STX PO Inverted Hammer Candlestick

Inverted Hammer with high volume but still need to rally back above $2.57 resistance.
Immediate support is the uptrend green line. If this uptrend line is broken the next support is the gap support at $2.00.

Sincere Watch Time to Take Profit

Short term support broken signal to take profit.

Price will probably retrace to major support trendline and 50 EMA.

Can silicon microchips mimic living organisms?

The Silicon Guinea Pig

Can silicon microchips mimic living organisms? Some researchers believe they can provide a fast, cheap way to screen thousands of drugs for toxic side effects.

At first glance, Michael Shuler's chip could pass for any small silicon slab pried out of a computer or cell phone. Which makes it seem all the more out of place on a bench top in the Cornell University researcher's lab, surrounded by petri dishes, beakers, and other bio-clutter and mounted in a plastic tray like a dissected mouse. The chip appears to be on some sort of life support, with pinkish fluid pumping into it through tubes. Shuler methodically points out the components of the chip with a pencil: here's the liver, the lungs are over here, this is fat. He then injects an experimental drug into the imitation blood coursing through these "organs" and "tissues"-actually tiny mazes of twisting pipes and chambers lined with living cells. The compound will react with other chemicals, accumulate in some of the organs, and pass quickly through others. After several hours, Shuler and his team will be closer to answering a key question: is the compound, when given to an actual human, likely to do more harm than good?

This so-called animal on a chip was designed to help overcome an enormous obstacle to discovering new drugs: there is currently no quick, reliable way to predict if an experimental compound will have toxic side effects-if it will make people sick instead of making them well. Testing in animals is the best drugmakers can do, but it is slow, expensive, often inaccurate, and objectionable to many. To minimize the number of animal tests, drug companies routinely screen drug candidates using cell cultures-essentially clumps of living human or animal cells growing in petri dishes or test tubes. The approach is relatively cheap and easy, but it gives only a hazy prediction of what will happen to a compound on the circuitous trip through the tissues and organs of an animal.

Shuler is among a handful of researchers who are developing more sophisticated cell cultures that simulate the body's complex organs and tissues. MIT tissue engineer Linda Griffith, for one, has built a chip that mimics some of the functions of a liver, while Shuichi Takayama, a biomedical engineer at the University of Michigan, has built one that imitates the behavior of the vasculatory system (see "Other Animal-on-a-Chip Efforts," below). But while such efforts have produced convincing analogues of parts of human or animal bodies, Shuler has gone a step further. Working with colleague Greg Baxter, who launched Beverly Hills, CA-based Hurel to commercialize the technology, Shuler has combined replicas of multiple animal organs on a single chip, creating a rough stand-in for an entire mammal. Other versions of Shuler's chips attempt to go even further, using human cells to more faithfully reproduce the effects of a compound in the body.

Drug companies are interested, and no wonder: they routinely make thousands, even tens of thousands, of compounds in hopes of finding one that is effective against a particular target. Chips such as Shuler and Baxter's could mean a cheap, fast, and accurate way to weed out compounds that would eventually prove toxic, saving companies years and millions of dollars on the development of worthless drugs. According to a recent study by Tufts University's Center for the Study of Drug Development, for each drug that reaches market, the drug industry spends an average of $467 million on human testing-the vast majority of the money going to drugs that fail, either because they aren't effective or because they prove toxic. If more failures could be identified before animal testing even began, companies could focus more of their time and money on the winners. "Everyone in the industry hopes to have surrogates for animals and humans when it comes to testing compounds," says Jack Reynolds, head of safety sciences for Pfizer, the world's largest pharmaceutical firm. "This is the sort of technology we'd want in our toolbox."

http://www.technologyreview.com/Biotech/13614/

cell cultures that consist of plates with multiple wells

Liver Models Go to Market

New models of the human liver will help uncover toxicity problems before drugs reach the clinic.

Drug-induced toxicity is the leading cause of acute liver failure in the United States. Traditional drug-screening tests sometimes fail to uncover potential toxicity problems before drugs reach, or even pass, clinical trials. This puts patients at risk and leads to recalls that are costly for pharmaceutical companies. Now two MIT groups that have been developing new systems for modeling the human liver in the lab are forming startups to bring their products to the market.
TE-bio, founded by Linda Griffith, Steven Tannenbaum, and Walker Inman will launch next year in collaboration with Dupont and is talking with Pfizer as a potential research partner. Their microscale liver tissues are three-dimensional. Hepregen, founded by Sangeeta Bhatia and Salman Khetani, has developed cell cultures that consist of plates with multiple wells, each of which contains two-dimensional, structured growths of liver cells surrounded by supportive cells. Hepregen is currently raising money and talking with Merck and Novartis. Both models function better than the traditional cell cultures used by drug companies because they attempt to mimic the structural complexity of the human liver.

"There is a growing recognition of the need for in vitro alternatives in toxicology," says Michael Shuler, a chemical-engineering professor at Cornell University. Only one of every ten compounds tested by pharmaceutical companies becomes a product, says Shuler, and half of the failures are due to toxicity.

Before a compound can be brought to clinical trials, it must be screened for toxicity on cells in culture and in animals, usually rodents. "There is currently no good way of predicting whether a compound is toxic in humans," says Tannenbaum, professor of toxicology and chemistry at MIT. "Testing in animals is never going to be able to predict all human toxicity." And the tests that are done in simple cell cultures also have major limitations.

"The liver is a complex organ that has many different cell types," says Tannenbaum. These cells exchange chemical signals and even exert mechanical forces on each other that help maintain their function; they form complex structures, including bile ducts. "In order to get any functionality [in a model], you have to have multiple cell types organized into a structure like a liver," he says. When cells are taken out of the liver and cultured using traditional means, their gene-expression profiles change very quickly, and they begin to deteriorate in a few days.

This week, Bhatia and Khetani published a paper in Nature Biotechnology that describes the liver-like functions of the cells in their cultures. They make the cultures by seeding liver cells on plastic plates that are micropatterned with circular spots of collagen. The cells congregate on the collagen and are then surrounded by support cells called fibroblasts. Liver cells arranged in this carefully controlled pattern are better mimics of the human liver than are liver cells growing on their own. For four to six weeks, these cells maintain gene-expression profiles comparable to those of liver cells in the human body; they continue to produce the enzymes that break down and modify drugs; and they even form functioning bile ducts, important transport systems in the liver. When the clusters of liver cells were exposed to known human-liver toxins, they exhibited the same relative toxic effects.

Importantly, when exposed to low doses of particular drugs over periods of weeks, the cells displayed chronic toxicity. Such toxicity is clinically significant given the way that people actually take drugs--every day for long periods of time--but it's not possible to detect chronic effects in conventional liver cultures because they die too soon.

"These cells by many criteria look extremely [liver]-like," says Charles Rice, who directs the Center for the Study of Hepatitis C at Rockefeller University. Bhatia's liver cultures are "closer to in vivo" than traditional tissues used to study the liver in the lab, Rice says, be they liver-cancer cell lines or fast-deteriorating slices of liver tissue. "The scale and precision is really breathtaking. Pharmaceutical companies will be pretty interested." Rice is collaborating with Bhatia to use the liver models to grow hepatitis C, with good preliminary results. The virus, which infects 3 percent of the worldwide population and is the leading cause of liver transplants in the United States, is difficult to study in the lab.

These better-functioning culture systems may also help detect drugs that are toxic to the heart. Knowing how these compounds are processed in the liver is critical. A drug that is harmless in its original state may be turned into a heart-toxic compound after passing through the liver, says Cornell's Shuler. New ways of studying the liver are making it practical to test the toxicity of not only the drug itself, but also its metabolites. Shuler is developing what he calls a "body on a chip," a microfluidic system that connects multiple tissue types to mimic the interaction of organs in the body. He says that Bhatia's cultures could be plugged into such a system to provide the liver compartment. (Shuler's work has been commercialized by Hμrel of Beverly Hills, CA. Last year, Hµrel announced a collaboration with the drug company Schering-Plough.)
Another possibility that these new liver models opens up is that of testing the effects of drug combinations. Patients often take more than one drug at a time, and drugs that are safe when taken alone may have unexpected toxic interactions with each other. The new liver models can be used to do studies at high throughput, and they should make it more practical to test drug combinations for potential toxicity, says Shuler.

"This will revolutionize the way drug testing is done," predicts Tannenbaum. Hepregen will begin beta testing with pharmaceutical companies in the coming year; company cofounder Salman Khetani says that he and his colleagues are about a year from shipping their products.

http://www.technologyreview.com/Biztech/19778/page2/

JES 5 mins chart price capped by trendline

Monitor downtrend resistance line for upward price breakout

Testing Drugs with Stem Cells

Researchers are using human embryonic stem cells to determine the toxicity of potential pharmaceuticals.

Testing the toxicity of pharmaceutical candidates in lab rats before the compounds are judged safe enough for human clinical trials is notoriously unreliable. Often compounds that appear safe in the rodents prove to be toxic in humans.

To come up with a better way of predicting toxicity, Gabriela Cezar, assistant professor of animal science at the University of Wisconsin-Madison, is turning to human embryonic stem cells. In the current issue of Stem Cells and Development, Cezar and her colleagues reveal a novel way to test drug toxicity: by monitoring the behavior of embryonic stem cells exposed to a drug-candidate compound. Studying how potential drugs affect embryonic stem cells could provide a far more accurate prediction of a drug's potential toxicity than conventional animal models can.

During normal development, embryonic stem cells produce molecules that direct cellular metabolism and differentiation. Cezar hypothesized that exposure to a toxic drug may skew concentrations of these molecules, disrupting cell-to-cell interactions and causing a biological cascade resulting in potential developmental disorders.

As a proof of concept, Cezar's group looked at human embryonic stem cells' response to valproate, an anti-epileptic drug that has been linked with cases of autism and spina bifida in the offspring of mothers treated with the drug. "Developmental disorders and birth defects start in utero during pregnancy, and we have no way to measure or look at mechanisms that could be participating in the onset of these diseases," says Cezar. "With human embryonic stem cells, we can recapitulate development of the human brain and measure concrete changes of chemicals to drugs like valproate."

In the experiment, Cezar introduced various dosages of valproate, from very low to high, into three sets of embryonic stem-cell cultures, altering the dosages over different lengths of time. Control groups contained stem cells not exposed to the drug. Cezar then ran each sample through a mass spectrometer, which measured concentrations of the molecules present in culture.

Compared with the control group, samples with valproate exhibited significant changes in the concentrations of two key molecules: glutamate and kynurenin. Both molecules are heavily involved in early brain development, and Cezar found that exposure to valproate caused spikes in each molecule's concentrations, indicating that such molecules may serve as biomarkers for a drug's potential toxicity.

"We're predicting toxicity to humans in human cells," says Cezar. "Discovering these measurable molecules of toxicity, we hope to present other serious adverse reactions that are caused by testing drugs in animals, with the hope of bringing safer drugs to patients."

However, using embryonic stem cells as testing grounds for drug safety is still a relatively new concept, and according to some scientists, much more research is needed before it can be determined that the method is viable. Steven Tannenbaum, professor of chemistry and toxicology at MIT, says that drug metabolism in the body is a complex process. In particular, drugs taken into the body are processed first in the liver, taking on different forms before traveling through the rest of the body, and into the womb. "More than 90 percent of drugs are metabolized in the liver to other forms of the drug, some of which might be toxic," says Tannenbaum. "This group has taken valproic acid, which is normally extensively metabolized in the body, and exposed it under unrealistic conditions."

Cezar says that a possible solution may be to direct embryonic stem cells to grow into liver cells before exposing them to drugs--a project that she may take up in the future. "As long as we can make the cells from human embryonic stem cells, then once we have the mature cells in a dish, we could discover biomarkers in liver toxicity," says Cezar.

"It's a very versatile platform."

http://www.technologyreview.com/Biotech/19893/

The $2 Million Genome

James Watson, codiscoverer of the structure of DNA, now has a copy of his very own genome. Will you be next?

On Thursday, James Watson was handed a DVD containing his entire genome, sequenced in the past few months by 454, a company based in Branford, CT, that's developing next-generation technologies for efficiently reading the genome. At a cost of $2 million, 454 sequenced Watson's genome for roughly an order of magnitude less than it would have cost using traditional machines. While this is still too expensive for the average Joe, experts say that the advance marks a major milestone toward personal-genome sequencing--and more-personalized medicine--for all.

"We've heard people talking about personalized medicine for the last year or two, but this is the first concrete incarnation of that whole era," says George Weinstock, codirector of the Human Genome Sequencing Center at Baylor College of Medicine, in Houston. Scientists at Baylor collaborated on the genome project.

The $2 million and two months that it took to sequence Watson's genome is a far cry from the more than ten years and $3 billion required for the Human Genome Project's reference genome, released in 2003. Scientists ultimately hope to bring the cost down to less than $10,000, a target price that many believe will be the turning point in genomic medicine. At that price, many people could afford to have their genomes sequenced, and doctors could then use that data to give their patients more-personalized medical advice.

At a press conference at Baylor on Thursday announcing the completion of the genome, 454's founder, Jonathan Rothberg, compared the company's sequencing innovations with the technological advances that shrank computers to a size small enough for personal use. 454's machines run the sequencing reactions on chips smaller than a playing card, drilled with 800,000 tiny holes. Each chip can run hundreds of thousands of sequencing reactions in a single experiment, compared with the 96 reactions possible when scientists initially sequenced the human genome. (See "Sequencing in a Flash.")

While Watson's genome represents a landmark in human sequencing and will be the subject of extensive research, it's unlikely to be immediately useful to the geneticist on a personal level. Scientists did not find any of the hot-button mutations that guarantee that Watson would develop a certain disease. (Given that Watson has made it safely into his late seventies, this is relatively unsurprising.) They did, however, identify several mutations that boost the risk of cancer, including one linked to breast cancer. "I've had basal-cell carcinoma since the age of 28," Watson said at the press conference. "Whether there is any connection, I don't know." Adding that his sister had suffered from serious breast cancer, he said, "I take comfort in the fact that it largely affects women, and that I don't have any daughters. If I did, I would tell them to immediately check if they had [that mutation]."

Scientists also identified several hundred other interesting mutations--genetic variations that might affect the function or expression of a gene. While many mutations of this type have no observable effect,25 of Watson's variants have been linked to some phenotypic effect in other studies, says Richard Gibbs, director of Baylor's sequencing center. "But none have obvious health implications," he says.

Watson's genome will be difficult to interpret until scientists have gathered a larger database housing hundreds or thousands of people's genomes, along with their personal characteristics, medical histories, and other information. That information will allow geneticists to correlate specific variations with different medical and more-general attributes, such as musical skill or athletic ability, ultimately giving a new level of meaning to the genome.

Watson's genome, which is being deposited in a public database, is unlikely to remain alone for long. Illumina, a San Diego-based technology company that acquired 454's rival sequencing company, Solexa, earlier this year, plans to sequence the genome of one of the people who contributed DNA to the HapMap project, an effort to catalogue human genetic variation. (See "A New Map for Health.") The National Institutes of Health (NIH) is also planning a personal genome project: it aims to sequence the genomes of 100 different people in the next two years. NIH scientists are currently debating whose genomes would prove most useful to the research community. People included in the HapMap project, which focused on populations in Nigeria, China, Japan, and Utah, are likely candidates. (Craig Venter, a fellow genomic celebrity who pioneered Celera's human genome project, previously revealed that he was the subject of that effort. His DNA now resides in a publicly funded genetic database, and according to the journal Nature, he soon plans to publish a paper describing it.)

454 also aims to create a longer list of personal genomes. Michael Egholm, vice president of molecular biology at 454, predicts that the company will reach the $100,000-genome point within the next year, which he says will be a turning point at which scientists can afford to sequence hundreds of genomes for research purposes. The next step will be the $10,000 genome, which should bring the company within reach of the X Prize Foundation's $10 million award, announced last October, for the first privately funded team that can sequence 100 human genomes in 10 days. (See "The X Prize's New Frontier: Genomics.") "The goal is to make human sequencing routine," says Egholm. "Someday in the future, every human will have their DNA sequenced, probably at birth."

Watson's case also brings back to the forefront many of the ethical issues surrounding the genomic age. Rothberg and others picked Watson as the subject of their first personal genome partly as an homage to a genetic pioneer, but also because, as a geneticist, he is intimately acquainted with the medical and ethical quandaries likely to arise from learning about one's genome and making it publicly available. For example, someone might find out that she has the genetic variant for a largely untreatable or unpreventable disease, such as Alzheimer's. Watson, who has a family history of Alzheimer's, has said that he does not want to know if he carries a specific variation known as APOE4 that's linked to increased risk of the disease.

One of the public's biggest worries about personal genomics is the possibility of genetic discrimination when applying for a job or trying to get health insurance. Various states have legislation preventing this practice, but a corresponding federal bill has been languishing in Congress for years. Peter Traber, Baylor's president, said at the press conference that he hopes the completion of Watson's genome will spur passage of that bill.

Watson said he didn't think too much about the contents of his genome in the interim between giving a DNA sample and getting the results. "I knew I was risking possible anxiety when I saw it," he said. "But it's much more likely that if I don't sleep at night, it's due to thinking about Iraq."

http://www.technologyreview.com/Biotech/18809/