Colon Cancer Vaccine May Be Possible

A protein found in the intestines may lead the way to a vaccine that can treat colon cancers, and perhaps other tumors, too, according to researchers at Thomas Jefferson University. The protein, called Guanylyl cyclase C protein, or GCC protein, is normally only expressed in the intestinal lining and in colorectal cancer cells when they are spreading.

The researchers injected mice with colorectal cancer cells, some before immunization with GCC and some after. Unvaccinated animals had an average of 30 new tumors in the lungs and liver. Vaccinated animals had an average of three—not total immunity, but a considerably lower rate. The vaccinated mice also lived longer.

These results will need to be duplicated before human trials can begin, but this could be good news for the 1.2 million patients a year diagnosed with colon cancer globally.

Hey Buddy, Wanna Be a Gamer?

"But wait," you say. "Your other posts in the 'Hey Buddy, Wanna Be a...' series have been about contributing to scientific research. And now you want us to just play games?"

Not just play games, I say. But by playing foldit, you can both entertain yourself and contribute to scientific research, specifically in the realm of protein folding.

Those fine folks at David Baker's laboratory at the University of Washington (the same people who brought you the BOINC-based Rosetta@Home project for protein-folding simulation have created foldit to take advantage of the fact that there are some things that humans are just inherently better at (like image analysis and recognition) than computers are.

It turns out that because computers are not very good a visual processing, the Rosetta@Home software sometimes returns incorrect results. But humans—even with no training in biology at all—can do a better job of identifying things visually than modern computers can. In fact, many of the best players have no training in science at all.

The game is free to download and takes about 20 minutes to learn.

I love this kind of creative approach to solving one of the great problems in science today. Proteins are responsible for almost everything that happens in our bodies, but we understand so little about them. And now, thanks to people like me and you—who don't have to know anything about them can help the scientists advance our overall understanding and possibly find new ways to cure diseases.

Stop the Nonsense

Messenger RNA is used by the body to encode proteins based on the structure of certain genes. In mRNA as in DNA, genetic information is encoded in the sequence of four nucleotides arranged into codons of three bases each. Each codon encodes for a specific amino acid, except the stop codons that terminate protein synthesis.

But what happens if the DNA of the genes mutates, or becomes corrupted? Sometimes it causes the wrong proteins to be encoded. Sometimes, the DNA mutates in such a way that the Messenger RNA is prematurely truncated.

Example (thanks to Wikipedia):

    DNA: ATG ACT CAC CGA GCG CGA AGC TGA
   mRNA: AUG ACU CAC CGA GCG CGA AGC UGA
Protein: Met Thr His Arg Ala Arg Ser Stop

Now, suppose that a mutation occurs in the DNA:

    DNA: ATG ACT CAC TGA GCG CGA AGC TGA
   mRNA: AUG ACU CAC UGA GCG CGA AGC UGA

The RNA derives from the DNA (where UGA derives from TGA) In this case, UGA is a stop codon, so the protein produced by this interaction looks like this:

Protein: Met Thr His Stop

"Okay," you're saying, "but why go into all this detail?"

The answer is fairly simple. The type of mutation described above is called a "nonsense mutation." It has been estimated that n most genetic conditions, between 5-15 per cent of cases are caused by these types of mutations.

But a new drug by PTC Therapeutics, now in Phase II clinical trials, allows the cellular machinery to read through premature stop codons in mRNA, and thereby enables the translation process to produce full-length, functional proteins.

The drug, known as PTC124, has already had encouraging results in patients with Duchenne muscular dystrophy (the most severe form of muscular dystrophy) and cystic fibrosis. The drug has excited scientists because research suggests it should also work against more than 1,800 other genetic illnesses, including spinal muscular atrophy, hemophilia, lysosomal storage disorders, retinitis pigmentosa, familial hypercholesterolemia and some forms of cancer.

PTC124 won't be a cure-all for these types of conditions, but if it can be effective in 5-15% of cases, this could be one of the most promising new drugs of the decade.

Researchers Identify New Target for Blocking Cancer Cell Metastasis

Last week, the Van Andel Institute announced that its researchers have identified a protein involved in cancer cell metastasis, called DIP. DIP binds to and inhibits the activity of mDia2, a protein that works to control tumor cell metastasis, or the development of secondary tumors away from the primary cancer site.

When DIP binds to mDia2, it causes the affected cells to change shape and bubble, or bleb. This cell blebbing inhibits the control mDia2 has over tumor cell metastasis and may lead to development of secondary tumors.

If researchers can find a compound that will inhibit DIP, they believe it could prevent cancer cells from metastasizing, vastly improving the survivability of many forms of cancer.

A New Way to Do Research from Home

I've blogged on a number of occasions about distributed computing, which allows you to contribute your unused computing power to advance scientific research, because I think that's the single biggest thing most of us can do right now to improve the state of science and technology.

But now you can do even more. The Folding@Home project at Stanford University has new client software for their protein folding simulation that will allow it to run on a Sony PlayStation 3.

According to the Folding@Home website, with about 10,000 PS3s online, the researchers would be able to achieve performance on the petaflop scale. With software from Sony, the PlayStation 3 will now be able to contribute to the Folding@Home project, pushing Folding@Home a major step forward.

Two Studies Suggest New Cancer Treatment Path

A pair of studies conducted by the Memorial Sloan-Kettering Cancer Center have uncovered a regulatory mechanism for the PTEN gene, a commonly mutated tumor suppressor gene. The regulator, NEDD4-1, controls protein stability in cells, and is found in both the cytoplasm and the nucleus.

The first study found that NEDD4-1 is a key component in eliminating PTEN from cells by adding a molecular tag, ubiquitin, to PTEN causing degradation in the cellular machinery called proteasome. The second study found that the ubiquitination of PTEN by NEDD4-1 also regulates another important aspect of PTEN, its cellular localization.

Both studies showed that the PTEN mutation in patients prevented the addition of ubiquitin by NEDD4-1, providing a molecular mechanism for the detrimental effect of the mutant PTEN protein. They showed that the single ubiquitin tagging is necessary to import PTEN into the cell nucleus where it is protected from degradation and cancer is initiated.

The researchers say that the uncovered key role of PTEN degradation provides a potential route to new therapeutic strategies. They believe that a class of drugs, the proteasome inhibitors, that selectively block the degrading effects of ubiquitination, should now be studied as possible treatments for cancers with PTEN mutations.

Wheat Protects Self from Insects

Researchers at the USDA and Purdue University have discovered a gene in wheat that produces proteins that attack the stomach lining of Hessian flies, causing them to starve to death.

By killing the parasites, causes catastrophic losses if not controlled. Protection against Hessian flies will allow greater crop yields, which is good news for farmers and for countries with food shortages.

During the 1980s the state of Georgia suffered $28 million in lost wheat in one year after the fly overcame the plants' resistance gene used in the area at the time. The Hessian fly is particularly insidious because it actually can control the wheat plant's development.

Researchers Develop Better Alzheimer's Test

Researchers at Cornell University and Weill Cornell Medical College have developed the first real diagnostic test for Alzheimer's Disease. Currently, diagnoses are dependent upon clinical judgment of a physician, which can sometimes have difficulty distinguishing between Alzheimer's and other forms of dementia. In some cases, the diagnosis is not confirmed or rejected until the autopsy table, obviously far too late for any future treatments to do any good.

The new technique involves sampling cerebrospinal fluid for a panel of twenty-three protein biomarkers. The Cornell study combined cutting edge "proteomics" technology, detailed image analysis, and complex computational and statistical analyses to simultaneously compare 2,000 cerebrospinal fluid proteins from 34 patients with autopsy-proven Alzheimer's disease to those of 34 age-matched controls without the disease.

For more information, read the whole story here.

Researchers Discover Self-Assembling Nano-Ice

A research team at University of Nebraska-Lincoln have discovered a new type of nano-ice that self assembles, inside carbon nano-tubes and at high pressures, into double-helixes.

The research, conducted by chemistry professor Xiao Cheng Zeng and his team on the university's PrairieFire supercomputer, could have major implications for scientists in other fields who study the protein structures that cause diseases such as Alzheimer's and bovine spongiform ecephalitis (mad cow disease). It could also help guide those searching for ways to target or direct self-assembly in nanomaterials and predict the kind of ice future astronauts will find on Mars and moons in the solar system.

Another implication, Zeng said, is that these self-assembling helical ice structures may give scientists and engineers a different way to think about weak molecular bonds and the self-assembly process as they try to develop ways to direct self-assembly in making new materials. He said that while scientists have a good understanding of covalent bonds (the strong type of bonding where atoms share electrons), knowledge is not as complete about the weak bond, such as hydrogen bonds, that are essential to the self-assembly process. In weak bonding, atoms don't share electrons.

Read the full story HERE.

Project Profile: Rosetta@home

This week's profile is for the Rosetta@Home project. Rosetta@home uses the BOINC software platform for distributed computing to determine the 3-dimensional shapes of proteins in research, with the stated goal of finding cures for some major human diseases.

Basically, by running the BOINC software and setting up the Rosetta@home project, your wasted CPU cycles can be put to use helping cure some of the most devastating diseases affecting humans today, such as cancer and Alzheimer's disease.

From the Rosetta@home Science FAQ:

What is Rosetta?

Rosetta is a protein structure prediction and design program.

What is a protein?

A protein is a polymer of amino acids that is encoded by a gene.

What are amino acids?

Amino acids are chemical moieties that form the basic building blocks of proteins. There are 20 different amino acids that are specified by the genetic code. These 20 amino acids fall into different groups based on their chemical properties: acidic or alkaline, hydrophilic (water-loving) or hydrophobic (greasy).

What do proteins do?

Proteins perform many essential functions in the cells of living organisms. They replicate and maintain the genome (DNA), they help cells grow and divide, and stop them from growing too much, they give a cell its identity (eg liver, neuron, pancreatic, etc.), they help cells communicate with each other. Proteins, when mutated or when affected by toxins can also cause disease, such as cancer or alzheimer's. Bacterial and viral proteins can hijack a cell and kill it. In short, proteins do everything.

How do proteins perform all their different functions?

Each protein folds into a unique 3-dimensional shape, or structure. This structure specifies the function of the protein. For example, a protein that breaks down glucose so the cell can use the energy stored in the sugar, will have a shape that recognizes the glucose and binds to it (like a lock and key). It will have chemically reactive amino acids that will react with the glucose and break it down, to release the energy.

Why do proteins fold into unique structures?

It's long been recognized that most for most proteins the native state is at a thermodynamic minimum. In English, that means the unique shape of a protein is the most stable state it can adopt. Picture a ball in a funnel - the ball will always roll down to the bottom of the funnel, because that is the most stable state.

What forces determine the unique native (most stable) structure of a protein?

The sequence of amino acids is sufficient to determine the native state of a protein. By virtue of their different chemical properties, some amino acids are attracted to each other (for example, oppositely charged amino acids) and so will associate; other amino acids will try to avoid water (because they are greasy) and so will drive the protein into a compact shape that excludes water from contacting most of the amino acids that "hide" in the core of this compacted protein.

Why is it so difficult to determine the native structure of a protein?

Even small proteins can consist of 100 amino acids. The number of potential conformations available to even such a (relatively) small protein is astronomical, because there are so many degrees of freedom. To calculate the energy of every possible state (so we can figure out which state is the most stable) is a computationally intractable problem. The problem grows exponentially with the size of a protein. Some human proteins can be huge (1000 amino acids).

So how does Rosetta approach this problem?

The rosetta philosophy is to use both an understanding of the physical chemical properties different types of amino acid interactions, and a knowledge of what local conformations are probable for short stretches of amino acids within a protein to adopt, to limit the search space, and to evaluate the energy of different possible conformations. By sampling enough conformations, Rosetta can find the lowest energy, most stable native structure of a protein.

Why is distributed computing required for structure prediction by Rosetta?

In many cases where the native structure of a protein is already known, we have noticed that Rosetta's energy function can recognize the native state as more stable than any other sampled state. When starting from a random conformation, however, we've observed that the native state is never sampled. By applying more computing power to the problem, we can sample many more conformations, and try different search strategies to see which is the most effective.

How will Rosetta@home benefit medical science?

Please see our Disease Related Research page for information on how Rosetta is being applied to medical problems.