be met, and an additional ten requirements from which providers must choose five. This flexibility, combined with the issuance (June 2010) of certification rules for EHR systems and the establishment of Regional Extension Centers to assist providers with adoption, provide reason for optimism that, with respect to EHRs, we may be approaching a long anticipated “tipping point” of broad adoption.

Target Health has long been convinced of the benefits of paperless operations in clinical trial management. We are pleased to see these benefits applied more broadly in clinical care and expect that the enhanced ability to securely manage, track, analyze and communicate clinical data will improve the quality and efficiency of care delivery. Increasingly, we see the potential to merge care delivery and clinical trial management to enhance safety and efficiency in drug development.

These are exciting times in health care. The benefits of information technology are about to be applied – potentially at least – in a systemically meaningful way, offering meaningful opportunities to improve care, enhance patient & provider satisfaction, increase efficiency, and save money…worthy objectives all. We are committed to doing our part to assure success. By Mark L. Horn MD, MPH, Chief Medical Officer Target Health Inc.

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