Automated drug design using synthetic DNA self-assembly

Using a simple “drag-and-drop” computer interface and DNA self-assembly techniques, Parabon NanoLabs researchers have developed a new automated method of drug development that could reduce the time required to create and test medications, with the support of an NSF Technology Enhancement for Commercial Partnerships grant.

“We can now ‘print,’ molecule by molecule, exactly the compound that we want,” says Steven Armentrout, the principal investigator on the NSF grants and co-developer of Parabon’s technology.

“What differentiates our nanotechnology from others is our ability to rapidly, and precisely, specify the placement of every atom in a compound that we design.”

The Parabon Essemblix Drug Development Platform combines computer-aided design (CAD) software with nanoscale fabrication technology, developed in partnership with Janssen Research & Development, LLC, part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

To develop new drugs, scientists can use the CAD software to design molecular pieces with specific, functional components. The software then optimizes the design using a cloud supercomputing platform that uses proprietary algorithms to search for specific sets of DNA sequences that can self-assemble those components.

“When designing a therapeutic compound, we combine knowledge of the cell receptors we are targeting or biological pathways we are trying to affect with an understanding of the linking chemistry that defines what is possible to assemble,” says Hong Zhong, senior research scientist at Parabon and a collaborator on the grants. “It’s a deliberate and methodical engineering process, which is quite different from most other drug development approaches in use today.”

What howler monkeys can tell us about the role of interbreeding in human evolution

Did different species of early humans interbreed and produce offspring of mixed ancestry?

Recent genetic studies suggest that Neanderthals may have bred with anatomically modern humans tens of thousands of years ago in the Middle East, contributing to the modern human gene pool. But the findings are not universally accepted, and the fossil record has not helped to clarify the role of interbreeding, which is also known as hybridization.

Now a University of Michigan-led study of interbreeding between two species of modern-day howler monkeys in Mexico is shedding light on why it’s so difficult to confirm instances of hybridization among primates—including early humans—by relying on fossil remains.

The study, published online Dec. 7 in the American Journal of Physical Anthropology, is based on analyses of genetic and morphological data collected from live-captured monkeys over the past decade. Morphology is the branch of biology that deals with the form and structure of animals and plants.

The two primate species in the study, mantled howler monkeys and black howler monkeys, diverged about 3 million years ago and differ in many respects, including behavior, appearance and the number of chromosomes they possess. Each occupies a unique geographical distribution except for the state of Tabasco in southeastern Mexico, where they coexist and interbreed in what’s known as a hybrid zone.

The Meaning of Pupil Dilation

For more than a century, scientists have known that our pupils respond to more than changes in light. They also betray mental and emotional commotion within. In fact, pupil dilation correlates with arousal so consistently that researchers use pupil size, or pupillometry, to investigate a wide range of psychological phenomena. And they do this without knowing exactly why our eyes behave this way. “Nobody really knows for sure what these changes do,” said Stuart Steinhauer, who directs the Biometrics Research Lab at the University of Pittsburgh School of Medicine.

While the visual cortex in the back of the brain assembles the images we see, a different, older part of our nervous system manages the continuous tuning of our pupil size, alongside other functions—like heart rate and perspiration—that operate mostly outside our conscious control. This autonomic nervous system dictates the movement of the iris, like the lens of a camera, to regulate the amount of light that enters the pupil.

The iris is made of two types of muscle: in a brightly lit environment, a ring of sphincter muscles that encircle and constrict the pupil down to as little as a couple of millimeters across; in the dark, a set of dilator muscles laid out like bicycle spokes, which can expand the pupil up to 8 millimeters—approximately the diameter of a chickpea.

Cognitive and emotional events can also dictate pupil constriction and expansion, though such events occur on a smaller scale than the light reflex, causing changes generally less than half a millimeter. But that’s enough. By recording subjects’ eyes with infrared cameras and controlling for other factors that might affect pupil size, like brightness, color, and distance, scientists can use pupil movements as a proxy for other processes, like mental strain.

A direct line through the brain to avoid rotten food

Consuming putrid food can be lethal as it allows bacterial pathogens to enter the digestive system. To detect signs of decay and thus allowing us and other animals to avoid such food poisoning is one of the main tasks of the sense of smell. Behavioural scientists and neurobiologists at the Max Planck Institute for Chemical Ecology in Jena, Germany, have now for the first time decoded the neural mechanisms underlying an escape reflex in fruit flies (Drosophila) activated in order to avoid eating and laying eggs in food infected by toxic microorganisms. A super-sensitive and completely dedicated neural line, from olfactory receptor, via sensory neuron and primary brain neurons, is activated as soon as the tiniest amount of geosmin is in the air. Geosmin is a substance released by bacteria and mold fungi toxic to the fly. This stimulus overrides all other food odour signals, irrespective of how attractive they are on their own. Consequently, geosmin is a full STOP signal that prevents flies from eating and laying eggs in toxic food, similar to when we open the fridge and smell last week’s forgotten dinner.

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Drug fights hard-to-treat depression by targeting brain receptors in a new way

A first-of-its-kind antidepressant drug discovered by a Northwestern University professor and now tested on adults who have failed other antidepressant therapies has been shown to alleviate symptoms within hours, have good safety and produce positive effects that last for about seven days from a single dose. 

The novel therapeutic targets brain receptors responsible for learning and memory — a very different approach from existing antidepressants. The new drug and others like it also could be helpful in treating other neurological conditions, including schizophrenia, bipolar disorder, anxiety and Alzheimer’s disease.

The results of the phase IIa clinical trial were presented (Dec. 6) at the 51st Annual Meeting of the American College of Neuropsychopharmacology in Hollywood, Fla.

Also this week a paper reporting some of the background scientific research that provided the foundation for the clinical development of GLYX-13 was published by the journal Neuropsychopharmacology.

The compound, called GLYX-13, is the result of more than two decades of work by Joseph Moskal, research professor of biomedical engineering at Northwestern’s McCormick School of Engineering and Applied Science and director of the University’s Falk Center for Molecular Therapeutics.

Autism Blood Test Shows Promise

Diagnosing autism could soon be much simpler, with researchers saying this week that they’ve developed a blood test that appears to identify those with the disorder even before symptoms are apparent.

The early-stage test developed at Boston Children’s Hospital may be able to flag about two-thirds of those with autism, researchers reported in the journal PLOS ONE.

Currently, clinicians rely on observation to screen children for autism. Most kids are not diagnosed until after age 4, according to the U.S. Centers for Disease Control and Prevention.

But a blood test offers the promise of flagging kids and potentially enrolling them in early intervention programs even before symptoms appear.

In order to develop the test, researchers analyzed blood samples from 66 boys with autism and 33 without the developmental disorder in an effort to establish patterns. Ultimately, the scientists were able to focus on a group of 55 genes that they used to successfully identify autism with 68 percent accuracy in a second test group made up of 104 people with autism and 82 controls.

“It’s clear that no single mutation or even a single pathway is responsible for all cases,” said Isaac Kohane of Boston Children’s Hospital who worked on the research. “By looking at this 55-gene signature, which can capture disruptions in multiple pathways at once, we can say with about 70 percent accuracy, ‘this child does not have autism,’ or ‘this child could be at risk,’ putting him at the head of the queue for early intervention and evaluation. And we can do it relatively inexpensively and quickly.”

The blood test is not yet ready for prime time, researchers said, but it has been licensed to the company SynapDx for further exploration and potential commercialization.

Combining two genome analysis approaches supports immune system contribution to autism

Researchers using novel approaches and methodologies of identifying genes that contribute to the development of autism have found evidence that disturbances in several immune-system-related pathways contribute to development of autism spectrum disorders. The report published December 4 in the open-access journal PLOS ONE powerfully supports a role for the immune function in autism by integrating analysis of autism-associated DNA sequence variations with that of markers identified in studies of families affected by autism.

"Others have talked about immune function contributions to autism, but in our study immune involvement has been identified through a completely nonbiased approach," says Vishal Saxena, PhD, of the Massachusetts General Hospital (MGH) Department of Neurology, first, corresponding and co-senior author of the PLOS ONE paper. “We let the data tell us what was most important; and most tellingly, viral infection pathways were most important in this immune-related mechanism behind autism.”

Genetic studies of families including individuals with autism have indentified linkages with different locations in the genome. Since traditional interpretation methods implicate the gene closest to a marker site as the cause of a condition, those studies appeared to point to different genes affecting different families. However, Saxena’s team realized that, since autism has typical symptoms and affects the same biological processes, a common molecular physiology must be affecting the different families studied. To search for genetic pathways incorporating these autism-associated sites, they developed a methodology called Linkage-ordered Gene Sets (LoGS) that analyzes all of the genes within a particular distance from marker sites and ranks them according to their distance from the marker.

Another Muscular Dystrophy Mystery Solved; MU Scientists Inch Closer to a Therapy for Patients

Approximately 250,000 people in the United States suffer from muscular dystrophy, which occurs when damaged muscle tissue is replaced with fibrous, bony or fatty tissue and loses function. Three years ago, University of Missouri scientists found a molecular compound that is vital to curing the disease, but they didn’t know how to make the compound bind to the muscle cells. In a new study, published in the Proceedings of the National Academies of Science, MU School of Medicine scientists Yi Lai and Dongsheng Duan have discovered the missing pieces to this puzzle that could ultimately lead to a therapy and, potentially, a longer lifespan for patients suffering from the disease.

Duchenne muscular dystrophy (DMD), predominantly affecting males, is the most common type of muscular dystrophy. Patients with Duchenne muscular dystrophy have a gene mutation that disrupts the production of dystrophin, a protein essential for muscle cell survival and function. Absence of dystrophin starts a chain reaction that eventually leads to muscle cell degeneration and death. While dystrophin is vital for muscle development, the protein also needs several “helpers” to maintain the muscle tissue. One of these “helper” molecular compounds is nNOS, which produces nitric oxide that can keep muscle cells healthy after exercise.

“Dystrophin not only helps build muscle cells, it’s also a key factor to attracting nNOS to the muscles cells and helping nNOS bind to the cell and help repair it following activity,” said Lai, a research assistant professor in the Department of Molecular Microbiology and Immunology. “Prior to this discovery, we didn’t know how dystrophin made nNOS bind to the cells. What we found was that dystrophin has a special ‘claw’ that is used to grab nNOS and bring it close to the muscle cell. Now that we have that key, we hope to begin the process of developing a therapy for patients.”