On A High-fat Diet, Protective Gene Variant Becomes Bad Actor

New evidence in mice bolsters the notion that a version of a gene earlier shown to protect lean people against weight gain and insulin resistance can have the opposite effect in those who eat a high-fat diet and are heavier, reveals a report in the January 7th issue of the journal Cell Metabolism, a Cell Press publication.

The findings suggest that the 12 percent of people who carry the so-called Ala12 version of the gene that serves as a master controller of fat differentiation will be more sensitive than most to the amount of fat in their diets. (That fat-moderating gene is called peroxisome proliferator-activated receptor gamma isoform 2, or Pparg2.)

The Ala12 gene variant in question is less active and less efficient in driving fat cells' formation than the more common Pro12 version, the researchers explained. As a result, individuals carrying Ala12 are generally less obese and more sensitive to insulin, but that can change if they shift to a less sensible, fat-laden meal plan.

Genetic testing for the variant might therefore be used as a diagnostic tool, said Johan Auwerx of Université Louis Pasteur in France and the Ecole Polytechnique Fédérale de Lausanne in Switzerland. "Through dietary counseling, carriers could be informed that they really need to watch out for high fat in their diets," he said.

The findings also raise a potential caution about the long-term effects of drugs called thiazolidinediones (TZDs) now in use for the treatment of diabetes, he added. Those drugs stimulate activity of the Pparg2 receptor. The findings suggest it may be better—at least in some settings—to have a less active receptor.

Auwerx's team first described the Ala12 version of Pparg2 about 10 years ago when they found in a Finnish and a Japanese American population living in Hawaii that the mutation lowered the risk of diabetes. Others tried to reproduce the findings in Americans to no avail. Indeed, the Americans in the followup study, who were generally heavier than the groups Auwerx had examined earlier, showed the exact opposite pattern.

That led to the idea that effects of the gene might somehow be sensitive to initial body weight, but an animal study was needed to sort out the underlying details.

The researchers now show that mice with two copies of the Ala12 variant, when fed a balanced diet of normal mouse chow, are leaner and have improved insulin sensitivity and better plasma lipid profiles than mice with two copies of Pro12. They also live longer.

When mice with the same genetic background were instead sustained on a diet high in fat, those benefits disappeared. In fact, those Ala12 animals grew somewhat more obese than mice with the more common Pro12 variant of the gene, though not significantly so.

The result shows an important interaction between the Pparg2 gene and the environment, they report. The underlying basis for the effect seems to depend on changes in the way the Pparg2 receptor interacts with its cofactors and in its sensitivity to a fat-produced hormone known as adiponectin, which influences blood sugar control and fatty acid breakdown.

" Collectively, our results establish the diet-dependent influence of Pparg2 Pro12Ala variant on metabolic control via modulated cofactor interaction and changes in gene expression patterns in mice," the researchers concluded. "These data hence consolidate Pparg2 as an important factor at the interface between genes and the environment and may provide avenues to better, possibly Pro12Ala genotype-dependent treatment strategies for insulin resistance in type 2 diabetes and the metabolic syndrome."

Stem Cell Troops Called To Repair The Body Using New Drug Combinations

Scientists have tricked bone marrow into releasing extra adult stem cells into the bloodstream, a technique that they hope could one day be used to repair heart damage or mend a broken bone, in a new study published today in the journal Cell Stem Cell. When a person has a disease or an injury, the bone marrow mobilises different types of stem cells to help repair and regenerate tissue. The new research, by researchers from Imperial College London, shows that it may be possible to boost the body's ability to repair itself and speed up repair, by using different new drug combinations to put the bone marrow into a state of 'red alert' and send specific kinds of stem cells into action.

In the new study, researchers tricked the bone marrow of healthy mice into releasing two types of adult stem cells – mesenchymal stem cells, which can turn into bone and cartilage and that can also suppress the immune system, and endothelial progenitor cells, which can make blood vessels and therefore have the potential to repair damage in the heart.

This study, funded by the British Heart Foundation and the Wellcome Trust, is the first to selectively mobilise mesenchymal stem cells and endothelial progenitor cells from the bone marrow. Previous studies have only been able to mobilise the haematopoietic type of stem cell, which creates new blood cells. This technique is already used in bone marrow transplants in order to boost the numbers of haematopoietic stem cells in a donor's bloodstream.

The researchers were able to choose which groups of stem cells the bone marrow released, by using two different therapies. Ultimately, the researchers hope that their new technique could be used to repair and regenerate tissue, for example when a person has heart disease or a sports injury, by mobilising the necessary stem cells.

The researchers also hope that they could tackle autoimmune diseases such as rheumatoid arthritis, where the body is attacked by its own immune system, by kicking the mesenchymal stem cells into action. These stem cells are able to suppress the immune system.

Dr Sara Rankin, the corresponding author of the study from the National Heart & Lung Institute at Imperial College London, said: "The body repairs itself all the time. We know that the skin heals over when we cut ourselves and, similarly, inside the body there are stem cells patrolling around and carrying out repair where it's needed. However, when the damage is severe, there are limits to what the body can do of its own accord.

"We hope that by releasing extra stem cells, as we were able to do in mice in our new study, we could potentially call up extra numbers of whichever stem cells the body needs, in order to boost its ability to mend itself and accelerate the repair process. Further down the line, our work could lead to new treatments to fight various diseases and injuries which work by mobilising a person's own stem cells from within," added Dr Rankin.

The scientists reached their conclusions after treating healthy mice with one of two different 'growth factors' – proteins that occur naturally in the bone marrow – called VEGF and G-CSF. Following this treatment, the mice were given a new drug called Mozobil.

The researchers found that the bone marrow released around 100 times as many endothelial and mesenchymal stem cells into the bloodstream when the mice were treated with VEGF and Mozobil, compared with mice that received no treatment. Treating the mice with G-CSF and Mozobil mobilised the haematopoietic stem cells – this treatment is already used in bone marrow transplantation.

The researchers now want to investigate whether releasing repair stem cells into the blood really does accelerate the rate and degree of tissue regeneration in mice that have had a heart attack. Depending on the outcome of this work, they hope to conduct clinical trials of the new drug combinations in humans within the next ten years.

The researchers are also keen to explore whether ageing or having a disease affects the bone marrow's ability to produce different kinds of adult stem cells. They want to investigate if the new technique might help to reinvigorate the body's repair mechanisms in older people, to help them fight disease and injury.

How Did Life Begin? RNA That Replicates Itself Indefinitely Developed For First Time

One of the most enduring questions is how life could have begun on Earth. Molecules that can make copies of themselves are thought to be crucial to understanding this process as they provide the basis for heritability, a critical characteristic of living systems. New findings could inform biochemical questions about how life began.

Now, a pair of Scripps Research Institute scientists has taken a significant step toward answering that question. The scientists have synthesized for the first time RNA enzymes that can replicate themselves without the help of any proteins or other cellular components, and the process proceeds indefinitely.

The work was recently published in the journal Science.

In the modern world, DNA carries the genetic sequence for advanced organisms, while RNA is dependent on DNA for performing its roles such as building proteins. But one prominent theory about the origins of life, called the RNA World model, postulates that because RNA can function as both a gene and an enzyme, RNA might have come before DNA and protein and acted as the ancestral molecule of life. However, the process of copying a genetic molecule, which is considered a basic qualification for life, appears to be exceedingly complex, involving many proteins and other cellular components.

For years, researchers have wondered whether there might be some simpler way to copy RNA, brought about by the RNA itself. Some tentative steps along this road had previously been taken by the Joyce lab and others, but no one could demonstrate that RNA replication could be self-propagating, that is, result in new copies of RNA that also could copy themselves.

In Vitro Evolution

A few years after Tracey Lincoln arrived at Scripps Research from Jamaica to pursue her Ph.D., she began exploring the RNA-only replication concept along with her advisor, Professor Gerald Joyce, M.D., Ph.D., who is also Dean of the Faculty at Scripps Research. Their work began with a method of forced adaptation known as in vitro evolution. The goal was to take one of the RNA enzymes already developed in the lab that could perform the basic chemistry of replication, and improve it to the point that it could drive efficient, perpetual self-replication.

Lincoln synthesized in the laboratory a large population of variants of the RNA enzyme that would be challenged to do the job, and carried out a test-tube evolution procedure to obtain those variants that were most adept at joining together pieces of RNA.

Ultimately, this process enabled the team to isolate an evolved version of the original enzyme that is a very efficient replicator, something that many research groups, including Joyce's, had struggled for years to obtain. The improved enzyme fulfilled the primary goal of being able to undergo perpetual replication. "It kind of blew me away," says Lincoln.

Immortalizing Molecular Information

The replicating system actually involves two enzymes, each composed of two subunits and each functioning as a catalyst that assembles the other. The replication process is cyclic, in that the first enzyme binds the two subunits that comprise the second enzyme and joins them to make a new copy of the second enzyme; while the second enzyme similarly binds and joins the two subunits that comprise the first enzyme. In this way the two enzymes assemble each other — what is termed cross-replication. To make the process proceed indefinitely requires only a small starting amount of the two enzymes and a steady supply of the subunits.

"This is the only case outside biology where molecular information has been immortalized," says Joyce.

Not content to stop there, the researchers generated a variety of enzyme pairs with similar capabilities. They mixed 12 different cross-replicating pairs, together with all of their constituent subunits, and allowed them to compete in a molecular test of survival of the fittest. Most of the time the replicating enzymes would breed true, but on occasion an enzyme would make a mistake by binding one of the subunits from one of the other replicating enzymes. When such "mutations" occurred, the resulting recombinant enzymes also were capable of sustained replication, with the most fit replicators growing in number to dominate the mixture. "To me that's actually the biggest result," says Joyce.

The research shows that the system can sustain molecular information, a form of heritability, and give rise to variations of itself in a way akin to Darwinian evolution. So, says Lincoln, "What we have is non-living, but we've been able to show that it has some life-like properties, and that was extremely interesting."

Knocking on the Door of Life

The group is pursuing potential applications of their discovery in the field of molecular diagnostics, but that work is tied to a research paper currently in review, so the researchers can't yet discuss it.

But the main value of the work, according to Joyce, is at the basic research level. "What we've found could be relevant to how life begins, at that key moment when Darwinian evolution starts." He is quick to point out that, while the self-replicating RNA enzyme systems share certain characteristics of life, they are not themselves a form of life.

The historical origin of life can never be recreated precisely, so without a reliable time machine, one must instead address the related question of whether life could ever be created in a laboratory. This could, of course, shed light on what the beginning of life might have looked like, at least in outline. "We're not trying to play back the tape," says Lincoln of their work, "but it might tell us how you go about starting the process of understanding the emergence of life in the lab."

Joyce says that only when a system is developed in the lab that has the capability of evolving novel functions on its own can it be properly called life. "We're knocking on that door," he says, "But of course we haven't achieved that."

The subunits in the enzymes the team constructed each contain many nucleotides, so they are relatively complex and not something that would have been found floating in the primordial ooze. But, while the building blocks likely would have been simpler, the work does finally show that a simpler form of RNA-based life is at least possible, which should drive further research to explore the RNA World theory of life's origins.

Protein's Essential Role In Repairing Damaged Cells Revealed

University of Michigan researchers have discovered that a key protein in cells plays a critical role in not one, but two processes affecting the development of cancer.

"Most proteins involved in responding to DNA damage that can cause cancer either help detect the damage and warn the rest of the cell, or help repair the damage," says David O. Ferguson, M.D., Ph.D., the study's lead author. Ferguson is an assistant professor of pathology at the U-M Medical School and a member of U-M's Comprehensive Cancer Center.

Prior research has shown that the protein, Mre11, functioned as a "gatekeeper" to signal injury to the cell and prevent damaged cells from proliferating. Now, Ferguson and colleagues have discovered that in mammals, a function of the Mre11 protein also serves as a "caretaker," by repairing DNA.

Their findings, published in the journal Cell, could have important implications for cancer treatment by someday allowing oncologists to predict a tumor's sensitivity to radiation and other therapies, making it more vulnerable to treatment.

Under normal circumstances, the body's cells grow, divide and eventually die. When something damages a healthy cell's DNA -- such as radiation or exposure to a toxin -- a multiprotein complex steps in to repair the breakage and activate other fundamental cellular processes.

The MRN complex, comprised of the Mre11, Rad50 and NBS1 proteins, senses DNA damage, known as double-strand breaks, within the cell. The complex then transmits that information to an enzyme called the ATM (ataxia-telangiectasia mutated) checkpoint kinase.

The ATM kinase controls the cell's response to double-strand breaks, and slows cell growth to give the cell opportunities to repair them, says Ferguson.

When the MRN complex doesn't work properly, inherited human neurological diseases, such as ataxia-telangiectasia-like syndrome and Nijmegen breakage syndrome, result. Both feature MRN mutations and significantly predispose a person to immunodeficiency and cancer.

What Ferguson and colleagues discovered is that Mre11 not only senses and communicates damage, it also repairs DNA double-strand breaks by acting as a nuclease, an enzyme that modifies and processes the broken DNA ends.

The Ribosome: Perfectionist Protein-maker Trashes Errors

The enzyme machine that translates a cell's DNA code into the proteins of life is nothing if not an editorial perfectionist.Johns Hopkins researchers, reporting in the journal Nature January 7, have discovered a new "proofreading step" during which the suite of translational tools called the ribosome recognizes errors, just after making them, and definitively responds by hitting its version of a "delete" button.

It turns out, the Johns Hopkins researchers say, that the ribosome exerts far tighter quality control than anyone ever suspected over its precious protein products which, as workhorses of the cell, carry out the very business of life.

"What we now know is that in the event of miscoding, the ribosome cuts the bond and aborts the protein-in-progress, end of story," says Rachel Green, a Howard Hughes Medical Institute investigator and professor of molecular biology and genetics in the Johns Hopkins University School of Medicine. "There's no second chance." Previously, Green says, molecular biologists thought the ribosome tightly managed its actions only prior to the actual incorporation of the next building block by being super-selective about which chemical ingredients it allows to enter the process.

Because a protein's chemical "shape" dictates its function, mistakes in translating assembly codes can be toxic to cells, resulting in the misfolding of proteins often associated with neurodegenerative conditions. Working with bacterial ribosomes, Green and her team watched them react to lab-induced chemical errors and were surprised to see that the protein-manufacturing process didn't proceed as usual, getting past the error and continuing its "walk" along the DNA's protein-encoding genetic messages.

"We thought that once the mistake was made, it would have just gone on to make the next bond and the next," Green says. "But instead, we noticed that one mistake on the ribosomal assembly line begets another, and it's this compounding of errors that leads to the partially finished protein being tossed into the cellular trash," she adds.

To their further surprise, the ribosome lets go of error-laden proteins 10,000 times faster than it would normally release error-free proteins, a rate of destruction that Green says is "shocking" and reveals just how much of a stickler the ribosome is about high-fidelity protein synthesis.

"These are not subtle numbers," she says, noting that there's a clear biological cost for this ribosomal editing and jettisoning of errors, but a necessary expense.

"The cell is a wasteful system in that it makes something and then says, forget it, throw it out," Green concedes. "But it's evidently worth the waste to increase fidelity. There are places in life where fidelity matters."

Scientists identify gene that may explain hair loss

Researchers in Japan have identified a gene that appears to determine cyclical hair loss in mice and believe it may also be responsible for hair loss, or alopecia, in people. Scientists described how they generated a line of mice that were lacking in the Sox21 gene.

"The mice started to lose their fur from postnatal day 11, beginning at the head and progressing toward the tail region of the back," they wrote.

"Between day 20 and day 25, these mice eventually lost all of their body hair, including the whiskers. Intriguingly, new hair regrowth was initiated a few days later but was followed by renewed hair loss."

The cyclical alopecia continued for more than two years and the researchers observed that the mutant mice had enlarged oil-secreting sebaceous glands around the hair follicle and a thickened layer of skin cells during periods of hair loss.

"The gene is likely involved with the differentiation of stem cells that form the outer layer of the hair shaft," wrote the researchers, led by Yumiko Saga of the Division of Mammalian Development at the National Institute of Genetics in Mishima.

The scientists went on to examine human skin samples, where they found evidence of this same gene.

"We confirmed that Sox21 is also expressed in the hair shaft cuticle in humans ... These results indicate that the Sox21 gene could be responsible for some hair loss conditions in humans," the authors concluded.

"Mighty Mice" Gene Is Mutated In Beefy Bovines

The same genetic "secret formula" that gave unusually large muscles to the "mighty mice" engineered by Johns Hopkins is also at work naturally in specially bred cattle that have extra muscle, according to a new report from the researchers.

"Mutations in the myostatin gene in two different species produced the same result," says Se-Jin Lee, M.D., Ph.D., an assistant professor of molecular biology and genetics. "This strongly suggests that the normal human form of the gene, which we've already identified, helps suppress muscle growth. If we can find a drug that blocks myostatin activity, patients with muscular dystrophy or muscle wasting due to AIDS or cancer may really benefit."

Results of the study, which was supported by grants from the Edward Mallinckrodt, Jr. Foundation and MetaMorphix, Inc. are published in the Nov. 11 issue of the Proceedings of the National Academy of Science.

Cattle breeders knew nothing of myostatin when they succeeded in developing more muscular cattle breeds like the Belgian Blue and the Piedmontese. Hopkins researchers went searching for mutant forms of myostatin in these cattle after discovering what eliminating it could do to mice.

"We wondered right away if interfering with the gene in livestock could give us animals with more meat and relatively less fat," says Alexandra McPherron, Ph.D., a Hopkins postdoctoral fellow. "We first became aware that there might be some breeds of livestock that already have mutated myostatin when someone described a large-muscled breed of sheep to us."

Through literature and Internet searches, researchers learned of the Belgian Blue breed of cattle. From genetic information available online, they could see that the cattle's altered gene appeared to be in the same spot on the genetic code as human and mouse myostatin.

To confirm their suspicions, Lee and McPherron then analyzed DNA from cattle blood samples supplied by a ranch in Missouri. They also detailed the DNA blueprint of the myostatin gene from 12 non-double-muscled breeds of cattle and found that their copies of myostatin were all normal.

Scientists also sequenced the myostatin gene in humans, chickens, pigs, turkeys, sheep, baboons, zebrafish and rats, and found that there were relatively few differences among the species.

Rights to myostatin are owned by The Johns Hopkins University and exclusively licensed to MetaMorphix Inc. MetaMorphix was established in 1995 to capitalize on work by Hopkins and Genetics Institute, a private pharmaceutical company, in the field of growth and differentiation factors. Lee is a shareholder in and scientific founder of the company.

Under an agreement between MetaMorphix and The Johns Hopkins University, McPherron and Lee are entitled to shares of royalty received by the University from MetaMorphix. The University, McPherron and Lee also own MetaMorphix stock, which is subject to certain restrictions under University policy. Lee is also a consultant to MetaMorphix. The terms of this arrangement are being managed by the University in accordance with its conflict-of-interest policies.

You ever wonder what makes u fat?

British and French scientists have identified several variants of a
single gene that boost the risk of obesity, according to a study
published Sunday in the British journal Nature.

The biggest
protein myth is that you can only digest 30 grams of protein at one
time. Find out what's wrong with this belief and just how much protein
you need. This is a common question. I also get variations such as, how
much protein can you digest at one time?

There are two ways to answer this, because there really two questions being asked.

1) How much protein can the digestive system physically absorb into the bloodstream from a meal?

And the MORE IMPORTANT QUESTION...

2) How much protein can you body actually utilize?

The answers...

1) About 95% and higher, unless you have some type of digestive system malfunction.

So
if you get convinced by supplement companies to drink a 42g protein
shake in 5 minutes, you'll still probably absorb at 38 or more grams of
that protein.

Your muscle growth is not limited by the amount of protein you can DIGEST or ABSORB.

Your muscle growth IS LIMITED by the amount of protein that your body can utilize for protein synthesis.

So the answer to #2...

2) A lot less than you think.

You
really don't need 40, or 30, or probably even 20g of protein per meal
to keep your protein synthesis humming along. See Nutrition Help Expert
Brad Pilon's post on "How Much Protein Do We Really Need"

Any
protein that your body can't use for growth will be shuttled into a
process where it is broken down (de-aminated: meaning the nitrogen is
removed from the molecule and it becomes a carbon skeleton) to be used
in energy pathways.

Now, there are benefits for eating extra protein (in my opinion) when dieting, mainly that it helps to suppress appetite.

But the bottom line to the question I am asked almost everyday is...

a) Your body can digest and absorb almost all of the protein you eat without problem.

b)
Your muscles can only do so much with protein...the muscle growth
process is RARELY, if ever limited by the amount of protein we consume.
Almost all of us can easily get enough protein for maximum muscle
growth without the need for eating 50g of protein 6 times per day.
Ronnie Coleman, Jay Cutler, and Gunter Schlerkcamp excluded, of course.

Overall,
I'd think twice about the need to slam down a 40-50g protein
shake...just think of the children and puppies you'll save by not
gassing them out with protein farts.

Real food should cover all your protein needs.

Craig
Ballantyne is a Certified Strength & Conditioning Specialist and
writes for Men's Health and Oxygen magazines. His trademarked Turbulence Training for Fat Loss Nutrition Guidelines have helped thousands of men and women with weight loss and fat burning in less than 45 minutes three times per week. More nutrition help and fat loss workouts show you how to burn fat without long, slow cardio sessions or fancy equipment. Craig's bodyweight for abs exercises help you lose fat without any equipment at all.

N.Y. Research Team Discovers How Antidepressants And Cocaine Interact With Brain Cell Targets

n a first, scientists from Weill Cornell Medical College and Columbia University Medical Center have described the specifics of how brain cells process antidepressant drugs, cocaine and amphetamines. These novel findings could prove useful in the development of more targeted medication therapies for a host of psychiatric diseases, most notably in the area of addiction.

Their breakthrough research, featured as the cover story in a recent issue of Molecular Cell, describes the precise molecular and biochemical structure of drug targets known as neurotransmitter-sodium symporters (NSSs), and how cells use them to enable neural signaling in the brain. A second study, published in the latest issue of Nature Neuroscience, pinpoints where the drug molecules bind in the neurotransmitter transporter — their target in the human nervous system.

“These findings are so clear and detailed at the level of molecular behavior that they will be most valuable to developing more effective therapies for mood disorders and neurologic and psychiatric diseases, and to direct effective treatments for drug addiction to cocaine and amphetamines,” says co-lead author Dr. Harel Weinstein, Chairman and Maxwell M. Upson Professor of Physiology and Biophysics, and director of the Institute for Computational Biomedicine at Weill Cornell Medical College. “This research may also open the door to the development of new therapies for dopamine-neurotransmitter disorders such as Parkinson’s disease, schizophrenia, and anxiety and depression.”

To make their observations, the research team led by Dr. Jonathan Javitch, senior author of the Molecular Cell study and contributing author to the Nature Neuroscience study, and professor of Psychiatry and Pharmacology in the Center for Molecular Recognition at Columbia University Medical Center, stabilized different structural states of the neurotransmitter-sodium-symporter molecule that relate to steps in its function. This allowed the team to study how substrates and inhibitors affect the transition between these different states, and thus to understand the way in which its function is accomplished.

“Crystallography had allowed the identification of only one structural form of the molecule, but our experiments and computations were able to identify how this form changes and thereby add an understanding of the functional role of the different forms that the molecule must adopt to accomplish transport activity,” says Dr. Javitch.

The main surprise was the realization that two binding sites on the transporter molecule need to be filled simultaneously and cooperate in order for transport to be driven across the cell membrane. For these studies, the scientists used the crystal structure of a bacterial transporter that is very similar to human neurotransmitter transporters. They performed computer simulations to reveal the path of the transported molecules into cells. Laboratory experimentation was used to test the computational predictions and validate the researchers’ inferences.

Together, these procedures revealed a finely-tuned process in which two sodium ions bind and stabilize the transporter molecule for the correct positioning of the two messenger molecules — one deep in the center of the protein, and the other closer to the entrance. Like a key engaging a lock mechanism, this second binding causes changes in the transporter throughout the structure, allowing one of the two sodium molecules to move inward, and then release the deeply bound messenger and its sodium partner into the cell.

In the bacterial transporter studied, antidepressant molecules bind in the outer one of two sites, and stop the transport mechanism, leaving the messenger molecule outside the cell.

The second team of researchers, involving a collaboration of the Weinstein and Javitch labs with colleagues in Denmark (the labs of Ulrik Gether and Claus Loland), found that in the human dopamine transporter cocaine binds in the deep site, unlike the antidepressant binding in the bacterial transporter. Therefore, the researchers conclude that anti-cocaine therapy will be more complicated, because interfering with cocaine binding also means interference with the binding of natural messengers.

“This finding might steer anti-cocaine therapy in a completely new direction,” says Dr. Weinstein.

Molecular understanding at this level of structural and dynamic detail is rare in the world of drug development, the authors note. Only about 15 percent of all drugs have a known molecular method-of-action, even though the effects of these drugs within the body — after very stringent and controlled laboratory testing — are well understood pharmacologically.

Contributing authors to the Molecular Cell study include Dr. Lei Shi from Weill Cornell Medical College, who had a major role in the computational simulations; Dr. Matthias Quick from Columbia University Medical Center and the New York State Psychiatric Institute, who had a major role in the experimental component; and Dr. Yongfang Zhao from Columbia University Medical Center.

Lead authors of the Nature Neuroscience study are first author Dr. Thijs Beuming of Weill Cornell Medical College and senior authors Drs. Claus Loland and Ulrik Gether of The Panum Institute of the University of Copenhagen, Denmark. Additional co-authors include Drs. Julie Kniazeff, Marianne Bergmann and Klaudia Raniszewska of The Panum Institute of the University of Copenhagen; Drs. Lei Shi and Luis Gracia of Weill Cornell; and Dr. Amy Hauck Newman of the National Institute on Drug Abuse (NIDA).

The NIH supported these studies, and it is noteworthy that both the Molecular Cell and the Nature Neuroscience study share an NIH funding source, a Program Project grant awarded by the National Institute on Drug Abuse and directed by Dr. Weinstein, with Drs. Javitch and Gether each directing one of the projects. Additional support came from the Danish Medical Research Council, the Lundbeck Foundation, the Novo Nordisk Foundation and the Maersk Foundation — all in Europe.

Researchers Create DNA Logic Circuits That Work In Test Tubes

A Caltech group led by computer scientist Erik Winfree reports that they have created DNA logic circuits that work in salt water, similar to an intracellular environment. Such circuits could lead to a biochemical microcontroller, of sorts, for biological cells and other complex chemical systems. The lead author of the paper is Georg Seelig, a postdoctoral scholar in Winfree's lab.

"Digital logic and water usually don't mix, but these circuits work in water because they are based on chemistry, not electronics," explains Winfree, an associate professor of computer science and computation and neural systems who is also a recipient of a MacArthur genius grant.

Rather than encoding signals in high and low voltages, the circuits encode signals in high and low concentrations of short DNA molecules. The chemical logic gates that perform the information processing are also DNA molecules, with each gate a carefully folded complex of multiple short DNA strands.

When a gate encounters the right input molecules, it releases its output molecule. This output molecule in turn can help trigger a downstream gate--so the circuit operates like a cascade of dominoes in which each falling domino topples the next one.

However, unlike dominoes and electronic circuits, components of these DNA circuits have no fixed position and cannot be simply connected by a wire. Instead, the chemistry takes place in a well-mixed solution of molecules that bump into each other at random, relying on the specificity of the designed interactions to ensure that only the right signals trigger the right gates.

"We were able to construct gates to perform all the fundamental binary logic operations--AND, OR, and NOT," explains Seelig. "These are the building blocks for constructing arbitrarily complex logic circuits."

As a demonstration, the researchers created a series of circuits, the largest one taking six inputs processed by 12 gates in a cascade five layers deep. While this is not large by the standards of Silicon Valley, Winfree says that it demonstrates several design principles that could be important for scaling up biochemical circuits.

"Biochemical circuits have been built previously, both in test tubes and in cells," Winfree says. "But the novel thing about these circuits is that their function relies solely on the properties of DNA base-pairing. No biological enzymes are necessary for their operation.

"This allows us to use a systematic and modular approach to design their logic circuits, incorporating many of the features of digital electronics," Winfree says.

Other advantages of the approach are signal restoration for the production of correct output even when noise is introduced, and standardization of the chemical-circuit signals by the use of translator gates that can use naturally occurring biological molecules, such as microRNA, as inputs. This suggests that the DNA logic circuits could be used for detecting specific cellular abnormalities, such as a certain type of cancer in a tissue sample, or even in vivo.

"The idea is not to replace electronic computers for solving math problems," Winfree says. "Compared to modern electronic circuits, these are painstakingly slow and exceedingly simple. But they could be useful for the fast-growing discipline of synthetic biology, and could help enable a new generation of technologies for embedding 'intelligence' in chemical systems for biomedical applications and bionanotechnology."

The other authors of the paper are David Soloveichik and Dave Zhang, both Caltech grad students in computation and neural systems.

VentureBeat: $3 million raised for experience-sharing site

Experience Project: The San Francisco company has raised $3 million in a first round of funding to expand its anonymous social experience site.

Experience Project has quietly drawn a big community of people who share life experiences with one another anonymously. Since it started a little more than a year ago, users have created a million distinct experiences on intimate subjects, such as "I live in a sexless marriage."

D.E. Shaw Group led the round. Other investors include Maples Investments and Baseline Ventures. Despite the tough economic environment, founder Armen Berjikly said he got to know the investors over several months, but once he decided to do it, the deal was done in a matter of weeks.

Sprout: The San Francisco- and Honolulu-based start-up behind an easy-to-use tool for creating Flash applications has been having a very good year. It launched in January at DEMO (where it snagged a "DEMO god" award), made its app builder publicly available in March, then released a bunch of new features in April. Now it has raised $5 million in a second round of venture funding.

Through Sprout, you can use a "what you see is what you get" interface reminiscent of Photoshop to build applications that the company calls "sprouts." The apps are basically widgets, but with the interactivity of a Flash Web site. The process is made especially accessible through Sprout's templates, which can be customized with just a few clicks.

The release of Sprout version 2.0 is imminent, says Chief Executive
Carnet Williams, and the new funding will be used expand the
engineering, business development, marketing and support teams. The
round was led by Polaris Venture Partners, with participation from existing investor Global Venture Capital and Lotus founder Mitch Kapor. The start-up had previously raised $3.3 million.

Viator:
The San Francisco-based travel Web site, which specializes in daytime
tours, has raised $6.7 million in a third round of funding, according
to VentureWire.

Founded in 1995, the company makes money
by purchasing tours at bulk rates than selling them to individuals. It
offers 5,500 tours to more than 400 destinations.

The funding was led by Carlyle Venture Partners and Technology Venture Partners,
and it follows $10 million raised in 2005 and 2006. The new money will
be used to expand into the international and cruise markets.

Gevo: The Pasadena developer of synthetic biofuels just wrapped up a $17 million third round of funding. New investors Burrill & Co. and Malaysian Life Sciences Capital Fund joined clean-tech regulars Khosla Ventures and Virgin Green Fund. The biofuel start-up has already raised more than $30 million since the beginning of last year.

Like competitors LS9, OPX Biotechnologies and Amyris,
Gevo is trying to change the face of the biofuel industry by using
synthetic biology to engineer enzymes and microorganisms to convert
cellulosic crops and waste into advanced biofuels like isobutanol and
butanol. Butanol, the company claims, is superior to first-generation
biofuels like corn ethanol. It has higher energy content, does not
absorb water and can easily be transported through the existing gas
infrastructure. Perhaps most important, it can be directly pumped into
current vehicles.

The company is working on an alternative jet fuel for Richard Branson's Virgin Airways and is otherwise focusing on optimizing the conversion efficiencies of its proprietary microorganism strains and enzymes.

Biofuel Innovators with Alternatives to Oil

Oil soars to $125 per barrel and economies around the world sputter or fall into recession. Enough is enough. Many biofuels can be blended with gasoline and diesel refined from oil, then pumped into our existing vehicles. Even making our fuels with ten percent biofuel and ninety percent refined oil is enough to drop demand for oil and send the price south.

At the moment, this approach has major drawbacks. Food prices are soaring as more ethanol is made from corn, and biodiesel from soy and palm oil. Rain forests are being slashed and burned to increase production of soy and palm oil. Next generation biofuels, however, promise to minimize these downsides while ending our dependency on oil.

“Once viewed as an environmentally-friendly, silver bullet alternative to fossil fuels, biofuels have recently become "public enemy number one” in regard to rising food prices. But what role does the growing biofuels market really play in the current food crisis?” Asks James Greenwood, President and CEO, Biotechnology Industry Organization, who goes on to answer the question.

“There are a number of factors contributing to rising food costs. Poor harvests over the past year in Australia, Canada, South America and Eastern Europe. Protectionist tariff policies affecting the rice-producing nations of South Asia. A weak dollar is driving up the demand for U.S. exports of grains, a dynamic exacerbated by hedge fund and pension fund managers who are pouring unprecedented levels of investment in grain commodities. Growing incomes and meat-eating preferences of an emerging middle class in countries like India and China are increasing global demand for animal feed and the fuel required for production and transport. But the most significant factors driving up food prices are ever-rising energy and transportation costs.

“In coming years, biotechnology will allow us to create biofuels from non-food crops, crops that yield more per acre, require less fertilizer and are more tolerant of drought and other adverse conditions. These scientific breakthroughs will only enhance the world's ability to feed and fuel itself in a responsible and sustainable way. As biofuels production transitions to these second and third generation biofuels, biotechnology will play an essential role in providing the world with cleaner fuel and more affordable food.”

The U.S. Agriculture Department projects that the combination of a shrinking corn crop and the swelling appetite for corn ethanol will keep the price of the nation's largest crop in record territory into 2009. USDA economists expect U.S. farmers to produce 12.1 billion bushels of corn, down 7.3% from the record 13.1 billion bushels they harvested in 2007, as farmers grow more soy.

In the U.S., ethanol is currently in far greater demand than biodiesel. By law, 36 billion gallons of ethanol must be in use by 2020 in the USA. This ethanol will primarily be blended with gasoline. E10, a blend of ten percent ethanol and ninety percent petroleum refined gasoline will be common. By contrast, in the U.S. most diesel fuel is consumed by heavy vehicles with expensive engines that must run for years. Warranties can be voided and maintenance cost increase unless the diesel fuel meets exacting standards.

Biofuel innovators were discussed and presented at the Platts Advanced Biofuels Conference, which I attended. With improved biofuels we will achieve increased energy security while reducing greenhouse gas emissions. This article examines short-term and longer-term biofuel solutions.

In the heart of Silicon Valley, Khosla Ventures is funding innovative solutions for clean transportation and other major global problems. Brilliant innovators such as Vinod Khosla and Samir Kaul are involved in a number of companies creating cleaner fuels with cellulosic ethanol, biomass gasification, and synthetic biology.
Platt conference keynote speaker Vinod Khosla predicts that within five years fuel from food will no longer be competitive with cellulosic ethanol. He also predicts, “In five years, oil will be uncompetitive with biofuel, even at $50 per barrel, though oil will take longer to decline in price.”

Khosla Ventures identifies several sources of cellulosic ethanol. “There are four principal sources of biomass and biofuels we consider (1) energy crops on agricultural land and timberlands using crop rotation schemes that improve traditional row crop agriculture AND recover previously degraded lands (2) winter cover crops grown on current annual crop lands using the land during the winter season (or summer, in the case of winter wheat) when it is generally dormant (while improving land ecology) (3) excess non-merchantable forest material that is currently unused (about 226 million tons according to the US Department of Energy), and (4) organic municipal waste, industrial waste and municipal sewage.” Khosla Papers and Presentations

Sugarcane is the currently the most efficient feedstock for larger scale ethanol production. While corn ethanol delivers little more energy output than the total energy necessary to grow, process, and transport it; sugarcane ethanol delivers eight times the energy output as lifecycle energy input. Also, sugarcane typically produces twice as much fuel per acre as corn.

Brazil produces almost as much sugarcane ethanol as the United States produces corn ethanol, but at a fraction of the energy cost. Sugarcane is also grown in the southern U.S., from Florida to Louisiana to California.

Brazil is free from needing foreign oil. Flex-fuel vehicles there get much better mileage than in the U.S. If you drive into any of Brazil’s 31,000 fueling stations looking for gasoline, you will find that the gasoline has a blend of at least 20% ethanol, as required by law. 29,000 of the fueling stations also offer 100% ethanol. Ethanol in the U.S. is normally delivered on trucks, increasing its cost and lifecycle emissions. Brazil's largest sugar and ethanol group, Cosan SA announced the creation of a company to construct and operate an ethanol pipeline.

Most sugarcane is grown in the southern state of Sao Paulo. Economics do not favor its growth in rain forests, although those who favor blocking its import make that claim. It is cattle, soy, palm oil, logging, and climate change that most threaten the rain forests. Some environmentalists are concerned that a significant percentage of Brazil’s sugarcane is grown in the cerrado, which is one of the world’s most biodiverse areas. The cerrado is rich with birds, butterflies, and thousands of unique plant species. Others argue that without sugarcane ethanol, more oil will come from strip mining Canadian tar sands and from a new “gold rush” for oil in the melting artic.



Sugarcane growers are planning the development of varieties that can produce a larger quantity of biomass per hectare per year. These varieties are being called “energy cane” and may produce 1,200 to 3,000 gallons of ethanol per acre, contrasting with 300 to potentially 500 gallons of ethanol from an acre of corn.
Although sugarcane ethanol is currently the low-cost winner, long-term economics are likely to favor cellulosic sources.

In his keynote speech, Vinod Khosla sited promising sources such as paper waste, wood waste, forest waste, miscanthus, sorghum, hybrid poplar trees, winter cover crops, and perennial crops have deep roots and sequester carbon. Cellulosic ethanol could potentially yield 2,500 gallons per acre.

Large-scale reliance on ethanol fuel will require new conversion technologies and new feedstock. Much attention has been focused on enzymes that convert plant cellulose into ethanol. Because cellulose derived ethanol is made from the non-food portions of plants, it greatly expands the potential fuel supply without cutting our precious food supplies.

Pilot plants are now convert wood waste into ethanol. Over the next few years, much larger plants are likely to come online and start becoming a meaningful part of the energy mix. In Japan, Osaka Project, Verenium utilizes demolition wood waste as a feedstock in producing up to 1.3 million liters of cellulosic ethanol annually. A second phase, planned for completion in 2008, will increase production to 4 million liters per year. Verenium Ethanol Projects

Norampac is the largest manufacturer of containerboard in Canada. Next generation ethanol producer TRI is not only producing fuel, its processes allow the plant to produce 20% more paper. Prior to installing the TRI spent-liquor gasification system the mill had no chemical and energy recovery process. With the TRI system, the plant is a zero effluent operation, and more profitable.

The spent-liquor gasifier is designed to processes 115 Metric tons per day of black liquor solids. The chemicals are recovered and sent to the mill for pulping; the energy is recovered as steam which offsets the production of steam using purchased natural gas. All thermal energy in the plant is now renewable.
Producing cellulosic ethanol over the next few years is unlikely to be cost competitive with oil refining, unless other benefits accrue such as Norampac’s improved plant efficiency, savings in energy, heat, steam, reduction of plant waste, and/or production of multiple products from the plant. In the longer term, 100 million gallon per year cellulosic plants may be profitable without byproduct benefits.

Another Khosla Ventures portfolio company is Range Fuels which sees fuel potential from timber harvesting residues, corn stover (stalks that remain after the corn has been harvested), sawdust, paper pulp, hog manure, and municipal garbage that can be converted into cellulosic ethanol. In the labs, Range Fuels has successfully converted almost 30 types of biomass into ethanol. While competitors are focused on developing new enzymes to convert cellulose to sugar, Range Fuels' technology eliminates enzymes which have been an expensive component of cellulosic ethanol production. Range Fuels' thermo-chemical conversion process uses a two step process to convert the biomass to synthesis gas, and then converts the gas to ethanol.

The U.S. Department of Energy is negotiating with Range Fuels research funding of up to $76 million.
Range Fuels was awarded a construction permit from the state of Georgia to build the first commercial-scale cellulosic ethanol plant in the United States. Ground breaking will take place this summer for a 100-million-gallon-per-year cellulosic ethanol plant that will use wood waste from Georgia's forests as its feedstock. Phase 1 of the plant is scheduled to complete construction in 2009 with a production capacity of 20 million gallons a year.

Abengoa Bioenergy, also announced the finalization of a $38-million collaboration agreement signed with the DOE for the design and development of the Hugoton, Kansas cellulosic ethanol plant which will process over 11 million gallons of ethanol per year with renewable energy as a byproduct. The biomass plant will be situated next to a conventional grain-to-ethanol plant with combined capacity of 100 million gallons, using scale to make cellulosic ethanol more cost-competitive. Abengoa Bioenergy will invest more than $500 million in the next five years in their production of biomass into ethanol in the U.S., Brazil, and Europe.
Poet, the nation’s largest ethanol maker with 22 plants now turning out 1.2 billion gallons a year, plans to open a 25-million-gallon cellulosic facility in 2009 alongside its expanded grain ethanol plant in Emmetsburg, Iowa. Corn cobs from local fields will supply it. Ethanol 2.0

Ethanol is not the only bio-game in town. Many European cars and most U.S. heavy vehicles use diesel not gasoline. New generations of biodiesel, biobutanol, and synthetic fuels are being developed that could be blended with diesel or replace it. Some of these fuels could also be blended with gasoline and jet fuel. BP and DuPont have teamed to produce biobutanol which has a higher energy density than ethanol, can be delivered in existing pipelines, and can be blended with a wider range of fuels.

Amyris will use synthetic biology to develop microorganisms that produce biofuels. LS9 Inc. is in the early stage of using synthetic biology to engineer bacteria that can make hydrocarbons for gasoline, diesel, and jet fuel.

Algae have the potential to be an efficient producer of oil for biodiesel with byproducts of including hydrogen and carbohydrates which could be converted into ethanol. Biodiesel from algae can be done today. The challenge is to make production large scale and cost effective. Ideal forms of algae need to be developed. Oil must be “brewed” with the right solution, light, mixing and stirring. Cost-effective photobioreactors must be developed.

“If we were to replace all of the diesel that we use in the United States" with an algae derivative, says Solix CEO Douglas Henston, "we could do it on an area of land that’s about one-half of 1 percent of the current farm land that we use now."

Mike Janes, Sandia National Labs, is even more optimistic, "Recent studies using a species of algae show that only 0.3 percent of the land area of the U.S. could be utilized to produce enough biodiesel to replace all transportation fuel the country currently utilizes….In addition, barren desert land, which receives high solar radiation, could effectively grow the algae, and the algae could utilize farm waste….With an oil-per-acre production rate 250 times the amount of soybeans, algae offers the highest yield feedstock for biodiesel."

At the Platts Advanced Biofuels Conference, most algae experts, from scientists to CEOs of algael fuel companies, see challenging years ahead before cost-effective commercial scale production of biofuel from algae will be possible. As one expert quipped, “The greatest progress to scale is being done by Photoshop.”
A number of companies are actively exploring the potential for fuel from algae. "Algae have great potential as a sustainable feedstock for production of diesel-type fuels with a very small CO2 footprint," said Graeme Sweeney, Shell Executive Vice President Future Fuels and CO2. Shell is investing in using algae to produce fuel.

These innovators will only make a difference if they receive funding and distribution. Some of the energy giants are helping. Shell is recognized as the largest biofuel distributor among the “oil majors.” Shell has invested heavily in Choren biomass-to-liquids (BTL) in Europe. Shell has invested in Iogen, a maker of cellulosic ethanol catalysts and technology.

Biofuels have the potential to provide solutions for energy security and transportation with a much smaller carbon footprint. Other solutions include reduction in solo driving due to urban density and corporate programs, public transit, more fuel efficient vehicles, and the shift to electric vehicles that require no fossil fuel or biofuel. The new biofuels have the potential to encourage sustainable reforesting and soil enrichment. Biofuel 2.0 provides a path to fuel from wood and waste, not food and haste.
John Addison publishes the Clean Fleet Report. He owns a modest number of shares of Abengoa.

Labels: ABG.MC, biobutanol, biodiesel, biofuels, BP, cellulosic ethanol, clean fleet, cleantech, DD, RDSA, SU, VRNM

Cancer Prevention Drug Being Developed By NCI

While researching new ways to stop the progression of cancer, researchers at the University of Oklahoma Health Sciences Center, have discovered a compound that has been shown to prevent cancer in the laboratory. The research appears in the journal Gene Regulation and Systems Biology.

The compound, which still faces several rounds of clinical trials, successfully stopped normal cells from turning into cancer cells and inhibited the ability of tumors to grow and form blood vessels. If successful tests continue, researchers plan to create a daily pill that would be taken as a cancer preventive.

"This compound was effective against the 12 types of cancers that it was tested on," said Doris Benbrook, Ph.D., principal investigator and researcher at the OU Cancer Institute. "Even more promising for health care is that it prevents the transformation of normal cells into cancer cells and is therefore now being developed by the National Cancer Institute as a cancer prevention drug."

The synthetic compound, SHetA2, a Flex-Het drug, directly targets abnormalities in cancer cell components without damaging normal cells. The disruption causes cancer cells to die and keeps tumors from forming.

Flex-Hets or flexible heteroarotinoids are synthetic compounds that can change certain parts of a cell and affect its growth. Among the diseases and conditions being studied for treatment with Flex-Hets are polycystic kidney disease, kidney cancer and ovarian cancer.

Benbrook and her research team have patented the Flex-Het discovery and hope to start clinical trials for the compound within 5 years. If the compound is found to be safe, it would be developed into a pill to be taken daily like a multi-vitamin to prevent cancer.

The compound also could be used to prevent cancer from returning after traditional radiation and chemotherapy treatments, especially in cancers that are caught in later stages such as ovarian cancer where life expectancy can be as short as 6 months after treatment.

"It would be a significant advancement in health care if this pill is effective in preventing cancer, and we could avoid the severe toxicity and suffering that late stage cancer patients have to experience," Benbrook said. test

Amyris unveils bio-diesel fuel deal, joins forces with Brazilian company

An Emeryville biotech company that gained fame creating a less-costly anti-malaria drug has turned to its next challenge: making clean fuel for the world's cars, trucks, jets and generators.

Today, Amyris said it has signed a deal with a large Brazilian ethanol maker to create renewable diesel using its synthetic biology technology.

The feedstock will be Brazil's plentiful sugarcane, already being used to make ethanol in that country. Santelisa Vale, the nation's second-largest ethanol and sugar producer, will devote 2 million tons of crushing capacity to the project.

A joint venture between Amyris and Crystalsev, majority-owned by Santelisa, will make the fuel. A pilot plant is expected to go into operation in early 2009 and commercial production could commence in 2010, according to Amyris.

The US National Cancer Institute Extends its Contract with GENEART - Order Volume USD 1.9M

GENEART, the global leader in gene
synthesis and specialist in the field of Synthetic Biology, today
announces the continuation of the collaboration with the US National
Cancer Institute, which is part of the NIH. The contract was awarded
and extended by SAIC Frederick, Inc. on behalf of the NCI. Within the
scope of the ongoing contract, GENEART has already produced more than
3,500 genes with an order volume of about USD 3.5M. The follow-up
order comprises a volume of USD 1.9M for the synthesis of another 200
highly complex genes. With the genes synthesized by GENEART, the NCI
complements the NIH "Mammalian Gene Collection (MGC) Program". This
comprehensive collection of human and mouse genes represents a
significant resource for basic research as well as for clinical
research and development.

The 3,500 genes so far synthesized by GENEART include a large number
of highly complex sequences, which could not be isolated with
classical methods of biotechnology in the course of the MGC project
between 2002 and 2006. A major fraction of genes in this group showed
a high number of repetitive DNA sequence elements, or were toxic for
the production host E. coli. To efficiently synthesize this large
number of genes in a high-throughput manner, GENEART had to further
advance its existing technologies and establish new production
techniques.

Professor Dr. Ralf Wagner, CSO of the GENEART AG, adds: "The
advancements in technology have elevated our gene synthesis platform
to a new level, and further strengthen our leadership role in this
market. We therefore expect to profit far more than average from the
increasing demand for complex genes, gene clusters and entire genomes
in pharmaceutical research and in the synthetic biology field."

Christian Ehl, CFO of the GENEART AG, elaborates: "This order has
been the greatest challenge in our company history so far, and we
have mastered it with great success. Our performance demonstrates the
capability of our team, and it proves the power of the GENEART
Technology Platform. We are especially delighted about the extended
collaboration with NCI because it confirms our ability to perform.
Additionally, the NCI/NIH project provides us with a singular
reference in the field. This will certainly help us to acquire more
major projects in the global market."

One Step Closer To Elusive Cancer Vaccine

When cells become cancerous, the sugars on their surfaces undergo distinct changes that set them apart from healthy cells. For decades, scientists have tried to exploit these differences by training the immune system to attack cancerous cells before they can spread and ravage the body.

Now, researchers at the University of Georgia Cancer Center have synthesized a carbohydrate-based vaccine that – in mice – has successfully triggered a strong immune response to cancer cells. The finding, published in the October issue of the journal Nature Chemical Biology, brings the scientists one step closer to a much-sought-after “cancer vaccine.”

“In mice we can illicit very strong antibody responses and we have shown that the antibody responses are functional – that they can kill cancer cells,” said lead author Geert-Jan Boons, Franklin professor of chemistry.

Vaccines are currently used to prevent diseases by priming the immune system to recognize and attack a virus or bacteria. The vaccine that Boons and his team have developed, on the other hand, is a therapeutic vaccine that trains the body’s immune system to fight an existing disease.

The discovery in the 1970s of unique sugars on cancer cells set scientists in search of a way to get the immune system to recognize and attack cells that express these cancer-associated sugars. Until now, however, the results have been less than spectacular.

Cancer cells originate in the body, and the immune system leaves them alone because it distinguishes between the body’s own cells and foreign invaders such as viruses and bacteria.

Boons explained that early cancer vaccines were created by linking the tumor-associated carbohydrate with a foreign protein. The immune system, perhaps not surprisingly, attacked the protein and the linker molecules, but generally left the carbohydrate alone.

“We needed to come up with a vaccine that does not give our immune system a chance to go after anything else but the tumor-associated carbohydrate,” Boons said. “In other words, there should no junk that can induce an immune response to something other than the tumor-associated carbohydrate.”

Rather than using naturally derived and purified proteins and linkers, Boons and his team created a vaccine synthetically from scratch by stacking molecules together and arranging them in the appropriate configuration. In 2005, they created a fully synthetic vaccine that stimulated an immune response to the tumor-associated carbohydrate alone. The vaccine stimulated only low antibody levels, however, so the researchers began optimizing the components of the vaccine to illicit a stronger immune response.

Their optimized vaccine includes a tumor-associated carbohydrate that triggers the immune system’s B cells, a part of a protein that triggers the immune system’s T cells and a linker molecule that stimulates the production of generalized immune components known as cytokines.

The results of their three-pronged approach were astounding, particularly with respect to a critical component of the immune system known as IgG.

“When we tested our best vaccine we got really, really fabulous antibody levels that have never been seen before,” Boons said. “The levels of IgG antibody production were 100 times better than with conventional approaches.”

The vaccine has been successful in creating an antibody response that can kill cultured epithelial cells – those commonly involved in most solid tumors, such as breast and colorectal cancer – derived from mice and in stimulating an immune response in healthy mice. The researchers are currently testing the vaccine in mice with cancer, and Boons hopes to start phase I clinical trials in humans within a year.

Despite his enthusiasm for his work, Boons cautions that it’s too early to predict how the vaccine will perform in humans.

“There’s a very big step going from mice to humans,” he said. “Other cancer vaccines have worked in mice but not in humans.”

In addition to testing the new vaccine, Boon’s team is exploring the specific components of the immune response as they relate to cancer, determining the exact cytokines and antibodies that are most effective against cancer cells.

“We’re looking at which molecules are being upregulated at each level of immune response,” Boons said. “That gives us a road map to further optimize each component of the vaccine.”

The research is supported by the National Cancer Institute.

Source

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What is the Chiari Malformation?

The Chiari I Malformation is considered a congenital malformation, although there have been some reported cases of an acquired form. It is characterized by a small or misshapen posterior fossa (the compartment in the back of the skull), a reduction in cerebrospinal fluid pathways and a protrusion of the cerebellar tonsils through the bottom of the skull (foramen magnum) into the spinal canal. The tonsils would normally be round but often become elongated as they protrude down the spinal canal. Diagnosis can be difficult because not all patients will have the classical sign of deeply herniated tonsils.

Since the advent of MRI, the incidence of the Chiari I Malformation has risen
dramatically. MRI is safe and painless and currently the most reliable means available for diagnosing Chiari Malformations. Chiari Malformations are also known as herniation of the cerebellar tonsils, cerebellar ectopia, hindbrain herniation and Arnold-Chiari malformations.
A German pathologist, Professor Hans Chiari, first described abnormalities of the brain at the junction of the skull with the spine in the 1890's. He categorized them in order of severity, types I, II, III, and IV.

The Chiari type II Malformation is usually found in children with spina bifida or myelomeningocele. Not only is part of cerebellum unusually low and lying below the bottom of the skull, but the brain stem can be malformed in several ways. Types III and IV represent gross herniations of the cerebellum and are very rare.

What are the symptoms?
Many people with the Chiari I Malformation experience no symptoms. When symptoms are present, they usually do not appear until adolescence or early adulthood, but can occasionally be seen in young children. The majority of patients complain of severe head and neck pain. Headaches are often accentuated by coughing, sneezing or straining. Patients may complain of dizziness, vertigo, disequilibrium, muscle weakness or balance problems. Often fine motor skills and hand coordination will be affected.

Vision problems can also occur. Some patients experience blurred or double vision, difficulty in tracking objects or a hypersensitivity to bright lights. Physical examination may reveal nystagmus (involuntary eye movements). Other symptoms include tinnitus (buzzing or ringing in the ear), hearing loss or vocal cord paralysis. Patients may have difficulty swallowing, frequent gagging and choking and, in some cases, sleep apnea may be present.

The Chiari I Malformations may also be associated with other disorders such as hydrocephalus (build up of fluid in the ventricles of the brain) or Syringomyelia. Syringomyelia is a disorder in which cerebrospinal fluid enters the spinal cord, forming a cavity known as a syrinx. It is recommended that patients diagnosed with a Chiari Malformation have the entire spine imaged to rule out the presence of a syrinx, since it may be a consideration in treatment and prognosis.

Is there a treatment?
Surgical procedures to enlarge the posterior fossa are considered a treatment option for patients with the Chiari I Malformation. Techniques are quite diversified amongst neurosurgeons, and patient responses vary greatly. A successful surgery will alleviate pressure on the neural elements and may result in an improvement of symptoms.

The decision to treat a Chiari Malformation surgically requires careful consultation between patient and physician. Factors to be considered are the patient's current neurological condition and progression of symptoms over a period of time.

Is this condition hereditary?
Research into the risk of inheritance for the Chiari I Malformation is still in its early stages. In some families, more than one member has been documented to have the Chiari I Malformation. Familial recurrences are suggestive of a possible genetic component of the condition, but unfortunately there is no conclusive answer to the question of inheritance at this time. It is currently recommended that only those relatives experiencing symptoms commonly associated with the Chiari I Malformation need undergo investigational procedures.

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Codon Devices Awarded $1.5 Million Grant by National Institute of Standards and Technology

Codon Devices, Inc., the Constructive Biology Company™, today announced that it has been awarded a $1.5 million grant from the U.S. Commerce Department’s National Institute of Standards and Technology (NIST).

With the support of the grant, Codon Devices will develop an integrated microfluidics platform to significantly reduce the cost and complexity of building complex DNA fragments. This platform will advance the state of the art in gene synthesis to improve the utility of synthetic biology approaches for biotechnology research.

"We are thrilled that NIST has recognized Codon Devices with this ATP award,” said Brian M. Baynes, Founder and President of Codon Devices. “Funding from this initiative will enable us to develop a new generation of rapid, automated systems for construction of longer, more complex DNA sequences. By integrating this technology with our BioFAB™ Production Platform, we will make these new tools available to our customers and partners and accelerate critical applications such as drug discovery and development of renewable energy systems.”

The NIST award was granted under the Agency’s Advanced Technology Program (ATP). Awarded projects were selected for funding by a competitive, peer-reviewed process that evaluated the scientific and technical merit of each proposal and the potential for broad-based benefits to the nation. NIST promotes U.S. innovation and industrial competitiveness by advancing measurement science, standards and technology in ways that enhance economic security and improve our quality of life.

About Codon Devices

Codon Devices, Inc., based in Cambridge, MA, is a privately-held biotechnology company focused on enabling commercial applications of synthetic biology. Codon Devices' proprietary synthesis and design technologies improve the productivity of its industrial, pharmaceutical and academic customers in a paradigm shift to what the Company calls Constructive Biology™. The Company's focus is on developing and delivering high-value products and design services in a variety of application areas, including engineered gene libraries, engineered cells that produce novel pharmaceuticals, improved vaccines, agricultural products, and biorefineries for the production of industrial chemicals and energy. Codon Devices' BioFAB™ Production Platform uses sophisticated informatics, robotics and sequencing technologies to accurately synthesize genetic codes orders of magnitude more rapidly and cost-effectively than other currently available technology. More information about Codon Devices is available at www.codondevices.com.

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Guarding against the misuse of synthetic genomics

Synthetic genomics research involves using chemically created pieces of DNA known as oligonucleotides to design and assemble parts of, or complete chromosomes and genes.

In theory, these can then be used to generate new 'lifeforms' that can produce new biological drugs or biologically produced green fuels, which are impractical to engineer using more conventional biotechnology approaches.

However, as with any new technology that has the ability to be used for good comes the possibility that it can be subverted for evil means such as bioterrorism.

The 66 page report, entitled "Synthetic Genomics: Options for Governance", is a result of a 20 month examination of the field and has highlighted areas three key areas for policy intervention to ensure that this promising technology cannot be misused.

The need for such a review has accelerated over the last 5 years or so as the speed at which genetic constructs can be developed has increased dramatically, as has the number of companies that have the ability to develop them -this in turn has led to prices dropping rapidly.

"Designing ways to impede malicious uses of the technology while at the same time not impeding, or even promoting beneficial ones, poses a number of policy challenges for all who wish to use or benefit from synthetic genomics" said Michele Garfinkel, policy analyst at the J Craig Venter Institute and lead author of the report.

The first area involves those companies that supply synthetic DNA, oligonucleotides, genes or genomes and how they can ensure that they can trust that the researchers they are shipping their goods to are 'legitimate' users and not potential terrorists. In addition, the report recommends that these firms should collect customer details and information about their orders.

Some companies are already going beyond these recommendations of their own volition.

According to Dr Michael Dyson, Codon Devices' European managing director; every sequence they are asked to synthesise is checked against a database of high-risk sequences that could be used for nefarious means.

If a sequence is flagged up then the manufacture is stopped and discussions with the purchaser are initiated to find out exactly what the sequence is and what it will be used for.

The second area covers recommendations to control and/or monitor the use of DNA synthesisers, such that owners would have to be licensed and register the instruments as well as needing a license to buy reagents and services.

The third area involves the compilation of a manual for "biosafety in synthetic biology laboratories" as well establishing a recognised clearing house for best practice.

The review also calls for the broadening of the US Institutional Biosafety Committee's (IBC) review responsibilities to consider risky experiments as well as enhancing the enforcement of compliance with US National Institutes of Health (NIH) biosafety guidelines.

While these suggestions may appear to some to be somewhat draconian and could hinder honest research into beneficial systems, the committee was keen to stress that all the recommendations were designed to impose the minimum burden on researchers, industry and government.

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This 'new life form' is just reassembled car parts

Great scientific advances - unlike these latest claims - open up whole new areas of knowledge, says Nick Gay

Dr Nick Gay
Wednesday October 10, 2007
The Guardian

The Guardian's front-page story reported Craig Venter's claims that he is "poised to announce the creation of the first new artificial life form on Earth" (I am creating artificial life, declares US gene pioneer, October 6). On the face of it this seems to be a spectacular advance. Unfortunately the truth is rather different.

To provide an analogy, it is as if he had selected a set of car parts, assembled them into a car and then claimed to have invented the car. It will not "herald a giant leap forward in the development of designer genomes". It is merely the crudest and most facile kind of reductionism, an experimental approach that provides no insight whatever into the fundamental nature of cellular processes.

In fact the ability to carry out such a project relies on the work of thousands of scientists who have studied the molecular biology of the cell during the last 50 years and defined the function of basic cellular processes such as the replication of DNA and the conversion of RNA into proteins, and developed key methods such as the chemical synthesis of nucleic acids. Simply reassembling these cellular components into an "artificial" organism will not further our understanding of these life processes.

Your article also claims that his work "could unlock the door to new energy sources and techniques to combat global warming". It is certainly possible that the plant enzyme responsible for removing carbon dioxide from the atmosphere could be engineered to be more efficient, but this would not need Venter's artificial life - it could be achieved easily with the existing methods of genetic manipulation.

In another article on the same day you referred to the sequencing of Venter's own genome (Gene genie, October 6). This is an obvious, if somewhat egocentric, thing to do and a number of other single-genome sequences are in progress. But the idea alluded to, that you could predict the date of your death using this information, is absurd. Most human diseases are caused by the action of many genes in a complex interaction with the environment. The origin and progression of these polygenic diseases is poorly understood, and sequence information alone will not provide the answers.

It should also be noted that the ability to sequence whole genomes has little to do with Venter. It derives from the work of Fred Sanger at Cambridge in the 1970s. Venter, remember, was the man who tried to patent the human genome sequence and then exploit it for profit.

It is a feature of great scientific advances that they open up whole new areas of knowledge to view. This is well illustrated by the award this week of the Nobel prize for medicine to Martin Evans, Mario Capecchi and Oliver Smithies for the discovery and exploitation of stem cells.

These findings have led to a revolution in our understanding of cell and developmental biology and offer the prospect of new therapies for human diseases such as Alzheimer's. Venter's "artificial life" is not in the same league.

· Dr Nick Gay is a reader in cell signalling and development at the department of biochemistry, University of Cambridge

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