Science Weekly podcast: Ham the astrochimp, and the LHC keeps going

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It’s 50 years since the first ape went into space; why the LHC isn’t going to shut down for a year; Alok’s first book; and Isabella Rossellini on her Green Pornos

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A Sharper Future for Retinal Implants

Green light: Hippocampal neural cells (stained green with a fluorescent dye) grown on a light-sensitive, polymer hybrid base. Credit: Nature Communications/Guglielmo Lanzani/18 Jan 2011

Retinal implants can already restore 1) ___ to people who have lost it as a result of degenerative eye diseases such as macular degeneration and retinitis pigmentosa. Now, new research suggests a way to make higher-quality, more biocompatible retinal implants by integrating living neural 2) ___ with a soft organic polymer semiconductor. A retinal implant restores 3) ___ by sending a signal from a video camera attached to a pair of glasses to electrodes implanted on the back of a person’s retina. But the silicon or platinum components typically used to for the electrodes tend to produce images of limited quality, and can leave the retina scarred.

Organic semiconducting polymers are softer and more flexible than silicon, and they have useful mechanical and electrical properties, making them ideal for biomedical applications. In fact, they are already used in some medical devices such as glucose sensors and the electrodes that record neural 4) ___ in the brain. Researchers at the Italian Institute of Technology have now shown how organic polymer could be used to make better electrodes for retinal implants.

One of the first possible applications for a polymer-neuron interface could be in optogenics, says Guglielmo Lanzani, a professor at IIT who led the research. “Our short-term goal was to establish communication between a semiconductor and a 5) ___,” says Lanzani. The most advanced existing retinal implant, called the Argus II, is made by a company called Second Sight, and is currently undergoing 6) ___ trials. The signal from the camera activates 60 electrodes on a chip, and these in turn stimulate neurons in the retina, causing an image to form in the 7) ___. But the images that the Argus II produces are blurry, and users can only make out rough shapes and read large letters. “The platinum electrodes are very thin, they’re very flexible, but they’re not this lovely, soft substrate,” says Gerald Chader of the Doheny Vision Research Center and a collaborator at the Bioelectronic Research Lab at USC.

The Lanzani lab grew neural cells in a 8) ___ dish directly on top of the polymer. Light shined on the polymer activates the photodiodes, which stimulate individual neurons much the way light-sensitive photoreceptor cells in a healthy eye cause neurons to fire. In contrast, the Argus II stimulates up to hundreds of thousands of neurons at one time. Developed further, the Lanzani approach could lead to a retinal implant that produces much clearer 9) ___. The research team also grew rat embryonic hippocampal neurons on a substrate consisting of photodiodes made of indium tin oxide coated with a layer of photoconducting organic polymer, and another organic layer that functioned as an adhesive. The rat neurons and the diodes were immersed in an ionic solution. The diodes, when activated by light, triggered a charge imbalance in the ionic solution, which caused the neurons to 10) ___.

Currently, Lanzani plans to use printing techniques to position the photodiodes on the device precisely, more closely mimicking the geometry of the photoreceptor cells in the human retina. He says the photodiodes could be color-sensitized, to produce images in 11) ___ rather than just black and white. Source: MIT Technology Review, February 2, 1011, by Nidhi Subbaraman

ANSWERS: 1) sight; 2) cells; 3) vision; 4) activity; 5) neuron; 6) clinical; 7) brain; 8) petri; 9) vision; 10) fire; 11) color

Ancient Egypt

The Ancient Egyptians, like the Ancient Greeks and Romans, have provided modern historians with a great deal of knowledge and evidence about their attitude towards medicine and the medical knowledge that they had. This evidence has come from the numerous papyruses found in archaeological searches. Like prehistoric man, some of the beliefs of the Egyptians were based on myths and legend. However, their knowledge was also based on increased understanding of human anatomy.

Ancient Egypt developed a large, varied and fruitful medical tradition. Herodotus described the Egyptians as “the healthiest of all men, next to the Libyans,” due to the dry climate and the notable public health system that they possessed. Although Egyptian medicine, to a good extent, dealt with the supernatural, it eventually developed a practical use in the fields of anatomy, public health, and clinical diagnostics.

Imhotep in the 3rd dynasty is sometimes credited with being the founder of ancient Egyptian medicine and with being the original author of the Edwin Smith Papyrus, detailing cures, ailments and anatomical observations. The Edwin Smith Papyrus is regarded as a copy of several earlier works and was written circa 1600 BC. It is an ancient textbook on surgery almost completely devoid of magical thinking and describes in exquisite detail the examination, diagnosis, treatment, and prognosis of numerous ailments. Medical information in the Edwin Smith Papyrus may date to a time as early as 3000 BCE.

The Kahun Gynecological Papyrus treats women’s complaints, including problems with conception. Thirty four cases detailing diagnosis and treatment survive. Dating to 1800 BC, it is the oldest surviving medical text of any kind.

The world’s first prosthetic limb was found on a 3,000-year-old Egyptian mummy. This false toe is made of out of wood and leather and found on a 3,000-year-old mummified body of an Egyptian noblewoman. The appendage can bend in three places – just like a real toe – and scientists are certain that it is a prosthetic. The Cairo toe is the world’s oldest artificial body part.

Ancient papyrus informs us that the Ancient Egyptians were discovering how the human body worked. They knew that the heart, pulse rates, blood and air were important to the workings of the human body. A heart that beat feebly told doctors that the patient had problems.

The Ancient Egyptians wrote down their knowledge and this is found on what is known as the Papyrus Ebers: “46 vessels go from the heart to every limb, if a doctor places his hand or fingers on the back of the head, hands, stomach, arms or feet then he hears the heart. The heart speaks out of every limb.”  The papyrus continues: “There are 4 vessels to his nostrils, 2 give mucus and 2 give blood; there are 4 vessels in his forehead; there are 6 vessels that lead to the arms; there are 6 vessels that lead to the feet.”

The work of an embalmer was described in detail by Herodotus when visiting Ancient Egypt in the 5th Century BCE: “First they take a crooked piece of metal and with it draw out some of the brain through the nostrils and then rinse out the rest with drugs. Next they make a cut along the side of the body with a sharp stone and take out the whole contents of the abdomen. After this they fill the cavity with myrrh, cassia and other spices and the body is placed in natron for 70 days.”

Gene Therapy Used to Treat a Soft Tissue Tumor

According to an article published online in the Journal of Clinical Oncology (2011; 31 January 2011), results of an intermediate stage clinical trial of several dozen people has provided evidence that a method that has worked for treating patients with metastatic melanoma can also work for patients with metastatic synovial cell sarcoma, one of the most common soft tissue tumors in adolescents and young adults. This study is the first to use genetically modified immune cells, in a technique known as adoptive therapy, to cause cancer regression in patients with a solid cancer as opposed to melanoma. The approach represents a method for obtaining immune cells from any cancer patient and converting them into ones that can recognize cancer cells expressing the target antigen, NY-ESO-1.

NY-ESO-1 is a protein found in up to 50% of melanomas and cancers of the breast, prostate, esophagus, lung, and ovary, and in 80% of synovial sarcomas. According to the authors, since NY-ESO-1 is expressed in a substantial number of cancers, beside melanoma and synovial sarcoma, it is an attractive target for immune-based therapies against these cancers as well.

This work builds upon previously published results in patients with metastatic melanoma. Those studies showed that metastatic melanoma patients could be treated by infusion with their own genetically modified T cells, or white blood cells, that had receptors on their surfaces that recognized an antigen on the melanoma cells.

For the study, 17 patients with synovial cell sarcoma or metastatic melanoma, whose tumors expressed NY-ESO-1, received therapy with their own immune cells engineered to express a T cell receptor capable of recognizing the NY-ESO-1 antigen. To perform this treatment, the investigators isolated normal white blood cells, called lymphocytes, from each patient’s blood and modified these cells by inserting the gene encoding the anti-tumor T cell receptor into them. These genetically modified cells were then able to recognize and destroy NY-ESO-1-expressing cancer cells.

Results showed tumor regression in four of the six patients with synovial cell sarcoma and in five of the 11 melanoma patients. A partial response that lasted 18 months was observed in one of the synovial cell sarcoma patients, while two of the melanoma patients demonstrated complete ongoing regression responses that lasted 20 months or longer, which for patients with these diseases, is significant.

According to the authors, now that it has been shown that a patient’s own cells genetically engineered to express a receptor against the NY-ESO-1 antigen can mediate tumor regression, future plans are to optimize this treatment and to extend treatment of patients with other common cancers.

NIH Researchers Identify Genetic Cause of New Vascular Disease – Rare Disease is First Discovered in Undiagnosed Diseases Program

The National Institutes of Health’s Undiagnosed Diseases Program (UDP), entering its third year, receives medical referrals from around the country when cases challenge the diagnostic know-how and resources of the medical community at large. Patients enrolled in the program undergo extensive medical diagnostic testing and evaluation at the NIH Clinical Center in Bethesda, MD. UDP is an initiative jointly led by the NHGRI, the NIH Clinical Center and the NIH Office of Rare Diseases Research that draws upon numerous areas of medical and basic research specialization within the NIH. More than 200 medical cases have been enrolled from among more than 1,200 sets of patient records submitted by patients seeking answers to mysterious disorders. The program’s goal is to provide answers to patients with difficult-to-diagnose conditions and to advance medical knowledge about both rare and common diseases.

According to an article published in the New England Journal of Medicine (2011;364:432-442), clinical researchers at the UDP have identified the genetic cause of a rare and debilitating vascular disorder not previously explained in the medical literature. Seven medical cases like those described in this study have been reported in medical journals over the past century, but these previous studies did not include any insights about the molecular basis of the disorder.

The condition has been named ACDC, or arterial calcification due to CD73 deficiency. ACDC is associated with progressive and painful arterial calcification affecting the lower extremities, yet spares the coronary arteries. The condition is caused by calcium buildup in arteries below the waist and in the joints of patient’s hands and feet, and has been observed in nine individuals from three unrelated families, who are the only people known to have the disorder. Although symptoms of the disorder include leg and joint discomfort, medical evaluations of the patients ruled out rheumatoid arthritis or other joint-related problems. Genetic analyses suggested a novel disorder and pinpointed the cause of the condition as mutations, or variants, in the NT5E gene.

To understand this new disease, the NIH clinical team examined members of two families with UDP in the US, and a third case outside the country. Members of two of the three families were enrolled and examined as part of the UDP. The patients presented with pain and cramping in the calves, thighs, buttocks and feet due to poor circulation. MRIs and x-rays of the patients’ vasculature indicated calcium deposits in artery walls. For one of the patients, advancement of the condition had been treated with surgeries to reroute blood flow through alternate vessels, as well as a joint amputation in the foot. Peripheral blood vessels compensate to some extent for diminished blood flow in affected arteries.

In one of the families with five affected siblings, the clinical research team suspected a recessive inheritance, in which offspring receive two copies of a gene variant – one from each parent – that produces disease symptoms only when combined. Then, by analyzing DNA from all members of the family, the researchers were able to detect genomic regions where the siblings’ DNA contained two copies of a particular DNA segment compared to their parents’ DNA, which contained just a single copy. The comparison revealed one such region, which was subsequently analyzed for sequence variants not present in a population of 200 unaffected people. The siblings all had the same variant in a gene called NT5E. This gene normally makes the CD73 protein, which produces a small molecule, adenosine, which protects the arteries from calcifying. The authors also detected variants in NT5E in all the other affected patients in the study.

The authors then performed laboratory tests to characterize the molecular basis of the arterial calcification disorder and to validate various molecular activities in cells with NT5E variants. The authors identified an elevated activity of a key enzyme in tissue calcification, called TNAP, that was due to the lack of extracellular adenosine. Mechanistically, TNAP degrades an inhibitor of calcification, called pyrophosphate. The researchers then “connected the dots” of the elevation in TNAP activity with increases in arterial calcification. They also suggest that the location of calcification may correspond to the distribution of specific adenosine receptors in the body.


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Level of Tumor Protein Indicates Chances Cancer Will Spread

Cancer cells can break away from a primary tumor and spread, or metastasize, to other parts of the body, where they form new tumors. Metastatic cancer is often fatal, and health care practitioners seek to contain cancer early, before it can metastasize.

According to an article published in the Journal of Clinical Investigation (2 February 2011; doi:10.1172/JCI40433), researchers at the NIH and the University of Hong Kong have discovered that high levels of a particular protein in cancer cells are a reliable indicator that a cancer will spread. The findings raise the long term possibilities of new tests to gauge the likelihood that a cancer will spread and, ultimately, of a treatment that could prevent cancer from spreading.

The protein, known as CPE-delta N, is a form of carboxypeptidase E (CPE). Ordinarily, CPE is involved in processing insulin and other hormones. CPE-delta N, a variant of CPE, was present in high amounts in tumors that had spread and, to a much lesser degree, in surrounding tissues. According to the authors, testing for CPE-delta N, if combined with existing diagnostic methods, offers the possibility of more accurately estimating the chances that a cancer will spread and that conceivably, a patient’s CPE-delta N levels could be a key guide in individualizing their cancer care to improve outcome.

The study estimated the likelihood of metastasis in tumor samples and tissues from patients with liver cancer and two rare tumors, pheochromocytoma and paraganglioma. Study results showed that tumor samples from patients whose cancers had later metastasized had elevated levels of CPE-delta N. Tests indicating high levels of the protein predicted the spread of a cancerous tumor even when conventional staging-diagnostic techniques to gauge the extent and seriousness of a cancer-indicated that spread was unlikely. The finding raises the possibility that testing for CPE-delta N might be used in combination with conventional staging to further refine treatment. For example, if conventional staging indicated that a cancer was unlikely to spread, but a patient’s tumor had high CPE-delta N levels, that patient might be referred for more intensive therapies normally reserved for higher stage cancers.

The study tested for CPE-delta N, indirectly, by measuring levels of a molecule that assists in manufacturing the protein. RNA (ribonucleic acid) works with the information in a gene to make a particular protein-in this case, CPE-delta N. In an analysis of tissue from 99 patients with liver cancer, the amount of CPE-delta N RNA from the patients’ tumors was compared with the RNA levels in surrounding tissue. Results showed that when the level of CPE delta-N RNA in tumors was more than twice that in the surrounding tissue, the cancer was highly likely to return or to metastasize within two years. At or below this threshold level, the cancer was much less likely to recur. Using this threshold measure, the study was able to accurately predict metastasis or recurrence in more than 90% of cases. Conversely, their predictions that tumors would not return in the two-year period were accurate 76% of the time.

Next, CPE-delta N RNA levels were measured from stored tumor tissue originally removed from 14 patients with pheochromocytoma, a rare tumor of the adrenal glands, and paraganglioma, a rare tumor primarily occurring in the adrenals but sometimes in other parts of the body. Because the adrenal glands are very small, tissue surrounding the tumor was not obtainable, so the amount of CPE-delta N RNA was only measured in the tumor tissue. The number of copies ranged from 150,000 to 15 million per 200 micrograms of tissue. In all of the cases where cancer was found to have recurred or metastasized, CPE-delta N RNA levels were greater than 1 million. The study found no metastasis or recurrence in cases in which tumors had less than 250,000 copies. Patients’ status was tracked for up to eight years.

In another analysis, cells from liver, breast, colon, and head and neck, tumors were examined and it was observed that those known to spread most aggressively had the highest levels of CPE-delta N RNA.

Next, the study tested a potential strategy for preventing the spread of cancer by halting the production of CPE-delta N in two different mouse models. The strategy involved treating metastatic tumors with antisense RNA, which binds to RNA, preventing it from making a protein. In the first experimental model, highly metastatic liver cancer cells were transplanted beneath the skin of mice. Half the transplants were first treated with antisense RNA specific for CPE-delta N, the other half were not. After 30 days, the tumors in the mice not treated with antisense RNA for CPE-delta N were much larger than the treated tumors in the remaining mice. Next, the tumors were removed from the first set of mice and transplanted into the livers of a second group of mice. After 35 days, only the untreated tumors had spread and formed new tumors.

According to the authors, the method used in the study might some day be used to treat cancers in human beings. However, currently, there are no means to deliver the antisense RNA to tumor cells. A potential approach might involve modifying a virus to carry the antisense RNA into cells.

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FDA Approves Drug to Reduce Risk of Preterm Birth in At-Risk Pregnant Women

The FDA has approved Makena (hydroxyprogesterone caproate) injection to reduce the risk of preterm delivery before 37 weeks of pregnancy, in pregnant women with a history of at least one spontaneous preterm birth. The drug is not intended for use in women with a multiple pregnancy, such as a twin pregnancy, or other risk factors for preterm birth.

The FDA approved Makena under the agency’s accelerated approval regulations that allow promising drugs to be approved based on a surrogate endpoint benefit (here, reducing the risk of delivery before 37 weeks of pregnancy) that is reasonably likely to predict a clinical benefit. Under these regulations, the manufacturer must conduct additional studies after the product is approved to demonstrate that the drug does, in fact, have a clinical benefit. An international trial is ongoing to learn if there is also improvement in the outcome of babies born to women given Makena. Such outcomes include reducing the number of babies who do not survive or who suffer serious health problems shortly after birth.

A health care provider would give Makena once a week by injection into the hip. Treatment should begin at 16 weeks and no later than 21 weeks of pregnancy.

The FDA reviewed data on the safety and effectiveness of Makena in a multicenter randomized double-blind clinical trial. The study included 463 women 16 to 43 years of age who were pregnant with a single fetus and had a history of a prior spontaneous preterm birth. Among women treated with Makena, 37% delivered early (before 37 weeks) as compared with 55% of women in the control group. A separate study evaluated the development of children born to mothers enrolled in the controlled trial. In this study, children ages 2.5 years to 5 years reached similar developmental targets, regardless of the mother’s treatment. The confirmatory study that is ongoing will be followed by a similar infant follow-up study, to be completed about 2018. That study is expected to include 580-750 infants, depending on the number of study sites and mothers willing to participate.

The most common side effects reported with Makena included pain, swelling, or itching at the injection site; hives, nausea and diarrhea. Serious adverse reactions were rare; there was a single report each of blood clot in the lungs (pulmonary embolism) and an infection at the injection site.

The FDA originally approved hydroxyprogesterone caproate under the trade name Delalutin in 1956 for use in pregnant women. The approved indications include threatened miscarriage. The original manufacturer requested the withdrawal of Delalutin from the market in 2000 for reasons unrelated to safety.

Makena is sponsored by Hologic, Inc., based in Sunnyvale, California.

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