Two NIH Common Fund High Risk – High Reward Researchers named as 2013 Allen Distinguished Investigators

The Paul G. Allen Family Foundation, co-founded by Paul G. Allen (Microsoft co-founder) and his sister, Jo Lynn Allen, with a goal of “transforming lives and strengthening communities by fostering innovation, creating knowledge, and promoting social progress” through its philanthropic efforts.  In 2010 the Foundation created the Allen Distinguished Investigators Awards to support high-risk, high-reward ideas in science.  The program awards grants to ambitious scientists, who are pioneering innovative early-stage research.  Two NIH High Risk – High Reward Investigators, Jeff Gore, a 2012 New Innovator from MIT, and Markus Covert, a 2009 Pioneer from Stanford University, were selected as 2013 Allen Distinguished Investigators.  Dr. Gore will use the $1.5 million prize to investigate decision making and the evolutionary origins or cooperation using yeast as a model.  Dr. Covert will also receive $1.5 million and plans to use this grant to study whole-cell models of higher organisms, including human cells.  These awards will be funded over the course of three years and the Foundation hopes these grants will enable the awardees to unlock fundamental questions in biology that are essential to achieving world-changing breakthroughs.

Read more about the Allen Distinguished Investigators Award here ,
and read the Paul G. Allen Family Foundation Press Release for the 2013 Allen Distinguished Investigators here.

Two HRHR researchers awarded world’s largest brain research prize

Two NIH Common Fund High Risk-High Reward Awardees were named as winners of The Brain Prize for 2013, which is awarded by the Grete Lundbeck European Brain Research Foundation.  Americans, Karl Deisseroth, a 2005 Pioneer Awardee, and 2012 Transformative Research Awardee, and Edward S. Boyden, a 2007 New Innovator, and 2012 Transformative Research Awardee and four European scientists were awarded the 2013 prize for their contributions to the development of “optogenetics.”  Optogenetics is a technique that merges the fields of optics and genetics using light to specifically control the activity of genetically selected neurons.  This revolutionary technique has allowed scientists to begin to gain a better understanding of the way circuits of neurons carry out complex functions. This technique has broad application potential in research from studying fundamental activities, such as memory formation and breathing, to more complex disorders and diseases, such as addiction, psychiatric disorders, and Alzheimer’s disease.

The Brain Prize, the world’s largest brain research prize, is awarded to scientists who have made an outstanding contribution to European brain research, and is awarded to scientists who have conducted research in Europe, or to scientists who have conducted research in collaboration with European scientists.

Read more about the Brain Prize here , and read the 2013 Brain Prize press release here.

Rats Communicate Via Brain-To-Brain Interface

Miguel A. L. Nicolelis, a 2010 NIH Director’s Pioneer Awardee from Duke University, and his colleagues, have connected the brains of rat pairs through the internet and shown that the rats can share sensory information, acting as a dyad rather than strictly as individuals.  Dr. Nicolelis’ lab is well known for their work on brain-to-machine interface (BTM), the current paradigm used to help develop technology that allows an amputee’s brain to control a prosthetic limb.  The team of researchers took the brain interfacing concept further and connected pairs of rat brains using a new paradigm they termed brain-to-brain interface (BTBI).  This BTBI enabled the rat pairs to act as a dyad exchanging sensorimotor information to achieve simple behavioral goals.  The researchers implanted microelectrode bundles in the cortical area in the brains of rats.  These microelectrodes allowed the researchers to record the neural activity of an “encoder” rat acting out a specific behavior and directly transmit this recorded signal to a “decoder” rat’s brain using intracortical microstimulation (ICMS), the stimulation of individual nerve cells using a small electric current, to inform the decoder rat to complete a specific activity.

The encoder rat was trained to press one of two levers in response to a light stimulus above one lever.  While the encoder rat pressed this lever, the neural activity was recorded and transformed into ICMS which was then applied to the brain of the decoder rat informing the decoder rat of which lever to press.  If the decoder rat pressed the correct lever, both rats received a reward.  If the decoder rat pressed the incorrect lever, neither rat received a reward.  The researchers took this experiment a step further and were able to perform this experiment in real time, with the encoder rat located in Natal, Brazil, and the decoder rat located at Duke University in North Carolina, transmitting the ICMS over the internet.  In a second set of experiments, the scientists trained the encoder rat to determine the width of an opening (wide or narrow) using its whiskers and to push either the right or left lever, respectively.  Again, the neural activity of the encoder rat’s brain during this task was recorded and transmitted by ICMS to the decoder rat informing the decoder of which lever to press.  In both activities, the decoder rats pressed the correct lever significantly more often than rats who were not receiving neural activity information via ICMS.  Further, the encoder rat changed both its behavior and its neural signals in response to feedback from the decoder rat’s behavior, indicating that the rat pairs were acting as dyads indicating a more complex system of communication.  The researchers also mechanically stimulated both the encoder and decoder rat’s whiskers and recorded the neural response to this stimulation.  They then stimulated the encoder rat’s whiskers, recorded the activity and sent it the decoder rat’s brain using ICMS and recorded the neural activity of the decoder rats brain in response.  Passive whisker stimulation in either the encoder or decoder rats induced significant neural activity in the decoder rat’s brain. 

Through this set of experiments the researchers demonstrated that tactile and motor information can be recorded in real-time from a rat’s brains and transmitted directly into another rat’s brain using BTBI.  In this BTBI rat dyad, the decoder rat relied exclusively on the neural patterns generated by the encoder rat in order to reproduce the encoder rat’s behavioral choice.  The ICMS patterns reflecting the neural activity in the encoder rat’s brain was sufficient to inform decoder rats to perform both tactile and motor activities significantly above chance in real-time.  The potential impact of this research is not limited to behavioral information exchange of animal dyads, but could be expanded to create a multi-brain system where groups of interconnected brain networks could communicate through large scale BTBI.

Read the Duke University Press Release here

Reference:

M. Pais-Vieira, M. Lebedev, C. Kunicki, J. Wang, M. A. L. Nicolelis, A Brain-to-Brain Interface for Real-Time Sharing of Sensorimotor Information. Sci. Rep. 3,  (2013). PMID: 23448946

Researchers define precise EEG Signature of Anesthesia-Induced Unconsciousness

More than 60,000 patients in the United States undergo general anesthesia for surgery every day. Currently, doctors use indirect measures of the brain state, such as heart rate and blood pressure, along with drug pharmacokinetics, pharmacodynamics and exhaled anesthetic gas typically are converted to a simple index score to indicate if a patient is adequately anesthetized during surgery. These indices are neither entirely reliable nor very informative. Inadequately administered anesthesia can result in intraoperative awareness and post-operative delirium. Drs. Emery N. Brown and Patrick L. Purdon, former NIH Director’s Pioneer Awardee and current NIH Director’s New Innovator Awardee, respectively, have studied brain activity during propofol-induced anesthesia using electroencephalogram (EEG) technology, which measures scalp electrical potentials, to better understand the mechanism of unconsciousness and to establish a direct method of tracking the transition between consciousness and unconsciousness during general anesthesia. In this study, the researchers gradually administered and reduced the anesthesia drug propofol in patients, while monitoring brain activity and behavioral loss of consciousness by asking patients to respond to auditory stimuli. This gradual induction and emergence from anesthesia allowed the researchers to precisely define an EEG brain signature, as well as behavioral markers that are associated with consciousness, unconsciousness, and the transition between these two states in patients undergoing propofol-induced general anesthesia. This research has provided a deeper understanding of the mechanism of propofol-induced loss of consciousness, and could be used to determine the EEG brain signatures of other anesthetics. Additionally, these results could be used to develop more direct and reliable methods for monitoring brain states of patients undergoing general anesthesia and could lead to new insights into the tailoring of drug dosage in real-time.

Reference:

P. L. Purdon et al., Electroencephalogram signatures of loss and recovery of consciousness from propofol. Proceedings of the National Academy of Sciences, (March 4, 2013, 2013).

Scientists Uncover How Tuberculosis “Pumps-Up” Tolerance To Drug Therapies

Shortening the time required to treat tuberculosis (TB) is key to reducing the development of drug resistance and lowering worldwide rates of TB infection and mortality. Reducing treatment duration however depends on: (1) understanding how Mycobacterium tuberculosis (Mtb), the bacteria that causes TB in humans, becomes tolerant to antibiotics; and (2) devising ways to prevent or overcome drug tolerance. NIH Director’s Pioneer Award recipient Dr. Lalita Ramakrishnan and colleagues at the University of Washington, in collaboration with Dr. Paul Edelstein at the University of Pennsylvania, report in a study appearing in the April 1, 2011 issue of Cell, that the development of drug tolerance in Mtb is due in part to the activity of “efflux” pumps in the cell membrane that presumably flush away any antibiotic agents that penetrate the Mtb cells. The authors found that these pumps are stoked into action by host cells called macrophages that are, ironically, part of the body’s frontline defenses against foreign invaders. Based on these findings, the study authors suggest that expanding treatment to include medications that inhibit these pumps could dramatically shorten the time needed to cure infection. While Mtb can infect many body tissues and organs, it primarily attacks the lungs. Once inside the lungs, the bacteria infect the aforementioned macrophages. The macrophages and other types of immune cells respond by aggregating into structures called granulomas which are thought to contain the spread of persistent pathogens. Having taken up residence within macrophages, some populations of Mtb cells quickly become tolerant to anti-TB drugs. Nearly all models of Mtb drug tolerance postulate that this temporary resistance to antibiotics arises when the bacterial cells enter a dormant state in which they stop replicating. Because most antibiotics are only effective against bacterial cells that are reproducing, dormant cells are effectively resistant to antimicrobial agents. In their latest paper however, Dr. Ramakrishnan and colleagues report finding multi-drug tolerant Mtb populations that were actively growing and reproducing inside of host macrophages suggesting that residence within macrophages rapidly induces tolerance. The study authors also found that, having infected macrophages, the Mtb cells deploy efflux pumps that are essential for the Mtb cells to grow within the macrophages and may be used by the bacterial cells to remove toxic substances such as antimicrobial agents. In addition to expanding our understanding of the pathogenesis of TB and drug tolerance, these findings suggest that inhibiting the activity of macrophage-induced bacterial efflux pumps using currently available drugs such as verapamil may be an effective means of reducing the duration of TB treatment. Shorter treatment is likely to translate into increased adherence which will in turn slow the development of multi-drug resistance, reduce transmission of infection to new hosts, and reduce TB-associated mortality around the world.

• Read the press release...
• Read the paper...
• Read more about the Pioneer Award program...

Reference:

Adams KN, Takaki K, Connolly LE, Wiedenhoft H, Winglee K, Humbert O, Edelstein PH, Cosma CL, Ramakrishnan L. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell, 2011 April 1; 145(1): 39-53. PMID: 21376383.

Novel Blood Test May Improve Diagnosis of Many Diseases

While simple blood tests can accurately and efficiently screen for some diseases, such as diabetes, the lack of blood tests for the majority of diseases can result in delayed or incorrect diagnoses. To overcome this diagnostic obstacle, Dr. Thomas Kodadek, a researcher at The Scripps Research Institute and funded in part by an NIH Director’s Pioneer Award, has developed a novel screening method that could detect disease-associated proteins in the blood of patients with a variety of conditions. In the January 7, 2011 edition of the journal Cell, Dr. Kodadek and colleagues describe their technique for using a collection of synthetic molecules to detect the presence of unique proteins in the blood of diseased individuals that do not appear in the blood of healthy individuals. By screening blood samples from mice with multiple sclerosis, the researchers identified several molecules in their synthetic collection that would only bind to proteins in the blood of the diseased mice, and could distinguish between “patient” mice and normal, healthy mice. Importantly, the researchers went on to demonstrate that in samples from humans, they could use the same technique to identify different molecules that bound to proteins uniquely present in the blood of patients with Alzheimer’s disease. This same binding did not occur in samples from healthy people of similar ages or in patients with another neurodegenerative disorder, Parkinson’s disease. These promising results suggest that this type of blood test has the potential to screen for a wide variety of different diseases, including diseases that currently lack a reliable diagnostic test.

• Read News Release...
• Read more about NIH Director’s Pioneer Awards...

Reference:

Reddy MM, Wilson R, Wilson J, Connell S, Gocke A, Hynan L, German D, Kodadek T. Identification of candidate IgG biomarkers for Alzheimer’s disease via combinatorial library screening. Cell, 2011 Jan 7; 144(1): 132-42. PMID: 21215375.