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.

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.

Researchers from the University of Tokyo have announced they have successfully grown kidneys and pancreas in mice missing the ability to grow their own said organs. According to Japan Today, the researchers injected embryonic stem cells from healthy mice into eggs of genetically engineered mice that do not grow kidneys and pancreases three days after fertilization and implanted the eggs into surrogate mice. The newborn mice turned out to have kidneys and pancreases and the researchers confirmed that they derived from the embryonic stem cells while vascular tracts and nerves were those of the host mice. Both types of organs functioned normally. Professor Hiromitsu Nakauchi, lead researcher, said a potential application of this technique in the future includes reproducing in reprogrammed swine the pancreas of a diabetic patient using stem cells produced from the patient’s skin tissue.

Embryonic stem cell research has been a very controversial issue. Interesting is the suggestion by Dr. Nakauchi that this technique could be used to take stem cells from a patient’s skin, not embryonic. If this was the case, I would fail to see how this would be an issue with anyone who is an opponent of embryonic stem cell research.

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.

Ten years ago if you had a car wreck and suffered deep lacerations the standard treatment would have been a tourniquet to prevent bleed out. While waiting to reach a hospital, the result of this treatment could have been loss of a limb or death. Now, it is the year 2008, and treatment procedures have slowly been changing to use a new revolutionary product to greatly reduce these incidents, the HemCon Bandage. The HemCon Bandage provides an instant antibacterial barrier to control bleeding, replacing the need for traditional gauze bandages or tourniquets. This innovative new treatment for hemostatic control is the reason that HemCon Medical Technologies is on Biotech Mashup’s list of 15 companies that have the potential to change medicine.

HemCon Medical Technologies launched in 2001 under the auspice of grants provided by the united states ARMY with additional capital from the two founders, Dr. Bill Wiesmann and Dr. Kenton Gregory. Doing a lot of hard work and having a little bit of luck, the doctors, have turned a small startup into what HemCon Medical is today. The company before last week had three products on the market; HemCon Bandage, ChitoFlex, and HemCon Dental Dressing. Using these products HemCon’s technology was only available to the military, hospitals, and emergency responders until now. This last week HemCon announced a new product, KytoStat, bringing the company’s technology from the hospital and military battlefield to your backyard. The KytoStat is the next generation band-aid, providing instant wound care.

The HemCon bandage contains chitosan, an organic substance found in crustacean shells. In 1984, scientists published in Neurosurgery the use of chitosan to stop bleeding in cats. Since then numerous journal articles have been published describing this new hemostatic agent but it was not until the doctors Wiesmann and Gregory founded HemCon did someone develop a chitosan bandage. As described by HemCon’s website the process starts with chitosan processed in Iceland from shrimp shells. After mixing it with acetic acid and turning it into a gel, the material is cast into square tiles. The squares are then freeze-dried in a vacuum chamber, compressed to about half their original thickness, and backed with a thin sheet of brown plastic. This completes the manufacturing of what is now a HemCon bandage, each bandage is then sealed in foil and sterilized by gamma radiation.

The benefits of a chitosan bandages are two fold; first when it is placed on a wound the chitosan has been found to have antimicrobial properties, second the bandage promotes clotting because blood cells and platelets carry a negative electrical charge and are attracted to chitosan, which bears a positive charge. The bandage has stopped or slowed down severe bleeding from combat wounds in 97 percent of the cases according to this special report in 2006. Hemcon’s media department responded to our inquiries with some interesting additional information, such as “are the HemCon dressings kosher? Hemcon dressings are made from shellfish, a creature that is considered forbidden from consumption by some religious groups. Although the dressing is not technically consumed, it is not considered kosher.” An interesting ethical dilemma may occur if a patient who must follow kosher laws is or could be saved by HemCon bandages.

HemCon may have a presence in the market, a new product that is direct to consumers and an exclusive license agreement with Cardinal Health but, a large number of challenges are still ahead. Two other companies offering next generation hemostatic control technologies are in the market, Celox Medical and Z-Medica. Celox Medical has a granule hemostatic agent which was tested by the United States Marine Corps and obtained 100 percent survival rates. Celox however, still does not have a product for sale. Z-Medica on the other hand sells the QuikClot, which is currently being used by the military, hospitals, and first responders. As well the company has multiple product offerings. In a recent study done by the Naval Medical Center, they compared all three hemostatic methods and found that all substantially improved outcomes verses traditional dressings but, Celox technology appeared to show the greatest improvement for control and survival. It should be noted this was a very small study with only 12 animals in each group and should be taken only lightly until larger studies can be carried out. This study points out that HemCon has some tough competition in the near future. Even with this competition Biotech Mashup feels that with the benefits of chitosan and the current leverage that HemCon has in the market, they stand a very good chance of greatly impacting the medical community and the standard of care for the foreseeable future.

If you are a computational biologist you may want to learn “Fly.” A group of researchers published in PLoS ONE Computation Biology that through the use of electrodes they have been able to monitor neuron impulses in a fly as it was “flying.” The group was able to simulate flying by harnessing the fly into a turntable mechanism which mimics the flies normal vertigo flight as it avoids predators and chases other flies. The electrodes that were attached to the fly recorded pulses from the neurons in a surprisingly regular pattern. One of the lead researchers, Nemenman commented “Historically, people have observed a lot more random spike intervals. The research is a departure from the traditional understanding in that we see that the precision of spike timing that carries information about the fly’s rotation is a factor of ten higher than even the most daring previous estimates.”

This departure from previous findings questions some assumptions of how neuron networks respond to heightened situations. Furthermore this could change how artificial neural networks are designed as many of the current approaches have relied on previous research looking at sensory neuron impulses. New understanding in how neural networks function could improve the design of computers, increase the efficiency of network interfaces, and help solve numerous other technical architecture problems.  

If I told you in the future you will be able breath into a device and know if you have cancer, would you believe me or would you ask me what new science fiction book I was talking about? Menssana Research would tell you that the future is now. They have developed and tested a new device that requires you to only breathe and then it can determine if you have cancer or other common ailments such as Tuberculosis. If successful in this endeavor, this will be a revolution in diagnostic testing and is the reason that Menssana Research has made Biotech Mashup’s top 15 picks for companies that have the potential to change medicine.

Diagnostic test using your breath is not a new idea. Spirometry, pulmonary lung function testing, is believed to date back as early as sometime between 129-200 A.D. when Galen did volumetric testing on a boy. In 1852, John Hutchinson, developed a water spirometer which is still in use today. Spirometry testing can be used to help determine a number of ailments such as, chronic bronchitis, pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, and emphysema. Similar to volumetric testing but distinct in that biomarkers can be used for disease determination is the analysis of volatile compounds in breath. Many credit the technology basis of volatile diagnostic testing to Linus Pauling, who in 1971 found that normal breath contains volatile organic compounds. However, some argue that this credit should be given to Robert Borkenstein, who in 1954, developed the breathalyzer to measure the amount of blood alcohol in an individual. Regardless of who is to be given credit little else has advanced this form of diagnostic testing for the last 35 years.

Menssana Research Incorporated, founded by Doctor Michael Phillips, believes it is time for a leap forward. The Breathscanner is the first clinical device offered by Menssana. The concept behind the Breathscanner seems simple; collect a person’s breath and analyze the unique volatile organic compounds, VOCs, which can be indicative of disease. The reality though is different as the typical concentration of VOCs in a breath is very low and nobody knows what VOC profiles indicate disease. To address these problems Menssana put to use two analytical techniques known to have very good sensitivity, gas chromatography and mass spectroscopy. Using these instruments to analyze the VOCs in someone’s breath they have been able to put together what they have coined “breath methylated alkane contour, BMAC.” A person’s BMAC is a unique profile which can be used to determine someone’s risk for numerous diseases such as, heart transplant rejection, lung cancer, breast cancer, pulmonary tuberculosis, and other diseases. The Breathscanner was recently shown at DARPA Tech 2007, and was a big hit.

In 2004, the FDA gave Humanitarian Device Exemption status to Menssana for a heart transplant rejection breath test. Even though HUD is intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year, this was a huge step for Menssana. Moving forward Menssana is well funded and pushing for commercialization of numerous new diagnostic tests. Speaking via email with Dr. Michael Phillips he was kind enough to respond to our request for information letting us know, “The next big things in breath testing will be:

The Lungscreen breath test for lung cancer: This has been validated in three published multicenter studies(…)It has a CE Mark that approves it for marketing in Europe. NIH has awarded us a $3M grant to perform a multicenter validation study in the USA in order to obtain FDA approval.

Breath test for breast cancer:  NIH funded us to perform a pilot study that demonstrated breath biomarkers of breast cancer (publications on our website). We are now evaluating a point-of-care breath test for breast cancer that will deliver results in minutes. No radiation, no breast compression, no pain - it is completely safe.

Breath test for pulmonary tuberculosis: NIH funded us to perform a pilot study that demonstrated breath biomarkers of pulmonary TB. We are currently analyzing the data from a large multicenter international validation study. Results soon, we hope.”

Biotech Mashup is very impressed with the work done by Menssana Research and how far they have come in developing this technology. However, we recognize that with the use of mass spectrometry and gas chromatography equipment for analysis, these types of test will still be required to be sent to a diagnostic laboratory thus taking days for the patient to know the test results. The diagnostics field is having a big push for results to be available in the office while you visit your doctor. We know Menssana may be addressing this as they are currently in development of a next generation system. We are eager for the day that we can walk into our doctor’s office and do a quick breath test to let us know if we are healthy or if we need immediate treatment.

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.