Two new research studies have discovered a long sought molecular link between our metabolism and components of the internal clock that drives circadian rhythms, keeping us to a roughly 24-hour schedule. The findings appear in the July 25th issue of the journal Cell, a publication of Cell Press.

The missing link is a well–studied mammalian protein called SIRT1, which was previously known to be switched on and off in accordance with cells’ metabolic state and is perhaps best known for its potential life-extending properties. … Continue Reading »

Josh: Certainly this study needs to be repeated and verified by other parties, since the traditional understanding of aging is not so much the “rusting out” of cells, but rather, the irreparable damage of their DNA. Eukaryotic cells, like those in animals, have telomeres on the ends of the chromosomes. These telomeres shorten every time the cell divides, but an enzyme called telomerase makes them longer again. However, telomerase gets turned off, or at least gets very down regulated, as our cells mature and we age. Thus, the cells can only divide a fixed number of times before the telomeres disappear and DNA damage occurs. In almost all cancer cells, telomerase has been re-activated, allowing the cells to divide indefinitely.

Age may not be rust after all. Specific genetic instructions drive aging in worms, report researchers at the Stanford University School of Medicine. Their discovery contradicts the prevailing theory that aging is a buildup of tissue damage akin to rust, and implies science might eventually halt or even reverse the ravages of age.

“We were really surprised,” said Stuart Kim, PhD, professor of developmental biology and of genetics, who is the senior author of the research. … Continue Reading »

Ever since the human genome was sequenced less than 10 years ago, researchers have been able to access a dizzying plethora of genomic information with a simple click of a mouse. This digitizing of genomic data—and its public access—is something that would have been unthinkable a generation earlier.

But as molecules go, DNA is pretty straight forward. With its simple composition and linear structure, it easily lends itself to mathematical models. Not so with proteins. In fact, proteins are an order of magnitude more complex than DNA. It is proteins, not DNA, that carry out the cell’s heavy lifting. However, with their intricately folded three-dimensional shapes determining a seemingly endless range of possible functions and their manifold interactions with other proteins and with DNA, the leg-work required to mathematically capture the protein universe seems absurd.

And it is.

That is why a team of Harvard Medical School researchers have decided to attack this issue from an entirely new angle. Rather than build a mountain range of proteomic data one grain of dirt at a time, they have developed a computer program that can take on the responsibility of assembling such a gargantuan model.

Enter Little b, a computational language that can penetrate the “mind” of a cell.

“Through incorporating principles of engineering, we’ve developed a language that can describe biology in the same way a biologist would,” says Jeremy Gunawardena, director of the Virtual Cell Program in Harvard Medical School’s department of systems biology. “The potential here is enormous. This opens the door to actually performing discovery science, to look at things like drug interactions, right on the computer.”

These findings will be published in the July 23 issue of Journal of the Royal Society Interface.

Most current computational methods of modeling biological systems are not unlike writing a document with pen and paper. Each new project starts from scratch; there are no facilities for cutting and pasting, for linking to other texts, for including images, etc.—things that come so “naturally” to electronic documents.

Harvard Medical School researcher Jeremy Gunawardena, a mathematician by training, teamed up with Aneil Mallavarapu, a cell biologist and computer scientist, to lead a project that would bypass these limitations.

“We knew that the secret to doing this would be to assimilate fundamental concepts of engineering, concepts like modularity and abstraction, into the biological realm,” says Mallavarapu, who was recently awarded the Merrimack prize by the Council for Systems Biology in Boston for developing this program.

Modularity involves breaking a problem down into separate modules and constructing each module so that it can interact with the others. Abstraction refers to extracting generic biological properties and incorporating them into the modules, so that they can use this abstract information in concrete contexts. Put another way, abstraction means that, unlike the old days of pen and paper, each new model does *not* need to be built from scratch. Models can be built upon each other and their individual modules refined and re-used.

To do this, Mallavarapu used the programming language LISP, a language widely used in artificial intelligence research. LISP is famous among computer scientists due to its ability to write code that, in turn, can write code, enabling a programmer to derive new mini-languages.

“LISP isn’t like typical programs, it’s more like a conversation,” says Gunawardena. “When we input data into Little b, Little b responds to it and reasons over the data.”

For example, Gunawardena’s lab works on kinases, a kind of protein that transfers phosphate chemicals to other proteins in order to regulate their activity. While this property is common to all kinases, there is a great deal of variety in how particular kinases carry this out. Little b, however, understands this basic property of kinases, this abstraction.

Here, the researchers demonstrated how they were able to interact with Little b to build complex models of kinase activity, using Little b as a kind of scientific collaborator, and not simply a passive tool.

On a larger scale, the researchers also used the program to query the development of fruit fly embryos. As a result, they discovered levels of complexity in these embryonic structures that previous research had missed.

“This language is stepping into an unknown universe, when your computer starts building things for you,” says Gunawardena. “Your whole relationship with the computer becomes a different one. You’ve ceded some control to the machine. The machine is drawing inferences on your behalf and constructing things for you.”

The researchers sometimes admit, half-joking, that Little b sometimes feels a little bit like “The Matrix”—referring, of course, to the film trilogy in which human beings lived in a computer-generated virtual world.

Mallavarapu and Gunawardena have a pretty clear vision for this project: they want every biologist in the world to use it.

But in order to bring the program out from the early adopter community, where it is currently being used by colleagues in the Harvard community, it needs to be more accessible.

“The next step is to create an interface that’s easy to use,” says Gunarwardena. “Think of web page development. Lots of people are creating web pages with little or no knowledge of HTML. They use simple interfaces like Dreamweaver. Once we’ve developed the equivalent, scientists will be able to use our system without having to learn Little b.”

And the more people use it, the smarter it gets. As researchers around the world input their discoveries into Little b, the program will assimilate that information into its language.

The ultimate goal is to have an in silico, virtual cell—a dynamic biological system living in software.

“Sure, it’s a long way off,” says Gunawardena, “but we’re getting there.”

Source: Harvard Medical School

Josh: While this is certainly an important genetic variation to find, I’m wondering if doctors would be able to use this information if they tested their patients. What could be done differently in treating high levels of triglycerides? This would be much more useful if a drug existed to treat this specific cause of elevated plasma TG levels.

A genetic variant found almost exclusively in individuals of Asian descent increases the risk of elevated triglycerides over four-fold, reports a comprehensive study in the August Journal of Lipid Research. In fact, all 11 subjects who carried both copies of this rare variant for apolipoprotein A-V had extremely high and dangerous triglyceride levels in their blood.

Apolipoprotein A-V is a recently discovered lipid-binding protein that likely plays an important role in metabolizing triglycerides. Some population studies with groups in China and Taiwan indicate that a polymorphism in the APOA5 gene (553 G>T shift) is associated with elevated plasma TG levels, which like cholesterol, increase the risk of heart disease. … Continue Reading »

Josh: The authors of this paper draw a conclusion that this has to be inherited genetically. However, they did not find a gene or set of genes that would be responsible. Perhaps the parents are more “aloof” because they’ve had to adapt and learn to understand their autistic children’s emotional state. I see no reason why this couldn’t be explained by environmental factors, since the children are born into the environment of their parents. The paper is focused on analyzing the phenotypes, which may or may not have genetic causes. Granted, statistics is an area I know little about, but I feel the data to make this conclusion simply isn’t there.

Some parents of children with autism evaluate facial expressions differently than the rest of us – and in a way that is strikingly similar to autistic patients themselves, according to new research by psychiatrist Dr. Joe Piven of the University of North Carolina at Chapel Hill and neuroscientist Ralph Adolphs, Ph.D., of the California Institute of Technology.

Piven, Adolphs and colleague Michael Spezio, Ph.D., formerly of Caltech but now at Scripps College in Claremont, Calif., collaborated to study 42 parents of children with autism, a complex developmental disability that affects an individual’s ability to interact socially and communicate with others. Based on psychological testing, 15 of the parents were classified as being socially aloof. … Continue Reading »

What does the genetics of blood cells have to do with brain cells related to Parkinson’s disease? From an unusual collaboration of neurologists and a pharmacologist comes the surprising answer: Genetic mechanisms at play in blood cells also control a gene and protein that cause Parkinson’s disease.

The finding, by scientists from the University of Wisconsin School of Medicine and Public Health (SMPH), Harvard University-affiliated Brigham and Women’s Hospital and the University of Ottawa, may lead to new treatments for the neurological disorder that affects as many as 1.5 million Americans.

The study is published in the Proceedings of the National Academy of Sciences Online Early Edition the week of July 21-25, 2008.

Patients with Parkinson’s disease (PD) have elevated levels of the protein called alpha-synuclein in their brains. As the protein clumps, or aggregates, the resulting toxicity causes the death of neurons that produce the brain chemical dopamine. Consequently, nerves and muscles that control movement and coordination are destroyed.

The researchers discovered that the activity of three genes that control the synthesis of heme, the major component of hemoglobin that allows red blood cells to carry oxygen, precisely matched the activity of the alpha-synuclein gene, suggesting a common switch controlling both.

The scientists then found that a protein called GATA-1, which turns on the blood-related genes, was also a major switch for alpha-synuclein expression, and that it induced a significant increase in alpha-synuclein protein. Finally, they demonstrated that a related protein — GATA-2 — was expressed in PD-vulnerable brain cells and directly controlled alpha-synuclein production.

“Very little was known previously about what turns on alpha-synuclein in brain cells and causes variations in its expression,” says Emery Bresnick, a UW-Madison professor of pharmacology who is an expert on GATA factors and their functions in blood. “Understanding how GATA factors work in the brain may provide fundamental insights into the biology of Parkinson’s disease.”

The new knowledge also may allow scientists to design therapies that keep alpha-synuclein levels within the normal range.

“Simply lowering alpha-synuclein levels by 40 percent may be enough to treat some forms of Parkinson’s disease,” says Dr. Clemens Scherzer of Harvard. “So far, researchers have focused on ways to get rid of too much ‘bad’ alpha-synuclein in Parkinson patients’ brains. Now we will be able to tackle the problem from the production site, and search for new therapies that lower alpha-synuclein production up front.”

Scherzer and Dr. Michael Schlossmacher, now at Ottawa, had independently analyzed the blood of PD patients and controls in a search for genes that were active in the disease. They both were surprised to notice large amounts of alpha-synuclein in the blood. To understand what it was doing there, Scherzer’s group used gene chip data to see whether any of the thousands of genes active in blood were linked to alpha-synuclein. They found a gene expression pattern composed of alpha-synuclein and the heme genes, one of which Bresnick had previously shown to be a direct GATA-1 target gene.

The neurologists contacted Bresnick. The UW group rapidly determined that GATA-1 directly activated the alpha-synuclein gene, and that finding led the collaborators to discover that GATA-2 is expressed in regions of the brain that are relevant to PD.

“We all were excited because we realized that GATA-2 was active in the relevant brain regions, and so there could be a connection,” says Bresnick. Together the researchers set out to examine whether common mechanisms activated alpha-synuclein transcription in both the blood and nerve cells.

The studies showed that GATA-1 and GATA-2 proteins find the alpha-synuclein gene, stick to it and then directly control it.

“This is not an indirect pathway; it is direct regulation of the gene,” says Bresnick. “This directness provides the simplest scenario for creating a therapeutic strategy.”

Bresnick, Schlossmacher and Scherzer are working with geneticists to see if possible abnormalities in the GATA-2 gene may exist in PD patients, stimulating more production of alpha-syinuclein.

“The discovery of the link between GATA proteins and the alpha-synuclein gene is like finding a long-sought-after molecular switch,” says Schlossmacher. “We were very fortunate to find in Emery Bresnick’s team the ideal partner in this endeavor.”

The family of GATA factors consists of six members, and some of them, beyond GATA-2, may also be influencing alpha-synuclein expression in the brain, adds Schlossmacher.

“Identifying these would further add to the complexity of regulating the production of the ‘bad player’ in Parkinson’s disease,” he says.

Says Bresnick, “The $10 million question will be does deregulation of the GATA mechanism in humans lead to alpha-synuclein overproduction and Parkinson’s disease.”

Source: University of Wisconsin-Madison

MIT biological engineers have developed a new imaging system that allows them to see cells that have undergone a specific mutation.

The work, which could help scientists understand how precancerous mutations arise, marks the first time researchers have been able to pinpoint the number and location of mutant cells—cells with a particular mutation—in intact tissue. In this case, the researchers worked with mouse pancreatic cells.

“Understanding where mutations come from is fundamental to understanding the origins of cancer,” said Bevin Engelward, associate professor of biological engineering and member of MIT’s Center for Environmental Health Sciences, and an author of a paper on the work appearing in this week’s online edition of the Proceedings of the National Academy of Science.

Peter So, professor of biological and mechanical engineering, Engelward and members of their laboratories developed technologies that made it possible to detect clusters of cells that appeared to be descended from the same progenitor cell.

Unexpectedly, more than 90 percent of the cells harboring mutations were within clusters. That offers evidence that the majority of mutations are inherited from another cell, rather than arising spontaneously in individual cells.

Since the type of mutation being studied (in this case a recombination event) occurs at a rate on par with other types of mutations, “it is as if we are peering in at the very general process of mutation formation, persistence and clonal expansion,” said Engelward.

“We think this raises the possibility that mutations resulting from cell division are a tremendous factor in increasing the mutagenic load,” she said.

The higher the mutagenic load, the more likely it is that cancer will develop.

Engelward and So started working together several years ago after a faculty retreat for MIT’s newly formed Biological Engineering Division. So was developing a new type of microscopy, known as two-photon imaging, and the researchers wondered whether it could be used to locate and image rare types of cells.

The team genetically engineered a strain of mice in which DNA would fluoresce if a mutation occurred in a particular sequence. That allowed them to use So’s newly developed high-resolution, high-throughput microscopy technique to detect individual cells that carry the mutation.

“The problem drove the development of a new imaging technology, which now can be used for lots of things,” said Engelward.

Lead author of the paper is Dominika Wiktor-Brown, a postdoctoral associate in biological engineering. Other authors of the paper are Hyuk-Sang Kwon, a research affiliate in the Department of Mechanical Engineering, and Yoon Sung Nam, a graduate student in biological engineering.

The work was truly a team effort between many people with very different areas of expertise, said Engelward. “The Department of Biological Engineering and the Center for Environmental Health Sciences are key in helping to bridge people across disciplines,” she said.

Source: Massachusetts Institute of Technology

For generations, people have consumed cranberry juice, convinced of its power to ward off urinary tract infections, though the exact mechanism of its action has not been well understood. A new study by researchers at Worcester Polytechnic Institute (WPI) reveals that the juice changes the thermodynamic properties of bacteria in the urinary tract, creating an energy barrier that prevents the microorganisms from getting close enough to latch onto cells and initiate an infection.

The study, published in the journal Colloids and Surfaces: B, was conducted by Terri Camesano, associate professor of chemical engineering at WPI, and a team of graduate students, including PhD candidate Yatao Liu. They exposed two varieties of E. coli bacteria, one with hair-like projections known as fimbriae and one without, to different concentrations of cranberry juice. Fimbriae are present on a number of virulent bacteria, including those that cause urinary tract infections, and are believed to be used by bacteria to form strong bonds with cells.

For the fimbriaed bacteria, they found that even at low concentrations, cranberry juice altered two properties that serve as indicators of the ability of bacteria to attach to cells. The first factor is called Gibbs free energy of attachment, which is a measure of the amount of energy that must be expended before a bacterium can attach to a cell. Without cranberry juice, this value was a negative number, indicating that energy would be released and attachment was highly likely. With cranberry juice the number was positive and it grew steadily as the concentration of juice increased, making attachment to urinary tract cells increasingly unlikely.

Surface free energy also rose, suggesting that the presence of cranberry juice creates an energy barrier that repels the bacteria. The researchers also placed the bacteria and urinary tract cells together in solution. Without cranberry juice, the fimbriaed bacteria attached readily to the cells. As increasing concentrations of cranberry juice were added to the solution, fewer and fewer attachments were observed.

Cranberry juice had no discernible effect on E. coli bacteria without fimbriae, suggesting that compounds in the juice may act directly on the molecular structure of the fimbriae themselves. This reinforces previous work by the WPI team that showed that exposure to cranberry juice alters the shape of the fimbriae, causing them to become compressed. Using an atomic force microscope as a minute strain gauge, the team also showed that the adhesive force exerted by bacteria on urinary tract cells declined in direct proportion to the concentration of cranberry juice in the solution.

“Our results show that, at least for urinary tract infections, cranberry juice targets the right bacteria—those that cause disease—but has no effect on non-pathogenic organisms, suggesting that cranberry juice will not disrupt bacteria that are part of the normal flora in the gut,” Camesano says. “We have also shown that this effect occurs at concentrations of cranberry juice that are comparable to levels we would expect to find in the urinary tract.”

Camesano notes that unpublished work has shown that while cranberry juice has potent effects on disease-causing bacteria, those effects are transitory. “When we takes E. coli. bacteria that have been treated with cranberry juice and place them in normal growth media, they regain the ability to adhere to urinary tract cells,” she says. “This suggests that to realize the antibacterial benefits of cranberry, one must consume cranberry juice regularly—perhaps daily.”

For those watching calories, Camesano says other recent work in her lab has shown that the effects of regular cranberry juice cocktail and diet (sugar-free) cranberry juice are identical. “That’s good news for people who do not like to consume a lot of sugary juice,” she says.

Source: Worcester Polytechnic Institute