If you’re a fan of habañero salsa or like to order Thai food spiced to five stars, you owe a lot to bugs, both the crawling kind and ones you can see only with a microscope. New research shows they are the ones responsible for the heat in chili peppers.

The spiciness is a defense mechanism that some peppers develop to suppress a microbial fungus that invades through punctures made in the outer skin by insects. The fungus, from a large genus called Fusarium, destroys the plant’s seeds before they can be eaten by birds and widely distributed.

“For these wild chilies the biggest danger to the seed comes before dispersal, when a large number are killed by this fungus,” said Joshua Tewksbury, a University of Washington assistant professor of biology. “Both the fungus and the birds eat chilies, but the fungus never disperses seeds – it just kills them.”

Fruits use sugars and lipids to attract consumers such as birds that will scatter the seeds. But insects and fungi enjoy sugars and lipids too, and in tandem they can be fatal to a pepper’s progeny.

However, the researchers found that the pungency, or heat, in hot chilies acts as a unique defense mechanism. The pungency comes from capsaicinoids, the same chemicals that protect them from fungal attack by dramatically slowing microbial growth.

“Capsaicin doesn’t stop the dispersal of seeds because birds don’t sense the pain and so they continue to eat peppers, but the fungus that kills pepper seeds is quite sensitive to this chemical,” said Tewksbury, lead author of a paper documenting the research.

“Having such a specific defense, one that doesn’t harm reproduction or dispersal, is what makes chemistry so valuable to the plant, and I think it is a great example of the power of natural selection.”

The paper is published the week of Aug. 11 in the online Proceedings of the National Academy of Sciences. Co-authors are Karen Reagan, Noelle Machnicki, Tomás Carlo, and David Haak of the University of Washington; Alejandra Lorena Calderón Peñaloza of Universidad Autonoma Gabriel Rene Moreno in Bolivia; and Douglas Levey of the University of Florida. The work was funded by the National Science Foundation and the National Geographic Society.

The scientists collected chilies from seven different populations of the same pepper species spread across 1,000 square miles in Bolivia. In each population, they randomly selected peppers and counted scars on the outer skin from insect foraging. The damage was caused by hemipteran insects – insects such as seed bugs (similar to aphids and leaf hoppers) that have sucking mouth parts arranged into a beaklike structure that can pierce the skin of a fruit.

The researchers found that not all of the plants produce capsaicinoids, so that in the same population fruit on one plant could be hotter than a jalapeño while fruit from other plants might be as mild as a bell pepper. But there was a much-higher frequency of pungent plants in areas with larger populations of hemipteran insects that attack the chilies and leave them more vulnerable to fungus.

The scientists also found that hot plants got even hotter, with higher levels of capsaicinoids, in areas where fungal attacks were common. But in areas with few insects and less danger of fungal attack, most of the plants lacked heat entirely. In those areas, chilies from the plants that did produce capsaicinoids had a lot less kick because they only produced about half the capsaicinoids as the plants did in areas where fungal attack was common.

Using chemical substances as a defense is not unique to peppers. Tomatoes, for example, are loaded with substances that give their unripened fruit a decidedly unpleasant taste, allowing the seeds a chance to mature and be dispersed. But unlike peppers, tomatoes and most other fruits lose their chemical defenses when the fruit ripens. That is a necessary step, scientists believe, because otherwise the fruit would not be consumed by birds and other animals that disperse the seed. The problem with that strategy, Tewksbury said, is that it leaves the fruit exposed to fungal attack.

“By contrast, peppers increase their chemical defense levels, or their heat, as they ripen. This is a very different model and peppers can get away with it because birds don’t sense pain when they eat capsaicin,” Tewksbury said. “I think a lot of plants would love to come up with this way of stopping fungal growth without inhibiting dispersers. It’s just very hard to do.”

The fact that chilies have capsaicin could be the reason humans started eating the peppers in the first place, he said. Chili peppers and corn are among the earliest domesticated crops in the New World.

“Before there was refrigeration, it was probably adaptive to eat chilies, particularly in the tropics,” Tewksbury said. “Back then, if you lived in a warm and humid climate, eating could be downright dangerous because virtually everything was packed with microbes, many of them harmful. People probably added chilies to their stews because spicy stews were less likely to kill them.”

All chilies originated in South America, and wild chilies now grow from central South America to the southwestern United States. Explorers carried the plants back to Europe, but they were not widely used there. From Europe, chilies made their way to Asia and Africa, where they have become a common ingredient in nearly every tropical cuisine.

“In the north, any adaptive benefit to using eating chilies would be much smaller than at the equator because microbial infection of food is less common and it’s easier to keep food cold. Maybe that’s why food in the north can be so boring,” Tewksbury said.

“Along the equator, without access to refrigeration, you could be dead pretty quickly unless you can find a way to protect yourself against the microbes you ingest every day.”

Source: University of Washington

Scientists from the Gladstone Institute of Cardiovascular Disease (GICD) and UCSF have identified a key regulatory factor that controls development of the human vascular system, the extensive network of arteries, veins, and capillaries that allow blood to reach all tissues and organs. The research, published in the latest issue of Developmental Cell, may offer clues to potential therapeutic targets for a wide variety of diseases, such as heart disease or cancer, that are impacted by or affect the vascular system.

Researchers in laboratory of GICD Director Deepak Srivastava, MD, found that microRNA (miR-126), a tiny RNA molecule, is intimately involved in the response of blood vessels to angiogenic signals. Angiogenesis, the process of vascular development, is a tightly regulated and well-studied process.A cascade of genes orchestrate a series of events leading to formation of blood vessels in an embryo.

“Some of these same gene regulatory networks are re-activated in the adult to direct the growth of new blood vessels” said Jason Fish, PhD, lead author of the study. “This can be beneficial, as in the case of a heart attack.”

Blood vessel formation can also contribute to disease in settings like cancer, where vessels feed a growing tumor.

“Finding that a single factor regulates a large part of the angiogenic process creates a significant target for therapeutic development for any disease involving the vascular system,” said Dr. Srivastava. “The next step is to find ways to modify this microRNA in the setting of disease and test its ability to alter the disease process.”

Researchers examined cells, called endothelial cells, that line the lumen or inside of blood vessels. Once the vascular endothelial cells adopt their fate during development, they come together to form cord-like structures that are remodeled to become lumenized blood vessels. In adults, angiogenic signals, such as vascular endothelial growth factor (VEGF), activate endothelial cells and cause them to form new blood vessels. Individual microRNAs, which titrate the level of specific proteins generated by the cell, were not previously known to affect VEGF signaling or regulate angiogenesis.

The team used three model systems. First, they looked for microRNAs that were enriched in endothelial cells from mouse embryonic stem (ES) cells. They found that miR-126 was the most abundant in and most specific for endothelial cells. They next investigated the function of miR-126 in cultured human endothelial cells and found that this microRNA was involved in the structure, migration, proliferation and survival of endothelial cells. Third, they turned to the zebrafish system to investigate the in vivo function of miR-126 for three reasons. (1) It is a tractable system for perturbing microRNA levels and examining the consequences in a live organism. (2) The developing fish does not require a functioning cardiovascular system to survive through the initial stages of development. (3) The embryos are transparent and can be easily and directly visualized as they are developing. Loss of miR-126 function did not affect the initial patterning of the vascular network, but blood vessels subsequently collapsed and considerable internal bleeding occurred, illustrating the requirement of miR-126 for normal vessel formation and maintenance.

Researchers also found that miR-126 regulated endothelial responses to angiogenic signals by regulating several components of the VEGF pathway, which is important during development of blood vessels and is required for their maintenance. miR-126 repressed the actions of the Sprouty-related protein, SPRED1, and phosphoinositol-3 kinase regulatory subunit 2 both negative regulators of VEGF signals.

They replicated the effects of the loss of miR-126 by increasing expression of Spred1 or inhibiting VEGF signaling. Thus, miR-126 normally promotes vessel formation and stability by “repressing the repressors” of VEGF signaling. Since inhibiting VEGF signaling has been a major target of modern cancer therapies, regulating miR-126 represents an additional approach to regulate blood vessel formation in such diseases.

Source: Gladstone Institutes

Researchers in Germany have discovered that methadone, an agent used to break addiction to opioid drugs, has surprising killing power against leukemia cells, including treatment resistant forms of the cancer.

Their laboratory study, published in the August 1 issue of Cancer Research, a journal of the American Association for Cancer Research, suggests that methadone holds promise as a new therapy for leukemia, especially in patients whose cancer no longer responds to chemotherapy and radiation.

“Methadone kills sensitive leukemia cells and also breaks treatment resistance, but without any toxic effects on non-leukemic blood cells,” said the study’s senior author, Claudia Friesen, Ph.D., of the Institute of Legal Medicine at the University Ulm. “We find this very exciting, because once conventional treatments have failed a patient, which occurs in old and also in young patients, they have no other options.”

Methadone, developed in Germany in the 1930s, is a low cost agent that acts on opioid receptors, and thus is used as an opioid substitute to treat addiction. Scientists have found that opioid receptors also exist on the surface of some cancer cells for reasons that are not understood. One research group tested the agent in human lung cancer cell lines and found that it can induce cell death.

In this study, Friesen and her colleagues tested methadone in leukemia cells in laboratory culture because this cancer also expresses the opioid receptor. Theirs is the first study to look at use of the agent in leukemia, specifically in lymphoblastic leukemia T-cell lines and human myeloid leukemia cell lines.

They found that methadone was as effective as standard chemotherapies and radiation treatments against non-resistant leukemia cells, and that non-leukemic peripheral blood lymphocytes survived after methadone treatment.

To their surprise, they found that methadone also effectively killed leukemia that was resistant to multiple chemotherapies and to radiation. Probing the mechanism of methadone’s action, the researchers found that it activates the mitochondrial pathway within leukemia cells, which activates enzymes called caspases that prompt a cell into apoptosis, also known as programmed cell death. Chemotherapy drugs use the same approach, but methadone activated caspases in sensitive leukemia cells, and also reversed deficient activation of caspases in resistant leukemia cells.

Friesen said the research team is beginning to study methadone treatment in animal models of human leukemia, and she also says that other cancers might be suitable for treatment with the agent.

In this study, the single doses used to kill leukemia cells were greater than doses used to treat opioid addiction, but the researchers have since found that they can use a daily low dose of methadone to achieve the same effect. Friesen adds that while methadone can, itself, become addictive, that addiction is much easier to break compared to addiction to true opioids. “Addiction shouldn’t be an unsolvable problem if methadone is ever used as an anti-cancer therapy,” she said.

Source: American Association for Cancer Research

The life expectancy for patients with human immunodeficiency virus (HIV) has increased by more than 13 years since the late 1990s thanks to advancements in antiretroviral therapy, according to researchers at the University of Alabama at Birmingham (UAB) and Simon Fraser University in Vancouver, British Columbia.

Improved survival has led to a nearly 40 percent drop in AIDS deaths among 43,355 HIV-positive study participants in Europe and North America, bolstering the call for improved anti-HIV efforts worldwide, the study authors said.

The study is published in the British medical journal The Lancet. It was compiled by The Antiretroviral Therapy Cohort Collaboration, which includes UAB, Simon Fraser University and more than a dozen other research sites around the world. … Continue Reading »

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 »

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

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