Among the most important and complex molecules in the human body, sugars control not just metabolism but also how cells communicate with one another. Graduating senior Jeffery Martin has put his basic knowledge of sugars to exceptional use by creating a lab-on-a-chip device that builds complex, highly specialized sugar molecules, mimicking one of the most important cellular structures in the human body — the Golgi Apparatus.

“Almost completely independently he has been able to come closer than researchers with decades more experience to creating an artificial Golgi,” said Robert Linhardt, the Ann and John H. Broadbent Jr. ‘59 Senior Constellation Professor of Biocatalysis and Metabolic Engineering at Rensselaer and Martin’s adviser. “He saw a problem in the drug discovery process and almost instantly devised a way to solve it.”

Cells build sugars in a cellular organelle known as the Golgi Apparatus. Under a microscope, the Golgi looks similar to a stack of pancakes. The strange-looking organelle finishes the process of protein synthesis by decorating the proteins with highly specialized arrangements of sugars. The final sugar-coated molecule is then sent out into the cell to aid in cell communication and to help determine the cell’s function in the body.

Martin’s artificial Golgi functions in a surprisingly similar way to the natural Golgi, but he gives the ancient organelle a very high-tech makeover. His chip looks similar to a miniature checker board where sugars, enzymes, and other basic cell materials are suspended in water and can be transported and mixed by applying electric currents to the destination squares on the checker board. Through this process sugars can be built in an automated fashion where they are exposed to a variety of enzymes found in the natural Golgi. The resulting sugars can then be tested on living cells either on the chip or in the lab to determine their effects. With the chip’s ability to process many combinations of sugars and enzymes, it could help researchers quickly uncover new sugar-based drugs, according to Martin.

Scientists have known for years that certain sugars can serve as extremely beneficial therapeutics for humans. One well-known example is heparin, which is among the most widely used drugs in the world. Heparin is formed naturally in the Golgi organelle in cells of the human body as well as in other animals like pigs. Heparin acts as an anticoagulant preventing blood clots, which makes it a good therapeutic for heart, stroke, and dialysis patients.

The main source of heparin is currently the intestines of foreign livestock and, as recent news reports highlight, the risk of contamination from such sources is high. So researchers are working around the clock to develop a safer, man-made alternative to the drug that will prevent outside contamination. A synthetic alternative would build the sugar from scratch, helping eliminate the possibility of contamination he explained.

“I am very grateful to have the privilege of working with Dr. Linhardt who has discovered the recipe to make fully synthetic heparin,” Martin said. “Because we know the recipe, I am going to use it as a model to test the device. If our artificial Golgi can build fully functional heparin, we can then use the artificial organelle to produce many different sugar variants by altering the combination of enzymes used to synthesize them. Another great thing about these devices is that they are of microscale size, so that if needed we could fill an entire room with them to increase throughput for drug discovery.”

There are millions of possible sugar combinations that can be formed and scientists currently only know the function of very few of them like heparin. “Since it is known that these types of sugars play a part in many important biological processes such as cell growth, cell differentiation, blood coagulation, and viral defense mechanisms, we feel that that this artificial Golgi will help our team to develop a next generation of sugar-based drugs, known as glycotheraputics,” Martin said. “We are going to start making new combinations and we simply don’t know what we are going to find. We could find a sugar whose signal blocks the spread of cancer cells or initiates the differentiation of stem cells. We just don’t know.”

Martin, a Barry M. Goldwater Scholar and native of the small town of Boylston, Mass., is graduating from Rensselaer on May 17, 2008 with a nearly perfect GPA. He plans to continue on at Rensselaer as a graduate student, working with Linhardt to test and further develop his artificial Golgi.

[Gabrielle DeMarco @ Rensselaer Polytechnic Institute]

Frasier Crane and his brother, Niles, both practiced psychiatry on their popular NBC sitcom “Frasier.” Mob boss Tony Soprano had his therapist on HBO’s hit show “The Sopranos.” And HBO has even made therapy the focus of two recent shows — “Tell Me You Love Me” and “In Treatment.”

But all of these TV portrayals may actually make viewers less likely to seek psychological services themselves. That’s according to a new study by three Iowa State University psychologists.

ISU psychology professors David Vogel and Douglas Gentile collaborated with graduate student Scott Kaplan on the study of 369 Iowa State students. It explored how exposure to television shows may contribute to negative perceptions about psychological services that can lead to lower intentions to seek such services. They produced a paper titled “The Influence of Television on Willingness to Seek Therapy,” which was published in the March issue of the Journal of Clinical Psychology, a professional journal.

Unflattering portrayals of mental health professionals

Kaplan has conducted a related content analysis on television portrayals of mental health professionals. It found that they’re not favorable.

“Generally, it seems like therapists are portrayed unethically — like sleeping with the client, or implanting false memories, or talking about their clients outside the session,” Vogel said. “These are things that almost never happen with real therapists, but on a show — because they’re probably more exciting — they happen more frequently.”

“Therapists also often are portrayed as buffoons,” Gentile said. “That’s either by being the jokester, like Frasier, or by being the butt of jokes. In either case, these are not positive portrayals. They do not show the skill, expertise and ethics of professional therapists.”

But it’s not just the portrayal of the therapists that may be keeping people out of therapy. It’s also the portrayal of those who seek counseling on TV.

“If you examine the portrayal of the clients, it’s probably as bad or worse,” Vogel said. “So why would you seek therapy if you believe you’re going to be perceived negatively and you’re going to see someone who’s incompetent and not able to help you?”

Because dramas and comedies are the two types of shows that often portray psychologists and psychotherapy, the ISU psychologists asked respondents how often they watched TV comedy and drama shows. They also asked them to assess perceptions of the stigma associated with seeking professional help, attitudes toward therapy, their intentions to seek therapy for psychological and interpersonal concerns, and their feelings of depression.

TV ties to therapy stigma

The study found a positive correlation between viewers’ exposure to comedy and drama shows and their perceptions of stigma associated with seeking professional help. This stigma was then related to lower willingness to seek professional mental health services.

“One of the things that’s important to note about this particular study is that we showed that TV exposure was related to your perceptions of the stigma associated with seeking help, which has been found to be one of the main factors found from inhibiting people from seeking that help,” Vogel said. “So you perceive that yourself, and other people, would be crazy to go (to therapy).”

That’s a problem for those people who could really benefit from professional mental health services. According to Vogel, the most recent studies in the mental health field have found that about half of population experiences a situation in their lives where psychological therapy could be helpful — about 20 percent in a single year. But in a given year, only about 10 percent of the people who could benefit from therapy will seek help from a psychologist or other mental health professional.

“Mental health services are already vastly underutilized, and this cultural stigma is part of the reason,” Gentile said. “And this study suggests that this cultural stigma exists partly because of the way that psychologists and their patients are portrayed on television.”

[Mike Ferlazzo @ Iowa State University]

But it’s not just weight gain that poses a risk. People who are underweight also have an elevated risk of dementia, unlike people who are normal weight or overweight.

US researchers carried out a detailed review of 10 international studies published since 1995, covering just over 37,000 people, including 2,534 with various forms of dementia. Subjects were aged between 40 and 80 years when the studies started, with follow-up periods ranging from three to 36 years.

The review, which included studies from the USA, France, Finland, Sweden and Japan, also included a sophisticated meta-analysis of seven of the studies, published between 2003 and 2007 with a follow-up period of at least five years.

All kinds of dementia were included, with specific reference to Alzheimer’s Disease and to vascular dementia — where areas of the brain stop functioning because the blood vessels that supply them are damaged by conditions such as high blood pressure or heart disease.

“Our meta-analysis showed that obesity increased the relative risk of dementia, for both sexes, by an average of 42 percent when compared with normal weight” says Dr Youfa Wang, Associate Professor of International Health and Epidemiology at Johns Hopkins Bloomberg School of Public Health, Baltimore.

“And being underweight increased the risk by 36 percent.

“But when we looked specifically at Alzheimer’s Disease, the increased risk posed by obesity was 80 percent. The increased risk for people with vascular dementia was 73 percent.

“The risks were greater in studies where sufferers developed Alzheimer’s Disease or vascular dementia before the age of 60 or in studies with follow-up periods of more than 10 years.

“We also found that obesity was more likely to be a risk factor for women when it came to developing Alzheimer’s Disease and for men when it came to vascular dementia.”

The authors estimate that 12 percent of the dementia risk in the study population could be attributed to obesity, with this rising to just over 21 percent in patients with Alzheimer’s Disease.

It’s estimated that up to 10 percent of people aged 65 or more suffer from some form of dementia and two-thirds of those have Alzheimer’s Disease.

“There has been controversy about the links between obesity and dementia for a number of years, but previous findings have been mixed and inconclusive” says Dr Wang.

“The advantage of carrying out a meta-analysis is that it provides researchers with access to a large number of study subjects and it is possible to iron out the inconsistencies and come to overarching conclusions.

“Our detailed analysis clearly shows a U-shaped relationship between weight and dementia, with people who are obese or underweight facing a greater risk.

“We believe that our results show that reducing the prevalence of obesity is a promising strategy for preventing the progression of normal ageing into Alzheimer’s Disease.”

[Annette Whibley @ Wiley-Blackwell]

Professor Downing found that constructed ponds and lakes on farmland in the United States bury carbon at a much higher rate than expected; as much as 20-50 times the rate at which trees trap carbon. In addition, ponds were found to take up carbon at a higher rate than larger lakes.

“Aquatic ecosystems play a disproportionately large role in the global carbon budget,” Downing said. “Despite being overlooked in the past, it’s small bodies of water that are important because they take up carbon at a high rate and there are more of them than previously thought. The combined effect is that farm ponds could be burying as much carbon as the world’s oceans, each year.”

Ponds capture carbon in two main ways:

The research estimated there are 304 million natural lakes and ponds in the world, covering an area of 4.2 million square kilometers, twice the area previously thought. As many as 90 percent of these water bodies are one hectare (two acres) or less in area.

Downing’s research team published its most recent findings in the Feb. 15 issue of the journal Global Biogeochemical Cycles in a paper titled, “Sediment organic carbon burial in agriculturally eutrophic impoundments over the last century.” The team included members from Europe, the United States and Canada. The work was sponsored by the National Center for Ecological Analysis and Synthesis and the Iowa Department of Natural Resources.

Downing has presented invited seminars on this research to the International Society of Limnology, the American Society of Limnology and Oceanography, and at several major research institutions in North America and Europe. Most recently, he was invited to discuss his research by the Pond Conservation, a charity in the United Kingdom dedicated to creating and protecting ponds and the wildlife they support. He will spoke today at University College London. An upcoming presentation is scheduled for the annual meeting of the European Pond Conservation Network in Valencia, Spain.

Jeremy Biggs, Pond Conservation director of policy and research, said the research has exciting implications. “It may be that ponds will be the modern equivalent of the swamps that formed coal in the past. But before we all rush into making ponds to trap carbon we need to do some basic research here in the UK. If the rate of carbon uptake in ponds in Europe is the same as that found in the USA study, we may well have discovered an important new natural way of trapping carbon,” he said.

Downing’s ongoing research, partnering with the United States Geological Survey, and his contributions to the Iowa Lakes Survey will investigate the role of small Iowa lakes in the absorption of atmospheric carbon dioxide and other important gases such as methane.

[John Downing @ Iowa State University]

The platypus, classified as a mammal because it produces milk and is covered in a coat of fur, also possesses features of reptiles, birds and their common ancestors, along with some curious attributes of its own. One of only two mammals that lays eggs, the platypus also sports a duck-like bill that holds a sophisticated electrosensory system used to forage for food underwater. Males possess hind leg spurs that can deliver pain-inducing venom to its foes competing for a mate or territory during the breeding season.

“The fascinating mix of features in the platypus genome provides many clues to the function and evolution of all mammalian genomes,” says Richard K. Wilson, Ph.D., director of the The Genome Center at Washington University and the paper’s senior author. “By comparing the platypus genome to other mammalian genomes, we’ll be able to study genes that have been conserved throughout evolution.”

The platypus represents the earliest offshoot of the mammalian lineage some 166 million years ago from primitive ancestors that had features of both mammals and reptiles. “What is unique about the platypus is that it has retained a large overlap between two very different classifications, while later mammals lost the features of reptiles,” says Wes Warren, Ph.D., an assistant professor of genetics, who led the project.

Comparison of the platypus genome with the DNA of humans and other mammals, which diverged later, and the genomes of birds, whose ancestors branched off an estimated 315 million years ago, can help scientists fill gaps in their understanding of mammalian evolution. The comparison also will allow scientists to date the emergence of genes and traits specific to mammals.

The Nature paper analyzes the genome sequence of a female platypus named Glennie from New South Wales, Australia. The project was largely funded by the National Human Genome Research Institute, part of the National Institutes of Health, and includes scientists from the United States, Australia, England, Germany, Israel, Japan, New Zealand and Spain.

“At first glance, the platypus appears as if it was the result of an evolutionary accident,” says Francis S. Collins, M.D., Ph.D., director of NHGRI. “But as weird as this animal looks, its genome sequence is priceless for understanding how mammalian biological processes evolved.”

“While we’ve always been able to compare and consider all of these creatures on the basis of their physical characteristics, internal anatomy and behavior, it’s truly amazing to be able to compare their genetic blueprints and begin to get a close-up look at how evolution brings about change,” Wilson says.

As part of their analysis, the researchers compared the platypus genome with genomes of the human, mouse, dog, opossum and chicken. They found that the platypus shares 82 percent of its genes with these animals. The chicken genome was chosen because it represents a group of egg-laying animals, including extinct reptiles, which passed on much of their DNA to the platypus and other mammals over the course of evolution.

The researchers also found genes that support egg laying - a feature of reptiles - as well as lactation - a characteristic of all mammals. Interestingly, the platypus lack nipples, so its young nurse through the abdominal skin.

The researchers also attempted to determine which characteristics of the platypus were linked to reptiles at the DNA level. When they analyzed the genetic sequences responsible for venom production in the male platypus, they found it arose from duplications in a group of genes that evolved from ancestral reptile genomes. Amazingly, duplications in the same genes appear to have evolved independently in venomous reptiles.

The platypus swims with its eyes, ears and nostrils closed, relying on electrosensory receptors in its bill to detect faint electric fields emitted by underwater prey. Surprisingly, the researchers found the genome contains an expansion of genes that code for a particular type of odor receptor. “We were expecting very few of these odor receptor genes because the animals spend the majority of their life in the water,” Warren says.

Similar genes are found in animals that rely on a sense of smell, such as rodents and dogs, and the scientists suspect that their addition in the platypus allows the animals to detect odors while foraging underwater.

At roughly 2.2 billion base pairs, the platypus genome is about two-thirds the size of the human genome and contains about 18,500 genes, similar to other vertebrates. The animal has 52 chromosomes, including an unusual number of sex chromosomes: 10. The platypus X chromosome bears resemblance to the sex chromosome of a bird, known as Z.

Sequencing and assembling the platypus genome proved far more daunting than sequencing any other mammalian genome to date. About 50 percent of the genome is composed of repetitive elements of DNA, which makes it a challenge to assemble properly.

The platypus genome sequence, along with those for other organisms, such as the mouse, dog, cow, and many other animals can be accessed at GenBank (www.ncbi.nih.gov/Genbank) at NIH’s National Center for Biotechnology Information.

[Caroline Arbanas @ Washington University School of Medicine]

A new game, named Foldit, turns protein folding into a competitive sport. Introductory levels teach the rules, which are the same laws of physics by which protein strands curl and twist into three-dimensional shapes - key for biological mysteries ranging from Alzheimer’s to vaccines.

After about 20 minutes of training, people feel like they’re playing a video game but are actually mouse-clicking in the name of medical science. The free program can be found here.

The game was developed by doctoral student Seth Cooper and postdoctoral researcher Adrien Treuille, both in computer science and engineering, working with Zoran Popovic, a UW associate professor of computer science and engineering; David Baker, a UW professor of biochemistry and Howard Hughes Medical Institute investigator; and David Salesin, a UW professor of computer science and engineering. Professional game designers provided advice during the game’s creation.

“We’re hopefully going to change the way science is done, and who it’s done by,” said Popovic, who presented the project today at the Games for Health meeting in Baltimore. “Our ultimate goal is to have ordinary people play the game and eventually be candidates for winning the Nobel Prize.”

Proteins, of which there are more than 100,000 different kinds in the human body, form every cell, make up the immune system and set the speed of chemical reactions. We know many proteins’ genetic sequence, but don’t know how they fold up into complex shapes whose nooks and crannies play crucial biological roles.

Computer simulators calculate all possible protein shapes, but this is a mathematical problem so huge that all the computers in the world would take centuries to solve it. In 2005, Baker developed a project named Rosetta@home that taps into volunteers’ computer time all around the world. But even 200,000 volunteers aren’t enough.

“There are too many possibilities for the computer to go through every possible one,” Baker said. “An approach like Rosetta@home does well on small proteins, but as the protein gets bigger and bigger it gets harder and harder, and the computers often fail.

“People, using their intuition, might be able to home in on the right answer much more quickly.”

Rosetta@home and Foldit both use the Rosetta protein-folding software. Foldit is the first protein-folding project that asks volunteers for something other than unused processor cycles on their computers or Playstation machines. Foldit also differs from recent human-computer interactive games that use humans’ ability to recognize images or interpret text. Instead, Foldit capitalizes on people’s natural 3-D problem-solving skills.

The intuitive skills that make someone good at playing Foldit are not necessarily the ones that make a top biologist. Baker says his 13-year-old son is faster at folding proteins than he is. Others may be even faster.

“I imagine that there’s a 12-year-old in Indonesia who can see all this in their head,” Baker says.

Eventually, the researchers hope to advance science by discovering protein-folding prodigies who have natural abilities to see proteins in 3-D.

“Some people are just able to look at the game and in less than two minutes, get to the top score,” said Popovic. “They can’t even explain what they’re doing, but somehow they’re able to do it.”

The game looks like a 21st-century version of Tetris, with multicolored geometric snakes filling the screen. A team that includes a half-dozen UW graduate and undergraduate students spent more than a year figuring out how to make the game both accurate and engaging. They faced some special challenges that commercial game developers don’t encounter.

“We don’t know what the best result is, so we can’t help people or hint people toward that goal,” Popovic explained. The team also couldn’t arbitrarily decide to make one move worth 1,000 bonus points, since the score corresponds to the energy needed to hold the protein in that shape.

Almost 1,000 players have tested the system in recent weeks, playing informal challenges using proteins with known shapes. Starting this week, however, the developers will open the game to the public and offer proteins of unknown shapes. Also starting this week, Foldit gamers will face off against research groups around the world in a major protein-structure competition held every two years.

Beginning in the fall, Foldit problems will expand to involve creating new proteins that we might wish existed - enzymes that could break up toxic waste, for example, or that would absorb carbon dioxide from the air. Computers alone cannot design a protein from scratch. The game lets the computer help out when it’s a simple optimization problem - the same way that computer solitaire sometimes moves the cards to clean up the table - letting the player concentrate on interesting moves.

Eventually, the researchers hope to present a medical nemesis, such as HIV or malaria, and challenge players to devise a protein with just the right shape to lock into the virus and deactivate it. Winning protein designs will be synthesized in Baker’s lab and tested in petri dishes. High-scoring players will be credited in scientific publications the way that top Rosetta@home contributors already are credited for their computer time.

“Long-term, I’m hoping that we can get a significant fraction of the world’s population engaged in solving critical problems in world health, and doing it collaboratively and successfully through the game,” Baker said. “We’re trying to use the brain power of people all around the world to advance biomedical research.”

Foldit includes elements of multiplayer games in which people can team up, chat with other players and create online profiles. Over time the researchers will analyze people’s moves to see how the top players solve puzzles. This information will be fed back into the game’s design so the game’s tools and format can evolve.

[Hannah Hickey @ University of Washington]