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.

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.

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.

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.

What do you get when you pit two bacteria in a death ring match? Researchers at MIT did this for their amusement, which they claim was research, and found out the winner uses a unique weapon to dominate its opponent.

Professor Anthony Sinskey’s laboratory at MIT was doing a weekly bacteria battle royale fight when they noticed that the soil-dwelling bacteria, Rhodococcus, who always loses these fights, won. Kazuhiko Kurosawa, postdoctoral associate, was intrigued by the winner’s fighting spirit and decided to try and stress the bacteria by placing it in different environments to see if it would produce any new antibiotics, it did not. Finally, Kurosawa decided to pit the bacteria in more death-match fights against a new competitor, Streptomyces. Normally Streptomyces produces an antibiotic which kills other bacteria but this time around Rhodococcus did the killing by making its own antibiotic.

The researchers realized these games had actually produced a new compound which they isolated and called rhodostreptomycin. This new antibiotic proved be very effective against other strains of bacteria such as Helicobacter pylori, the now famous bacteria which is known to cause stomach ulcers. More amazing is that this new antibiotic, an aminoglycoside, is actually a novel new molecule, it has a ring structure which has never been seen before. This new structure could be used as a building block for newer antibiotics, something that the medical community is in dire need of with the recent stories on Methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Tuberculosis. This battle royale technique could be used to make more antibiotics that have previously been undiscovered, the only step left is for MIT to stream the fights over the Internet so everyone can enjoy the action.

Genentech announced on Friday that the FDA has granted accelerated approval for Avastin, a VEGF inhibitor that has been previously discussed here, for treatment of metastatic HER2-negative breast cancer. The approval is based on a phase III study done by Genentech which showed a 52% reduction in death or disease progression compared to the current medical treatment for advanced breast cancer. Two more phase III trials are expected to have results in late 2008 and if successful the FDA should grant full approval.

Genentech is considered to be one of the first biotechnology companies. In 1977, the company produced the first human protein, somatostatin, in Escherichia Coli bacteria. Since then they have become a powerhouse in the biotechnology field with a market cap of 82.33 Billion and yearly revenue of 11.72 Billion. I am not surprised that Avastin, the first anti-angiogenesis therapy approved by the FDA, is continuing to have success. I also would not be surprised to hear Genentech announce a second therapeutic antibody targeting PGC-1alpha (peroxisome-proliferator-activated receptor-gamma coactivator-1alpha), a cofactor that activates a secondary angiogenesis pathway.

Update: As of 11:38Am Genentech’s stock is up over 8%.

Researchers at Pukyong National University have claimed that they have isolated a new antioxidant from the skin of bullfrogs.

The research team, lead by Kim Se-kwon, claims that the isolated chemical can reduce the effects of oxidation of skin cells by 73 percent. Currently, most skin products contain tocopherol, a powerful antioxidant. Dr. Kim claims that the new material discovered by his team is 10% more efficient than tocopherol.

I am continuously surprised by the discovery of new drugs from species which have been ignored or considered a nuisance for centuries.

Researchers at the Dana-Farber Cancer Institute have published in Nature today results that identify a new pathway for Angiogenesis, new blood vessel growth.

Previously Angiogensis was believed to only occur due to oxygen deprivation which activates Hypoxia Inducible Factors, ultimately stimulating production of vascular endothelial growth factor, VEGF. However the newly discovered pathway is regulated by estrogen-related receptor-alpha and is completely independent of VEGF.

In recent years, companies have developed a number of drugs that manipulate the angiogenic pathway – in both directions. Among them is Genentech’s Avastin, which is designed to starve tumors by blocking the formation of blood vessels in metastatic carcinoma of the colon or rectum. With the recent discovery of a new pathway companies will begin a new round of drug discovery for inhibition of this secondary pathway costing them billions more and possible explaining why a large percentage of drugs developed for angiogenic pathway manipulation have failed.