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.

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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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Codon Devices expands gene scaffolding reach

Constructive Biology expert, Codon Devices, has opened a European subsidiary in the UK to support the rapid growth of the advanced gene synthesis and protein engineering markets.

The new subsidiary, Codon Devices UK, will focus in offering service and support help to its expanding synthetic biology customer base in Europe, Scandinavia and Israel.

The use of synthetic biology methods to construct engineered cell lines that increase the efficiency of biological drug and vaccine formation or speed-up the drug discovery process is ever increasing.

In addition, such systems can be used to generate enzymes that produce industrial chemicals or aid in the breakdown of plants for biofuel applications.

Traditionally, researchers have had to clone specific genes and splice them into an organism's DNA.

Codon Devices' fee-for-service offering allows researchers to specify a sequence that Codon will then synthesise and ship to the customer, enabling them to spend more time studying the effects of the sequences.

"There is a move away from cloning genes yourself in the laboratory as long as you can find a vendor such as Codon to supply you with gene constructs for expression libraries protein structure libraries," said Dr Michael Dyson, European Managing Director and head of Codon'd European subsidiary.

Such is the groundswell of demand that Dr Dyson estimates that the market will reach a size of around $2bn a year in the near future, compared with $40m a year before 2005.

This growth is helped by reduced costs associated with making these sequences enabled by high throughput parallel synthesis techniques that. Codon's facility can currently make up to 5 megabase pairs a month and is still scaling up production.

Historically, manufacturing of DNA was to stick together oligonucleotides but was only really useful in making oligomers up to 100 base pairs, and anything bigger was very difficult to QC.

Codon has developed a parallel synthesis platform dubbed BioFAB, which uses sophisticated informatics, robotics and sequencing technologies to accurately synthesize genetic codes.

The company claims that its BioFAB system can produce the gene constructs more rapidly and cost-effectively than other currently available technology

Indeed, last July, the company announced the successful construction and delivery of a sequence-verified, 35-kilobase genetic construct for Microbia's Precision Engineering business unit.

The construct was an 80 per cent synthetic gene cluster that codes for an optimised biosynthetic pathway used to produce an active pharmaceutical ingredient.

The company is also heavily involved in partnering companies to help them overcome especially challenging projects.

"It's very complex biology and what we do is a generation away from simply constructing oligomers using the Caruthers synthesis, we look at how to best construct the molecules, how you error check them and checking them for function," said Dr Dyson.

Indeed, the global demand for Codon's approach is such that the company has plans to expand operations in the Pacific Rim regions.

"Codon is investing heavily to address the global need for this technology and our expansion into Europe is being matched by an expansion into Japan and the Pacific Rim," said Dr Dyson.

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Gene Expression Profiling of Cuticular Proteins across the Moult Cycle of the Crab Portunus pelagicus

Background

Crustaceans represent an attractive model to study biomineralization and cuticle matrix formation as these events are precisely timed to occur at certain stages of the moult cycle. Moulting, the process by which crustaceans shed their exoskeleton, involves the partial breakdown of the old exoskeleton and the synthesis of a new cuticle. This cuticle is subdivided into layers some of which become calcified and some which remain uncalcified. The cuticle matrix consists of many different proteins which confer the physical properties, such as pliability, of the exoskeleton.

Results

We have used a custom cDNA microarray chip, developed for the blue swimmer crab Portunus pelagicus, to generate expression profiles of genes involved in exoskeletal formation across the moult cycle. Twenty-one distinct moult cycle related differentially expressed transcripts representing crustacean cuticular proteins were isolated. Thirteen contain copies of the cuticle_1 domain, previously isolated from calcified regions of the crustacean exoskeleton. Four transcripts contain a chitin_bind_4 domain (RR consensus sequence), associated with both the calcified and un-calcified cuticle of crustaceans. Four transcripts contain an unannotated domain (PfamB_109992) previously isolated from C. pagurus. Additionally cryptocyanin, a hemolymph protein, involved in cuticle synthesis and structural integrity, also displays differential expression related to the moult cycle. Moult stage-specific expression analysis of these transcripts revealed that differential gene expression occurs both among transcripts containing the same domain and among transcripts containing different domains.

Conclusions

The large variety of genes associated with cuticle formation, and their differential expression across the crustacean moult cycle, point to the complexity of the processes associated with cuticle formation and hardening which involve many components and require strict regulatory mechanisms. This study provides a molecular entry path into the investigation of the gene networks associated with cuticle formation.

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Grant winner scoffs at genius label

By Elise Kleeman Staff Writer

PASADENA - Paul Rothemund does not consider himself a genius.

"At Caltech and elsewhere, I am surrounded by real geniuses all the time, people much quicker than me in a variety of ways," said the tall, brown-haired Caltech scientist.

Some, it seems, would disagree.

Rothemund, 35, was one of 24 recipients of the prestigious MacArthur Fellowship, a $500,000 prize often known as the "genius grant."

The no-strings-attached award can be used by the recipients any way they please and is intended to "enable recipients to exercise their own creative instincts for the benefit of human society," according to the MacArthur Foundation.

When they call you, Rothemund said, "they say, `The only thing you have to do is cash the checks. We have no expectations of you, you don't need to report back what you're doing, you're never going to hear from us again. Bye."'

Among this year's other prize winners are a blues musician, a spider silk biologist, a medieval historian, two painters, an author of short stories and another Caltech scientist - Michael Elowitz, a 37-year-old molecular biologist.

Like all the other winners, Elowitz found out about the prize a week before the rest of the Advertisement world.

"I received a phone call, which, among other things, swore me to secrecy," he wrote by e-mail last week from Greece, where he was attending a conference. "The element of secrecy, however transient, really added to the fun. It was one of the best phone calls for me in recent memory."

Both Elowitz and Rothemund are in the forefront of a new interdisciplinary field that some call synthetic biology.

"There's a convergence between a number of fields - chemistry, biology and computer science, where people are thinking about how to create biological circuits or how to program biology," said Erik Winfree, the director of the lab in which Rothemund works and himself a 2000 MacArthur Fellow.

Elowitz's work involves studying chains of interactions between genes and proteins that allow cells to process information, make decisions and communicate.

"He does some of the most beautiful experiments I know of," Winfree said. "They're simultaneously aesthetically pleasing - you could put them on your wall - and scientifically elegant, rigorous."

(In fact, Elowitz does display some images from his experiments on the walls of his lab.)

He studies genetic pathways by linking different genes in bacteria to the production of a rainbow of fluorescent colors. By videotaping how the bacteria's colors change, he can watch as the microbes pass through the steps of the genetic circuit.

"You have something that sort of looks like Froot Loops, except it's growing organisms," said Winfree of the bacteria.

Winfree describes Elowitz as "a joy because he's an enthusiastic, funny guy" who is "so excited about the things he's doing."

Rothemund also works with genetic material, using a loop of virus DNA to create what he calls "DNA origami."

By adding smaller, synthetic strands of DNA that act as staples, he figured out how make the viral DNA fold itself into any shape he wants, each about one-one-thousandth the width of a human hair.

So far, those shapes have included smiley faces, maps of North America, and snowflake patterns. But his technique could one day be the basis for the construction of smaller and faster computer chips.

"It was an exciting development," said Ned Seeman, a New York University chemist who also uses DNA as tiny molecular building blocks. "A lot of the things that we're doing in my lab have been reoriented because of the things Paul did."

Unlike previous, less successful techniques for constructing with DNA, Rothemund's is surprisingly simple.

The virus DNA is easy to come by and the DNA staples can be made to order, Rothemund said.

"They come in a FedEx package, and you take the little tubes and dump them together, add a little saltwater, heat them up and cool them off," he said.

Then, voila - in a single drop of water are a hundred billion shapes.

One "enormous challenge," though, "is figuring out how to put them where you want them and get them in the right orientation," he said.

"I haven't even begun to think of what to do with the money, but one non-scientific fantasy involves tennis lessons," Elowitz wrote. "I plan to resist the temptation to take up an extreme sport."

Source : www.whittierdailynews.com


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