BIOMED and a Presentation at TechnoStat in Israel


To our friends and colleagues in Israel, Dr. Jules Mitchel, President of Target Health will again be at BIOMED, being held at the Tel Aviv Convention Center (May 13-15). Let us know if you have time for a coffee or a cup of tea.


On the same trip, our CRO Partner in Israel, TechnoSTAT is hosting a Round Table entitled: How eSource Methodologies are Transforming Clinical Research: The Impact on Patients, Clinical Sites, Clinical Operations and Regulators as Paper Records Disappear. Dr. Mitchel will lead the Round table and share Target Health’s experience in the world of the paperless clinical trial. The Round Table is focusing on Medical Directors and CEOs in Pharma and Medical Device companies currently at their initial clinical trial phase or about to start their next clinical trial. Please let out friends and colleagues at TechnoSTAT know if you want to attend. It will be held in Raanana.


Springtime on Park Avenue in New York


We were driving back from the theater loving the pear blossoms. It was a very cold Winter, so all of NYC is welcoming the Spring.



Park Avenue in Late April – ©Target Health Inc. 2015


ON TARGET is the newsletter of Target Health Inc., a NYC-based, full-service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.


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. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.


Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor



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Evolutionary Biology


A tree of life drawn from DNA studies, with length denoting number of mutations in each branch. Note how animals comprise a very small part of the genetic diversity of life on Earth


Darwin envisioned natural selection acting so slowly that its effects would be imperceptible in a human lifetime. But in the late 1900s, evolutionary biologists began to detect small but significant changes taking place in a handful of species. In the past decade, many more cases of natural selection have come to light, and scientists now realize that species can adapt quickly to changes in their 1) ___. In fact, they are finding that we humans are unwittingly driving some of the fastest bursts of evolution right now. As greenhouse gases drive up the planet’s average temperature, for instance, some species are adapting to the changing climate. InCalifornia, biologist Arthur Weis and his colleagues found that a seven-year drought had spurred the evolution of field mustard plants. In 2007, they reported that the plants were now genetically programmed to flower eight days earlier in the spring. Thanks to powerful, cheap DNA sequencing technology, scientists can now pinpoint the molecular changes underlying this rapid 2) ___.


Darwin argued that even though different groups of species today might seem very different from each other, they were linked by common ancestry. His theory predicted the existence of species that would document that link. Just a year after the Origin of Species was published, Darwin was gratified to learn of the discovery of a bird called Archaeopteryx, a transitional animal. While it had feathers and wings, it also had reptilian traits not seen in living birds, such as a long tail and claws on its “hands.“ Important transitional fossils have been discovered just in the past decade. Many have been just as spectacular as Archaeopteryx, if not more so. In 2004, for example, scientists digging in the Arctic, led by Dr. Neil Shubin, unearthed the fossil bones of a fishy relative of all land vertebrates, including mammals, called Tiktaalik. This 375 million-year-old animal had limbs complete with elbows, wrists, and a flexible neck. But it still lived underwater, where it used its gills to 3) ___. These fossil bones demonstrate an important evolutionary link from fish to amphibians.


Whales in particular intrigued Darwin, because they were clearly mammals on the inside yet were so fish-like on the outside. In 1994, paleontologists reported the first fossil of a whale with legs, as Darwin had predicted. And over the past decade, they’ve uncovered a number of new fossils that fill in many of the details in the transition that whales made from land to sea between 50 and 40 million years ago. In 2001, Philip Gingerich of the University of Michigan and his colleagues reported the first ankle bone of a whale. This bone is particularly important to tracing the origin of whales, because it had a distinctive shape seen only in one group of mammals: even-toed hoofed mammals known as artiodactyls. Studies on whale DNA also completed over the past decade have consistently pointed to artiodactyls – and hippos in particular – as the closest living relatives of whales on land.


Studying DNA doesn’t just help scientists figure out which species are most closely related to one another. They can also discover how genes build structures like eyes in different species. That comparison has, in just the past decade, revealed some key insights into how those structures arose. Complex eyes evolved in a number of different lineages of animals, such as vertebrates like humans, octopi and other cephalopods, and insects. For decades, the evidence suggested that these complex 4) ___ had evolved independently in each lineage. Today, however, scientists see a much more intertwined history. In 2007, Todd Oakley of the University of California at Santa Barbara and his colleagues demonstrated that the different kinds of light receptors evolved from simple signal-detecting proteins in our distant ancestors some 600 million years ago. By the time early animals had evolved, these signal detectors had evolved into two different kinds of light receptors. Those early animals probably had eyes that were nothing more than simple light-sensitive spots. Only later did 5) ___ eyes evolve, and different lineages recruited different kinds of light receptors to capture images. Studies like Oakley’s indicate that complex eyes did indeed evolve independently, but they also co-opted many of the same ancient genetic tools to do so.


Evolution is the great recycler

Natural selection, as Darwin recognized, is an important force in evolution. And in the past decade, scientists studying genes have found many examples of its power. Only in the past few years have scientists started to explore this genomic wilderness in great detail, and they’ve used evolution as their guide. In the human genome, for example, there are an estimated 11,000 so-called pseudo-genes – stretches of DNA that once encoded proteins but no longer do so thanks to disabling mutations. These vestiges of genes once had important functions, such as synthesizing vitamins or allowing us to smell certain molecules. Scientists know that these pseudo-genes were once full-blown protein-coding genes, because they can find related versions of them in our primate relatives, in good working order.


Evolution lets scientists find needles in the genomic haystack

Darwin recognized that gender created an evolutionary force as powerful as natural selection. If animals have traits that members of the opposite gender find attractive – be they horns, feathers, or bright blue posteriors – those traits will become more common over the generations.




Darwin used his theory of sexual selection to explain the peacock’s striking tail feathers, among other extravagant physical traits in animals


Any adaptation that enables an individual to have more offspring than other members of its own sex may be favored by sexual 6) ___. Scientists have documented this so-called sexual conflict in great detail in the past decade, and they can even see its fingerprints on millions of years of evolution by measuring how quickly different genes have evolved. Darwin made one of his great predictions when he heard about a bizarre orchid in Madagascar called Angraecum sesquipedale. It grew a tube-shaped spur on its flower measuring over a foot long, at the bottom of which it produced nectar. Darwin was convinced that the extravagant shapes and colors of flowers evolved to use pollinating animals in clever ways to promote the plants’ own reproduction. One common strategy Darwin recognized was the way a flower would dust insects with pollen as they drank up its nectar. So Darwin proposed that somewhere in the forests of Madagascar lived an insect with a tongue long enough to drink up A. sesquipedale‘s well-hidden nectar. As the mystery insect drank, the orchid’s pollen would cover its body pressed against the flower. Twenty-one years after Darwin’s death, his prediction came true. A moth with a foot-long tongue turned up in Madagascar. Scientists have discovered many other extreme matches in nature. Not all of them are so friendly as the one between the orchid and its long-tongued pollinator. Rough-skinned newts in western North Americaproduce poison in their skin powerful enough to kill a crowd of people. The toxins do their damage by latching onto a particular receptor on the surface of neurons, disabling them. The reason for the newt’s overkill is its predator, the garter snake. Garter snakes make special versions of the receptor in question, with a shape that thwarts the toxin’s attachment. This precise defense allows the snake to dine on newts with impunity. In the past decade, this back-and-forth kind of evolution, known as coevolution, has come much more sharply into focus. For example, scientists have long puzzled over exactly how intimate partnerships like the one betweenDarwin’s moth and orchid came about.


Unfortunately, over the past decade, it has become increasingly clear that the world’s biodiversity is imperiled on a scale unmatched for millions of 7) ___. As forests are cleared, oceans acidified, diseases spread, and the atmosphere warmed, many species face serious threats to their survival. While this wave of extinctions is new, the history of life has seen many pulses in which vast numbers of species have been wiped out. Studies on extinction are revealing that it has a profound influence on the evolutionary process itself, reorganizing entire ecosystems and offering new opportunities for surviving species to exploit the niches left empty by vanished ones.  It can take millions of years for the planet to recover from mass 8) ___, and in some important ways it is never quite the same. As coral reefs die off and fish are hauled out of the sea, for example, less familiar forms of life such as jellyfish or even sulfide-belching bacteria may come to dominate the seas. Now that we live in the genome age, scientists are getting an unprecedented look at how species evolved from common ancestors. That’s because their common ancestry is recorded in their DNA, which is passed down from generation to generation. Using supercomputers and sophisticated new statistical methods to analyze DNA, scientists can test old hypotheses about how species are related to one another. They are starting to resolve some puzzles that previous generations of scientists simply couldn’t crack. Paleontologists have long argued, for example, that our closest living aquatic relatives are lungfishes and coelacanths, a conclusion that geneticists now confirm. Among our primate relatives, chimpanzees and bonobos are now widely recognized as our closest living kin.


Over the past decade, scientists have sequenced not just the human 9) ___, but the genomes of chimpanzees, monkeys, and many other animals. Now that they can comb through these genetic archives, they are starting to work out how the genomes of our ancestors changed after they branched off from other primates. Today, 150 years after the Origin of Species, we’re just getting to know our evolutionary selves. In 1996, Randolph Nesse, a psychiatrist, and George Williams, an evolutionary biologist, published a book entitled Why We Get Sick. They argued that in order to understand health and disease, scientists had to consider our evolutionary heritage. The book helped inspire a number of scientists – both medical researchers and evolutionary biologists – to establish a new field of inquiry called evolutionary medicine. The flu virus forces us through its continual evolution to develop new 10) ___ each year to combat its novel strains. In a sense, evolutionary biologists have been investigating medicine for a long time now.


Evolution also makes viruses and other pathogens such powerful threats to our survival, even in an age when we can sequence their DNA, because their DNA is a moving target, mutating and hitting upon new solutions to their goal of turning us into breeding grounds for disease. Tracing the evolution of our microscopic enemies can also reveal their vulnerabilities – the ways in which they can’t evolve effectively. These weak spots are becoming new targets for preventions and treatments. We can’t stop evolution, but we can learn how to use it to our advantage.


ANSWERS: 1) environment; 2) evolution; 3) breathe; 4) eyes; 5) complex; 6) selection; 7) years; 8) extinctions; 9) genome; 10) vaccines


Neil Shubin, Evolutionary Biologist


Dr. Neil Shubin (1960 to present) with one of the most important fossils found, showing the evolutionary transition of fish to amphibians and later to mammals.


Neil Shubin is an American paleontologist, evolutionary biologist and popular science writer of Russian descent. He is the Robert R. Bensley Professor of Organismal Biology and Anatomy, Associate Dean of Organismal Biology and Anatomy and Professor on the Committee of Evolutionary Biology at the University of Chicago along with being the Provost of the Field Museum of Natural History. He is well known for his discovery of Tiktaalik roseae. Shubin’s family is originally from Russia (Shubin being a frequent Russian surname).


Shubin earned a Ph.D. in organismic and evolutionary biology from Harvard University in 1987. He also studied at Columbia University and the University of California, Berkeley. Shubin was ABC News’s “Person of the Week“ in April 2006 when Tiktaalik was unveiled. and appeared on The Colbert Report on January 14, 2008, and again on January 9, 2013. He was elected to the National Academy of Sciences in 2011. He is also the host of the show Your Inner Fish on PBS. The show was produced by Windfall Films and Tangled Bank Studios, a production company for the Howard Hughes Medical Institute that makes materials available for science classroom education.




The image of Tiktaalik is reconstructed, based on the fossils discovered by Professor Neil Shubin. Paleontologists led by Prof Neil Shubin from the University of Chicago have discovered unique fossils of Tiktaalik roseae – the most compelling example yet of a creature that was at the cusp of the fish-tetrapod transition.


The fossilized pelves and a pelvic fin of Tiktaalik roseae reveal that the evolution of hind legs actually began as enhanced hind fins, according to the scientists. This challenges existing theory that large, mobile hind appendages were developed only after vertebrates transitioned to land. “Previous theories, based on the best available data, propose that a shift occurred from ?front-wheel drive’ locomotion in fish to more of a ?four-wheel drive’ in tetrapods. But it looks like this shift actually began to happen in fish, not in limbed animals,“ said Prof Shubin, who is the lead author of the paper published in the Proceedings of the National Academy of Sciences. Discovered in 2004 by Prof Shubin, Dr Edward Daeschler of Drexel University, and the late Dr Farish A. Jenkins, Jr., of Harvard University, Tiktaalik roseae is the best-known transitional species between fish and land-dwelling tetrapods.


Tiktaalik roseae lived in Devonian period around 375 million years ago. It was a predator with sharp teeth, a crocodile-like head and a flattened body. The animal looked like a cross between a fish and a crocodile, growing up to a length of 9 feet as it hunted in shallow freshwater environments. Tiktaalik roseae had gills, scales and fins, but also a mobile neck, robust ribcage and primitive lungs. In particular, its large forefins had shoulders, elbows and partial wrists, which allowed it to support itself on ground. Only specimens containing the front portion of the animal, however, have been described thus far. As the researchers investigated additional blocks recovered from their expeditions to the dig site in northern Canada, they discovered the rear portion of Tiktaalik roseae. The fossils included the complete pelvis of the original ?type’ specimen, making it possibly to directly compare the front and rear appendages of the animal. The scientists were immediately struck by the pelvis, which was comparable to those of some early tetrapods. It was still clearly fish-like, but the expanded size, mobility and robusticity of the pelvic girdle, hip joint and fin of Tiktaalikroseae made a wide range of motor behaviors possible. “It’s reasonable to suppose with those big fin rays that Tiktaalik roseae used its hind fins to swim like a paddle. But it’s possible it could walk with them as well. African lungfish living today have similarly large pelves, and we showed in 2011 that they walk underwater on the bottom,“ Prof Shubin said. “Regardless of the gait Tiktaalik roseae used, it’s clear that the emphasis on hind appendages and pelvic-propelled locomotion is a trend that began in fish, and was later exaggerated during the origin of tetrapods.“ Shubin NH et al. 2014. Pelvic girdle and fin of Tiktaalik roseae. PNAS, published online January 13, 2014; doi: 10.1073/pnas.1322559111.


The Association of Smoking Cessation and Glycemic Control in Patients With Type 2 Diabetes


Smoking increases the risk of developing type 2 diabetes. However, several population studies have also shown a higher risk in people 3-5 years after smoking cessation than in continuing smokers, while after 10-12 years, the risk equates to that of never-smokers. Small cohort studies have also suggested that diabetes control deteriorates temporarily during the first year after quitting. As a result, a study published online in The Lancet: Diabetes and Endocrinology (29 April 2015), examined whether or not quitting smoking was associated with altered diabetes control in a population study, for how long this association persisted, and whether or not this association could be affected by weight change.


For the investigation, a retrospective cohort study (Jan 1, 2005, to Dec 31, 2010) was performed of adult smokers with type 2 diabetes using The Health Improvement Network (THIN), a large UK primary care database. For the analysis, the authors developed adjusted multilevel regression models to investigate the association between a quit event, smoking abstinence duration, change in HbA1c, and the effect of weight change.


10,692 adult smokers with type 2 diabetes were included in the study, of whom 3,131 (29%) quit smoking and remained abstinent for at least 1 year. After adjustment for potential confounders, HbA1c increased by 0.21% (p<0.001) within the first year after quitting. HbA1c decreased as abstinence continued and became comparable to that of continual smokers after 3 years. This increase in HbA1c was not mediated by weight change.


According to the authors, in type 2 diabetes, smoking cessation is associated with deterioration in glycemic control that lasts for 3 years and is unrelated to weight gain, which, at a population level, could increase microvascular complications.


RNF216 Mutations as a Novel Cause of Autosomal Recessive Huntington-like Disorder


Huntington’s disease (HD) is a fatal genetic disorder that causes the progressive breakdown of nerve cells in the brain. It deteriorates a person’s physical and mental abilities during their prime working years and has no cure. HD is known as the quintessential family disease because every child of a parent with HD has a 50/50 chance of carrying the faulty gene. Today, there are approximately 30,000 symptomatic Americans and more than 200,000 at-risk of inheriting the disease.


According to an article published in Neurology (2015; 84:1760-1766), a study was performed to identify the genetic cause in 2 Belgian families with autosomal recessive Huntington-like disorder (HDL). For the study, homozygosity mapping and whole-exome sequencing was performed in a consanguineous family, as well as Sanger sequencing of the candidate gene in an independent family with HDL followed by genotype-phenotype correlation studies. Results from the study identified a homozygous mutation in the gene RNF216 p.(Gly456Glu) within a shared 4.8-Mb homozygous region at 7p22.3 in 2 affected siblings of a consanguineous HDL family. In an independent family, 2 siblings with HDL were compound heterozygous for mutations in RNF216 p.(Gln302*) and p.(Tyr539Cys). Chorea, behavioral problems, and severe dementia were the core clinical signs in all patients. Brain imaging consistently showed white matter lesions. Low gonadotropin serum levels and cerebellar atrophy could be demonstrated in the index family.


The following is from the authors: Mutations in RNF216 have recently been found in families with Gordon Holmes syndrome, a disease characterized by cerebellar symptoms and signs of sex steroid deficiency. Clinical features include cerebellar and brain stem atrophy, cerebellar ataxia, hypothalamic LHRH deficiency, hypogonadotrophic hypogonadism, lack of secondary sexual characteristics, and infertility. The mode of inheritance was proposed to be oligogenic (a term describing diseases caused by, or modulated by, a few genes), for most families. The authors have described novel RNF216 mutations causing an HDL phenotype with pure monogenic recessive inheritance. Subclinical serum evidence of hypogonadotropic hypogonadism links this disorder to Gordon Holmes syndrome. The study thus challenges the oligogenic inheritance model and emphasizes chorea as an essential clinical feature in RNF216-mediated neurodegeneration.


FDA Approves Raplixa to Help Control Bleeding During Surgery


The FDA has approved Raplixa (fibrin sealant [human]), the first spray-dried fibrin sealant used to help control bleeding during surgery. Raplixa is a biological product approved for use in adults to help control bleeding from small blood vessels when standard surgical techniques, such as suture, ligature or cautery, are ineffective or impractical. When applied to a bleeding site, Raplixa is dissolved in the blood and a reaction starts between the fibrinogen and thrombin proteins. This results in the formation of blood clots to help stop the bleeding. Raplixa contains fibrinogen and thrombin, two proteins found in human plasma. The two protein components are individually purified using a manufacturing process that includes virus inactivation and removal steps to help reduce the risk for the transmission of blood-borne viruses. The fibrin sealant components are then spray-dried, blended and packaged in a vial. Raplixa can be applied directly from the original product vial or by spraying with a delivery device onto a bleeding site. It is approved for use in conjunction with an absorbable gelatin sponge.


In support of approval, the FDA reviewed data from an 11 month clinical study involving 719 participants, undergoing different types of surgical procedures. The study demonstrated Raplixa’s effectiveness by comparing the reduction in the time needed for bleeding to stop when using this fibrin sealant and the time needed for bleeding to stop when using an absorbable sponge alone. The most commonly reported adverse reactions were surgical pain, nausea, constipation, fever and decreased blood pressure.


Raplixa is manufactured by ProFibrix BV, a wholly owned subsidiary of The Medicines Company, based in Parsippany, New Jersey.


Striped Bass with Creamy Shrimp Sauce and Fresh Pineapple


A truly delicious fish dish ©Joyce Hays, Target Health Inc.




1 pound striped bass fillet (or halibut)

1 Tablespoon olive oil for baking dish

3/4 to 1 pound cooked shrimp, chopped

1 container of tofutti

1/4 cup Kraft Mayo

Zest of 1/2 fresh lemon

Juice of 1/2 fresh lemon

3/4 cup fresh pineapple, chopped

1/4 cup fresh celery, chopped

1/2 cup fresh cilantro, chopped well

1/4 cup black sesame seeds, toasted

1/4 cup fresh scallions, well chopped

2 garlic cloves, juiced (squeezed)

1 teaspoon turmeric, pre-mixed with black pepper

2 Pinches chili flakes

Pinch salt

Pinch black pepper




Most of the ingredients are here ©Joyce Hays, Target Health Inc.




Preheat oven to 375

Brush the olive oil in your baking dish and put the cleaned fish into the dish. Set aside

Into a large bowl, put the chopped shrimp.

Save enough of the pineapple for a garnish, later.

Add all of the other ingredients to the shrimp, including most of the chopped pineapple, but not the striped bass, and stir to combine everything well

Pour the shrimp sauce over the striped bass

Bake for 15 to 20 minutes

Remove from oven and sprinkle some extra cilantro, and the reserved pineapple, on top of the fish before serving. Serve immediately





Stirring the ingredients together with the pieces of shrimp ©Joyce Hays, Target Health Inc.




Save some of the fresh pineapple pieces and cilantro, for a garnish ©Joyce Hays, Target Health Inc.



Oil a baking dish and put the fresh fish in ©Joyce Hays, Target Health Inc.



Creamy moist fish and seafood with the slight sweetness of the fresh pineapple ©Joyce Hays, Target Health Inc.



With warm weather, comes sweet delicious fresh fruit. This was dessert with a little of your favorite liqueur added. We added Grand Marnier ©Joyce Hays, Target Health Inc.



We know we like Hall Vineyards red wines, but wanted to see what their Sauvignon Blanc was like. With 5 being the highest, we give this a 4. Not bad at all, but not in our favorite top tier. Certainly, very good with this week’s fish recipe ©Joyce Hays, Target Health Inc.


So on Friday, we started our meal with the salad recipe from last week’s recipe for Avocado/Cucumber Salad with Black Sesame Seeds and Orange mini tomatoes and chilled Sauvignon Blanc. Then one of the most delicious fish recipes I have ever put together. The sauce kept the fish moist while baking, giving us the most velvety, melt-in-your-mouth fish, with the added creamy shrimp and pineapple sauce and some tiny macaronis to go with it. Dessert was fresh cut-up, very sweet strawberries with add-your-own, Grand Marnier, and globs of cool whip, if desired. This was a wonderful satisfying meal.


On Saturday, we saw the recently opened revival of, “The Heidi Chronicles“. The content of this play is dated, however, the acting is superb, and the sets are better than when this play first opened in the late 80s. In spite of the fact that the subject matter (women’s lib) was somewhat dated, I did enjoy this play as a historical timeline of the women’s movement in New York. The setting is basically the upper eastside of Manhattan in the 1980s, which doesn’t escape you, with all the neighborhood name dropping. I wouldn’t say rush to get tickets, but if you’re a woman from NYC, you might enjoy this play and if you like the acting of Elisabeth Moss, of Mad Men fame (which I do), you would feel very comfortable spending these 2.5 hours, at the Music Box theater. (BTW, the ladies’ room has been greatly expanded, so no long lines here). This was an enjoyable time for us.


This week, Manhattan was in full bloom. The mall down Park Avenue is a cloud of white pear trees and pink crab apple trees, and dark orange tulips in beds below. Late April early May, always takes my breath away! Hope your weekend was beautiful!



From Our Table to Yours!


Bon Appetit!