Researchers from George Washington University have published in Animal Cognition that monkeys make character judgments based on reputation. In the past research has suggested that primates use eavesdropping and third-party interactions to help judge character, now Dr. Francy’s Subiaul believes that his work provides further evidence that a primate system exist similar to human social skills. Dr. Subiaul performed three experiments which showed that chimpanzee’s demonstrate judgment of reputation of individuals through observational interactions with strangers.

This further brings to light questions regarding our use of animals for pharmaceutical testing. Clearly more evidence is suggesting social interactions of many animals that we use in vivariums. Anyone in science realizes the benefits these test bring to the table but we should recognize, at the minimum, the intelligence of these animals.

A review published in Acta Paediatrica has found that from 1996 to 2002 only 2 percent of 739 children drug trials had independent safety monitoring. Independent safety monitoring gives an unbiased review of the drugs side affects and can determine if a drug trial should be stopped due to unwanted and harmful results. This is particularly important in children as they are more prone to issues than adults and could live with harmful effects for the rest of their lives.

When I read this earlier today I was shocked. I had always believed that compared to adult trials, children drug trials had higher standards and more emphasis on safety, however this report strongly shows my ignorance. The lead author Dr. Helen Sammons commented that “We were very surprised by the low level of trials that had independent safety monitoring committees and are urging pharmaceutical companies to include these in all future trials involving children.” Some surprising statistics come out of this report:

·     Seven out of ten trials reported adverse events and a fifth of the trials reported a serious adverse event, ie. an untoward medical occurrence, not necessarily related to a drug.

·     Adverse drug reactions were reported in just under 37 per cent of trials, with 11 per cent of trials reporting moderate or severe adverse drug reactions.

·     Six clinical trials — which all had safety monitoring committees — were terminated early because of significant drug toxicity.

·     Deaths were reported in 11 per cent of the trials, but the majority were thought to be unrelated to the drug use.

·     Death rates were highest in trials involving newborn babies, with 56 per cent of the 99 trials included reporting a death.

·     Other major specialities in which deaths were reported included infectious diseases, neurology, respiratory and kidney problems.

It should be noted that almost three fourths of the trials had safety monitoring but were not independent and could be considered unreliable. Finally it should be mentioned that in many respects these type of trials are needed if children’s health and conditions are to ever improve but it should be done in a manner that is responsible.

Researchers at Rockefeller University have published in Science the first chemical mechanism on how DEET, mosquito repellent, works on mosquito’s preventing them from biting humans. According to the paper DEET inhibits signals from the olfactory co-receptor  OR83b. This receptor responds to 1-octen-3-ol, a chemical secreted by humans. When DEET is sprayed on human skin it competitively binds to OR83b preventing the mosquito from detecting 1-octen-3-ol.

According to the Department of Health and Human Services DEET has a range of side effects on humans, from skin rashes and seizures to eight reported deaths since 1961. Due to these effects many people do not use DEET, even though mosquitoes carry a multitude of diseases which can be passed to humans. With this recent research, many home remedies such as Citronella, lemongrass, peppermint, eucalyptus, cedarwood, and garlic, can be tested and compared to DEET to see if they behave similarly and can be made into a commercial product. Biotech Mashup can not wait for the day that everyone is spreading peppermint garlic butter on their skins to prevent mosquito bites.

As reported yesterday in LiveScience, Mark Briffa, a behavioral ecologist published in Proceedings of the Royal Society B that hermit crabs have different personalities. In the past he has examined how they behave in combat and the value they place on a shell.

Dr. Briffa’s method for determining a crab’s personality was to flip crabs upside down and measure how long it took them to exit their shell. Based on this measurement he did a statistical comparison between a crabs behavioral consistency verses their behavioral plasticity. From this result he found a pattern in behavior and was able to show statistically that certain crabs are more bold than others.

In 2006, I remember reading an interesting article in the New York Times, by Charles Siebert, describing the different personalities of the giant Pacific octopus, an article definitely worth a read if you have the time. What was so surprising by this report was the distinctive stories passed to Charles by the marine biologist working at the aquarium. They could specifically describe the distinct personalities of each octopus, the jealous one or the one sensitive to light who would spray you with water if you flashed him , etc. This brings up a very interesting and perplexing ethical question that I think is far too often overlooked in the Biotech community. Is animal testing an appropriate way for testing new drugs or technologies? For example, monkeys clearly have personalities, so is it proper to be injecting them with Ebola to determine if the new vaccine is successful? These are questions that if the community is being intellectually honest, at a minimum, should be discussing. We all know the benefits from testing on animal models but have we recognized or even acknowledged some of the negatives.

Most of us think of the heart as a highly sophisticated and durable pump. But another function of the heart is to secrete peptide hormones, which are small proteins that function as hormones. Multiple hormones are encoded by the atrial natriuretic factor (ANF) gene that help to regulate blood pressure and volume. At the Experimental Biology 2008 conference in San Diego this April, Dr. David Vesely, a doctor at the James A. Haley Veterans Hospital in Tampa and a professor at the University of South Florida (USF), will present findings that hormones from the heart are also extremely effective at fighting both pancreatic and breast cancers in mice, with no observed side effects. More than 75% of mice treated with the hormones were cured of human pancreatic cancer, and more than 66% of mice with human breast cancer were cured, according to Dr. Vesely. No other treatments were given. In uncured mice with pancreatic cancer, which is fast-moving and typically has a poor prognosis, tumors still shrank to less than 10% of their original size.

The hormone treatments have not yet been tried with humans, and a private biotechnology company is now raising money to start trials. We can only hope that the treatment will work equally well in humans, but the sobering fact is that a mouse with cancer is in a lot better luck than a human, since many treatments that work in mice do not translate to humans. 

Source: EurekAlert!

The main function of DNA is to encode the building blocks of proteins, and molecular biologists have become quite adept at cutting and pasting stretches of DNA to make nearly any protein they can envision. Unfortunately, small molecules, which are some of the most effective drugs, cannot usually be built so readily. Rather, synthetic organic chemists must use a bag of tricks and years of experience to synthesize compounds that on paper sometimes appear rather simple. However, several companies are taking advantage of a modular approach, programmed using DNA, for building diverse libraries of polyketides, naturally occurring small molecules with huge pharmaceutical promise. Two such companies include Biotica and Kosan Biosciences, which made Biotech Mashup’s list of the 15 companies with the potential to change medicine.

Polyketides, which are produced by diverse microorganisms found in places ranging from the soil to the oceans, are a structurally diverse family of natural products with an extremely broad range of biological activities and pharmacological properties. Numerous drugs spanning many therapeutic areas, such as antibiotics (e.g.erythromycin A), anti-cancer compounds and antifungals, have been derived from approximately 10,000 known polyketides. According to Biotica, polyketide natural products account for medicinal sales in excess of $20 billion per year.

The combinatorial potential of polyketide synthesis is what attracts the attention of scientists and pharmaceutical companies. Polyketide synthesis is performed by large modular multisubunit enzymes known as polyketide synthases (PKSs). The addition of each individual building block to a growing polyketide chain can be performed by a separate module of the PKS. These PKS mega-enzymes are composed of gene modules encoding the active sites for the successive activation, modification and elongation of carbon building blocks. By mixing and matching catalytic components, it is thus possible to genetically specify polyketide compounds using DNA and molecular biology. As described by Biotica, PKSs can be viewed as molecular assembly lines, in which every element of functionality of the polyketide product can be identified with a specific enzyme workstation.  It is estimated that a polyketide synthesis system with just 6 modules can theoretically produce over 100,000 compounds. Large polyketide libraries can be generated by assembling a gene with various combinations of altered DNA fragments. Novel compounds can also be produced using synthesized “starter units” that are fed to engineered microorganisms to be used as precursors.

Kosan is currently focusing on anti-cancer compounds, and has numerous drugs in its pipeline spanning the preclinical to Phase 2 development phases. Compounds currently in Phase 2 development target breast cancer, melanoma, and multiple myeloma. Biotica also has a portfolio of anti-cancer compounds, and is partnering with Wyeth on its mTOR inhibitor anti-cancer drugs. Importantly, both Biotica and Kosan are targeting Hsp90 (heat shock protein 90), a protein that interacts with several sets of signaling proteins and whose disruption leads to degradation of the interacting proteins that can promote cancer.

The ability to “program” small molecule synthesis in a combinatorial fashion is truly exciting. Given the proven utility of polyketides as drugs, we have good reason to believe there will be some great drugs coming from Biotica and Kosan.

Many of the drugs we use to fight cancer or ward off pain aim to inhibit the activity of proteins that the body naturally produces. Instead of inhibiting the activity of a protein, what if you could just instruct your body to stop making it altogether? Or instead of getting injected with a lab-produced protein that your body isn’t making enough of, wouldn’t it be more convenient to just tell your body to use the instructions in its own DNA to make more? Sangamo Biosciences is pursuing these exact approaches to gene regulation using an engineered class of proteins called transcription factors. These so-called “designer” proteins promise to change the way medicine is practiced, and that’s why Sangamo is one of Biotech Mashup’s top 15 picks for companies that have the potential to change medicine.

The instructions for making proteins reside in DNA. For a protein to be produced, the DNA must be copied into an intermediate molecule, RNA, and then translated into protein. The first step of copying DNA to RNA relies on a large class of proteins termed transcription factors. Transcription factors can recognize and bind to a specific DNA sequence. Whence bound, they can either repress or stimulate the copying of DNA into the RNA that is required for protein production. Sangamo’s technology is based upon a class of transcription factors termed zinc finger transcription factors, or ZF-TFs. ZF-TFs are especially useful because their DNA binding domains and functional domains can be assembled as modules. It is thus possible to attach a transcriptional repressor or activator to the same DNA binding sequence. In this manner, it is possible to increase or decrease the expression of any gene depending upon the choice of functional domain. Transcriptional activators and repressors are not the only functional domains that can be attached to ZF proteins. It is also possible to attach nucleases, proteins that cut DNA, to a ZF protein. Nucleases can be used for targeted repair of a defective gene, or gene disruption to completely knock-out the gene.

The technology gets even better. The DNA binding domain of ZF-TFs is also modular. So it is possible to pick individual protein fragments that are known to bind to 3-base stretches of DNA and string the protein pieces together so that they collectively recognize larger stretches. Stringing just six such protein fragments together permits the unique targeting of almost any 18-base pair DNA sequence. Sequences as short as 18 bases have so many possible combinations that they are almost guaranteed to be unique within the entire human genome.

According to Sangamo, an advantage of activating an endogenous gene, rather than supplying the lab-generated protein product, is that activation of the endogenous gene results “In the production of all of the normal splice variants and thus the natural protein isoforms in the ratios normally observed in nature.” For VEGF-A, a vascular endothelial growth factor, this is especially important. “VEGF A, in its natural state, has multiple splice variants that are involved in the normal physiologic response and appear to be required for the generation of normal, functional vasculature,” according to Sangamo.

Sangamo, located in Richmond, California,  has a large pipeline of therapeutic ZF-TFs aimed at diseases including diabetic neuropathy, HIV, congestive heart failure, cancer, and cardiovascular disease. The technology has its technical limitations, however. For instance, delivering protein therapeutics to the nucleus of a cell, where this class of compounds must function, is not straightforward. Viruses carrying DNA that encodes the ZF-TFs are one approach, but they carry their own set of risks. As with most technologies, when there is a will, there is a way. We believe that ZF-TFs hold such promise as therapeutics that delivery obstacles will be overcome.

As reported on Biospace.com, PDL BioPharma announced that due to the inability to sell the company or a portion of the company’s biotechnology and discovery assets they will instead remain independent and downsize, cutting 260 jobs. PDL BioPharma owns proprietary antibody humanization technology that has been licensed to numerous companies, including Biogen Idec, Inc. They are a direct competitor with companies such as Medarex, as viewed by Medarex in their 10Q that “XOMA and PDL BioPharma both offer technologies to convert mouse antibodies into antibodies closely resembling human antibodies…( )PDL BioPharma,..( ) have generated therapeutic products that are currently in development or on the market and that are derived from recombinant DNA that comprise human antibody components.”

Spinning this downsize PDL BioPharma stated, “As a substantially more streamlined biotechnology organization, PDL will work to efficiently maximize the value of its core technical strengths and 21 years of antibody expertise, while successfully advancing its current portfolio and partnering, when appropriate, to maximize value, offset the costs and mitigate the risks of mid- to late-stage development,” said L. Patrick Gage, Ph.D., interim chief executive officer of PDL. “In addition to PDL’s technical competencies, our talented employees, who have continued to move our company forward during the strategic review, are a fundamental strength of our company, and I thank them for their ongoing dedication and hard work.”

At one time PDL BioPharma was considered an up and coming company with an exciting technology. However, the biotech company has wasted millions on research and development that lead no where and acquisitions that added little or no value to the company. PDL BioPharma’s products were acquired through the purchase of ESP Pharma. Of the three drugs ESP Pharma had on the market, the major revenue generating drug Cardene will be going generic in 2009. The biggest rung in PDL BioPharma’s ladder is Genentech. Genentech pays royalties to PDL for Avastin and Herceptin. Avastin has been and continues to be a very successful drug for Genentech and in proxy for PDL BioPharma. Even with the mismanagement of PDL it seems like they will continue to be a player in the humanized antibody market due to the coat tails of Genentech.

Researchers from China reported, in Acta Biochimica et Biophysica Sinica, a way to improve antibody production. Traditionally, antibody production uses recombinant fusion protein as an antigen to raise antibodies against the epitope, part of the molecule recognized by the immune system, of a target protein. At noted by the authors however is the issue that “the concomitant anticarrier antibody in resulting antiserum reduces the production of the desired antibody and brings about unwanted non-specific immune reactions.” To alleviate these issues the authors used a green fluorescent protein transgenic mouse. The carrier protein mouse produced a higher concentration of antibodies against the desired target protein compared to control mice.

This is an interesting but already developed way to use transgenic animals.  Medarex has been using transgenic mice since 2001 to make 100% human protein antibodies for use in therapeutics. The more pressing question is the application of this technology. For years Medarex has been promising that they would have a product out with one of their partners; a long list including Bristol-Myers Squibb, Pfizer, Amgen, Roche, Genmab, and Eli Lilly. However this promise is still on the back burner. The closest they have come to being on the market is the work they have done with Centocor. This product, CNTO 1275, is in the process of getting Biologica License Approval. Hopefully Medarex will finally perform as stated but, if I was an investor I would be concerned as the stock has taken a dive in the last six months from above $17/share to the current price of $8.77/share.

MicroRNA’s are short single stranded ribose nucleic acids which regulate gene expression. They have been found in heart and muscle tissue, and some exclusively in the brain. The term was first introduced in 2001 in Science. Researchers at Rockefeller University have discovered that microRNA’s also help create our skin to protect us from bacteria and possible prevent skin cancer.

The lead authors, Yi and Fuchs, used mouse models to find where the microRNA was expressed. During the first 13th days of development, mouse skin is primarily composed of undifferentiated stem cells. On the 15th day, these stem cells exit the inner layer of the skin and begin to differentiate into cells that form the outermost, protective layer. During this time the expression of microRNA-203 skyrockets, suggesting that during development microRNA-203 has some responsibility in creating the skin barrier. When they compared this expression to humans, chickens, and zebrafish they found the pattern was identical. Yi was quoted saying “If it has been expressed in this very specific tissue for a long time and across several species, it means that it probably plays an important role there.” This group further found that the microRNA-203 suppresses a protein, p63, which stimulates skin cell growth. Without the presence of the RNA the skin grows uncontrolled, a possible reason for some skin cancers.

This is a great find to further introduce new targets for cancer drugs. In this case the authors suggest recovering microRNA-203 expression if it fails to prevent these type of cancers. In mice models this would be great evidence that certain squamous cell carcinomas are due to the lack of microRNA-203, however this could be extremely difficult to do in humans. Another possible cheaper alternative would be to design an inhibitor to the protein, p63.