Study paves way to design drugs aimed at multiple protein targets at once

An international research collaboration led by scientists at the University of North Carolina School of Medicine and the University of Dundee, in the U.K., have developed a way to efficiently and effectively make designer drugs that hit multiple protein targets at once.

This accomplishment, described in the Dec. 13, 2012 issue of the journal Nature, may prove invaluable for developing drugs to treat many common human diseases such as diabetes, high blood pressure, obesity, cancer, schizophrenia, and bi-polar disorder.

These disorders are called complex diseases because each have a number of genetic and non-genetic influences that determine susceptibility, i.e., whether someone will get the disease or not.

“In terms of the genetics of schizophrenia we know there are likely hundreds of different genes that can influence the risk for disease and, because of that, there’s likely no single gene and no one drug target that will be useful for treating it, like other common complex diseases,” said study co-leader, Brian L. Roth, MD, PhD, Michael J. Hooker Distinguished Professor of Pharmacology in the UNC School of Medicine, professor in the Division of Chemical Biology and Medicinal Chemistry in the UNC Eshelman School of Pharmacy, and director of the National Institute of Mental Health Psychoactive Drug Screening Program.

In complex neuropsychiatric conditions, infectious diseases and cancer, Roth points out that for the past 20 years drug design has been selectively aimed at a single molecular target, but because these are complex diseases, the drugs are often ineffective and thus many never reach the market.

Moreover, a drug that acts on a single targeted protein may interact with many other proteins. These undesired interactions frequently cause toxicity and adverse effects. “And so the realization has been that perhaps one way forward is to make drugs that hit collections of drug targets simultaneously. This paper provides a way to do that,” Roth said.

The new way involves automated drug design by computer that takes advantage of large databases of drug-target interactions. The latter have been made public through Roth’s lab at UNC and through other resources.

Japanese researchers build robot with most humanlike muscle-skeleton structure yet

Researchers at the University of Tokyo have taken another step towards creating a robot with a faithfully recreated human skeleton and muscle structure. Called Kenshiro, the robot has been demonstrated at the recent Humanoids 2012 conference in Osaka, Japan.

Genetic Researchers Grow A Fish That Has Legs

The fossil record has a lot of strange stories to tell about the evolution of life on Earth, and one of the strangest is how life moved from sea to land. Though clues from the record give the rough outlines of the story—limbs grew from fins in a series of stages in which fins grew longer and narrower—scientists are still filling in the details, trying to determine what genetic changes might have allowed the limbs to grow.

One of the best ways to learn those details is to reproduce the changes that occurred some 400 million years ago—to virtually back in time and alter the development of the land-goer’s living ancestors and see what happens.

Which is what biologist Renata Freitas and colleagues were up to when they added some extra Hoxd13—a gene known to play a role in distinguishing body parts during embryological development— to the tip of a zebrafish embryo’s fin, and watched as the developing fin kept growing.

Their lab findings led the researchers to hypothesize that the secret to limb development may have been a new element in some lobe-finned fish’s DNA. When present, this DNA element would have helped turn on the Hoxd13 gene on the fish embryo’s fins, leading them to lengthen and grow into limbs.

How Our Sense of Touch is a Lot Like the Way We Hear

Sliman Bensmaia, PhD, assistant professor of organismal biology and anatomy at the University of Chicago, studies the neural basis of tactile perception, or how our hands convey this information to the brain. In a new study published in the Journal of Neuroscience, he and his colleagues found that the timing and frequency of vibrations produced in the skin when you run your hands along a surface, like searching a wall for a light switch, play an important role in how we use our sense of touch to gather information about the objects and surfaces around us.

The sense of touch has traditionally been thought of in spatial terms, i.e. receptors in the skin are spread out across a grid of sorts, and when you touch something this grid of receptors transmits information about the surface to your brain. In their new study, Bensmaia, two former undergraduates, and a postdoctoral scholar in his lab—Matthew Best, Emily Mackevicius and Hannes Saal—found that the skin is also highly sensitive to vibrations, and that these vibrations produce corresponding oscillations in the afferents, or nerves, that carry information from the receptors to the brain. The precise timing and frequency of these neural responses convey specific messages about texture to the brain, much like the frequency of vibrations on the eardrum conveys information about sound.

Neurons communicate through electrical bits, similar to the digital ones and zeros used by computers. But, Bensmaia said, “One of the big questions in neuroscience is whether it’s just the number of bits that matters, or if the specific sequence of bits in time also plays a role. What we show in this paper is that the sequence of bits in time does matter, and in fact for some of the skin receptors, the timing matters with millisecond precision.”

Researchers have known for years that these afferents respond to skin vibrations, but they studied their responses using so-called sinusoidal waves, which are smooth, repetitive patterns. These perfectly uniform vibrations can be produced in a lab, but the kinds of vibrations produced in the skin by touching surfaces in the real world are messy and erratic.

AHRF Researcher Describes Cochlear Amplification Using Novel Optical Technique

It has long been known that the inner ear actively amplifies sounds it receives, and that this amplification can be attributed to forces generated by outer hair cells in the cochlea. How the ear actually accomplishes this, however, has remained somewhat of a mystery. Now, Jonathan A. N. Fisher, PhD, and colleagues at The Rockefeller University, in New York, describe how the cochlea actively self-amplifies sound it receives to help increase the range of sounds that can be heard.

Fisher and colleagues used a new optical technique that inactivates prestin, a motor protein involved in the movement of the outer hair cells. The outer hair cells are part of the hair cell bundles (which also include the inner hair cells)- the true sensory cells of the inner ear. The main body of the hair cells sits in the basilar membrane- the tissue that lines the interior of the bony cochlea. The “hair” part of these cells, called the stereocilia, sticks up into the fluid-filled space of the cochlea, where they are pushed by the fluid as sound waves travel through it.

The sound waves traveling down the cochlea produce actual waves that can be observed along the basilar membrane as visualized in the animation (from the Howard Hughes Medical Institute). The cochlea picks up different sound frequencies along its length, with higher frequency sounds picked up at center of the “snail” and the lower frequency sounds being picked up at the part of the cochlea closest to the eardrum.

The outer hair cells have been known to provide amplification of sound waves picked up by the inner hair cells by actively changing their shape to increase the amplitudes of the sound waves. These outer hair cells can do this because the membrane protein can contract and cause the stereocillia to be deflected by the overlying tectorial membrane.

Fisher and colleagues developed a light-sensitive drug that when illuminated by an ultraviolet laser can inactivate prestin in select locations within the cochlea. Using this novel technique, the researchers were able to affect prestin at very specific locations along the basilar membrane.

The researchers found that by inactivating prestin at very specific locations, the sound-evoked waves that carry mechanical signals to sensory hair cells were re-shaped and of smaller amplitude- indicating that without prestin, amplification is dampened  compared to what the researchers saw when prestin was allowed to function normally.

Does the Brain Become Unglued in Autism?

A new study published in Biological Psychiatry suggests that autism is associated with reductions in the level of cellular adhesion molecules in the blood, where they play a role in immune function.

Cell adhesion molecules are the glue that binds cells together in the body. Deficits in adhesion molecules would be expected to compromise processes at the interfaces between cells, influencing tissue integrity and cell-to-cell signaling. In the brain, deficits in adhesion molecules could compromise brain development and communication between nerve cells.

Over the years, deficits in neural cell adhesion molecules have been implicated in schizophrenia and other psychiatric disorders. One adhesion molecule, neurexin, is strongly implicated in the heritable risk for autism.

Cell adhesion molecules also play a crucial role in regulating immune cell access to the central nervous system. Prior research provided evidence of immune system dysfunction in individuals diagnosed with autism spectrum disorder (ASD). This led scientists from the University of California, Davis to examine whether adhesion molecules are altered in children with ASD.

"For the first time, we show that levels of soluble sPECAM-1 and sP-selectin, two molecules that mediate leukocyte migration, are significantly decreased in young children with ASD compared with typically developing controls of the same age," explained the authors. "This finding is consistent with previous reports of decreased levels of both sPECAM-1 and sP-selectin in adults with high-functioning autism."

They also found that repetitive behavior scores and sPECAM-1 levels were associated in children with ASD. Repetitive, stereotyped behaviors are a typical feature of ASD and these data suggest a potential relationship between molecule levels and the severity of repetitive behaviors.

Finally, they also discovered that head circumference was associated with increased sPECAM-1 levels in the typically developing children, but not in the children with ASD. This indicates that perhaps sPECAM-1 plays a role in normal brain growth, as larger head circumference is a known feature of individuals with autism.