May 1, 2019
First Place Poster
Congratulations to graduate student Victoria Goldenshtein for winning first place at Duke's annual Biomedical Engineering Department Retreat poster session!
We are looking for new post docs!
November 2, 2018
Tadross Lab receives BRAIN Initiative Grant
We are excited to announce that Dr. Tadross has been awarded a BRAIN Initiative grant totaling $3.8 million over 3 years. This funding will be used to create DART2.0, which will include enhancements such as (1) expanding our library of drug ligands, (2) creating subcellular drug localization, and (3) interrogating whole brain volumes.
October 31, 2018
Dr. Tadross receives NIH Director's New Innovator Award
We are happy to announce that Dr. Tadross has been granted a 2018 New Innovator Award, totaling $2.4 million over 5 years. This funding will be used to push the boundaries of the known universe, at least as it relates to deconstructing the role of excitatory and inhibitory inputs onto midbrain dopamine neurons in reward learning and addiction.
October 31, 2018
Tadross Lab awarded R01 Funding
The Tadross lab has received a NIH R01 grant totaling $1.7 million over 5 years.
This funding will be used to further explore the role of cell-type specific synaptic modulators on Parkinson's disease (PD) and levodopa induced dyskinesia (LID) mouse models. This work will provide unprecedented circuit and molecular insights into PD and LID pathophysiology, and may provide a roadmap for cell type-specific restriction as a potential paradigm for increasing drug efficacy.
October 31, 2018
Duke Research Blog: Drug Homing Method Helps Rethink Parkinson's
October 22, 2018
The brain is the body’s most complex organ, and consequently the least understood. In fact, researchers like Michael Tadross, MD, PhD, wonder if the current research methods employed by neuroscientists are telling us as much as we think.
Current methods such as gene editing and pharmacology can reveal how certain genes and drugs affect the cells in a given area of the brain, but they’re limited in that they don’t account for differences among different cell types. With his research, Tadross has tried to target specific cell types to better understand mechanisms that cause neuropsychiatric disorders.
To do this, Tadross developed a method to ensure a drug injected into a region of the brain will only affect specific cell types. Tadross genetically engineered the cell type of interest so that a special receptor protein, called HaloTag, is expressed at the cell membrane. Additionally, the drug of interest is altered so that it is tethered to the molecule that binds with the HaloTag receptor. By connecting the drug to the Halo-Tag ligand, and engineering only the cell type of interest to express the specific Halo-Tag receptor, Tadross effectively limited the cells affected by the drug to just one type. He calls this method “Drugs Acutely Restricted by Tethering,” or DART.
Tadross has been using the DART method to better understand the mechanisms underlying Parkinson’s disease. Parkinson’s is a neurological disease that affects a region of the brain called the striatum, causing tremors, slow movement, and rigid muscles, among other motor deficits.
Patients with Parkinson’s show decreased levels of the neurotransmitter dopamine in the striatum. Consequently, treatments that involve restoring dopamine levels improve symptoms. For these reasons, Parkinson’s has long been regarded as a disease caused by a deficit in dopamine.
With his technique, Tadross is challenging this assumption. In addition to death of dopaminergic neurons, Parkinson’s is associated with an increase of the strength of synapses, or connections, between neurons that express AMPA receptors, which are the most common excitatory receptors in the brain.
In order to simulate the effects of Parkinson’s, Tadross and his team induced the death of dopaminergic neurons in the striatum of mice. As expected, the mice displayed significant motor impairments consistent with Parkinson’s. However, in addition to inducing the death of these neurons, Tadross engineered the AMPA-expressing cells to produce the Halo-Tag protein.
Tadross then treated the mice striatum with a common AMPA receptor blocker tethered to the Halo-Tag ligand. Amazingly, blocking the activity of these AMPA-expressing neurons, even in the absence of the dopaminergic neurons, reversed the effects of Parkinson’s so that the previously affected mice moved normally.
Tadross’s findings with the Parkinson’s mice exemplifies how little we know about cause and effect in the brain. The key to designing effective treatments for neuropsychiatric diseases, and possibly other diseases outside the nervous system, may be in teasing out the relationship of specific types of cells to symptoms and targeting the disease that way.
The ingenious work of researchers like Tadross will undoubtedly help bring us closer to understanding how the brain truly works.
Source Publication: Duke Research Blog, written by Sarah Haurin
Source URL: https://researchblog.duke.edu/2018/10/18/rethinking-how-the-brain-works/
Source Date: October 22, 2018
Duke Biomedical Engineers Awarded $4.8 Million in NIH High-Risk, High-Reward Grants
October 2, 2018
In two NIH Innovator Awards with transformative potential, Yiyang Gong and Michael Tadross target the nuanced behaviors of neurons
Two biomedical engineers at Duke University have received awards from the National Institutes of Health’s High-Risk, High Reward Research program.
The program catalyzes scientific discovery by supporting exciting, high-risk research proposals that may struggle in the traditional peer review process despite their transformative potential. Program applicants are encouraged to think outside the box and to pursue creative, trailblazing ideas in any area of research relevant to the NIH mission.
“This program supports exceptionally innovative researchers who have the potential to transform the biomedical field,” said NIH Director Francis S. Collins, M.D., Ph.D. “I am confident this new cohort will revolutionize our approaches to biomedical research through their groundbreaking work.”
The Duke proposals both center on investigating activities of specific types of neurons using unique technology developed by each scientist.
For Yiyang Gong, assistant professor of biomedical engineering at Duke, that technology is a protein sensor that flashes when a neuron fires. These sensors are incredibly fast, capable of recording certain types of waveforms and single action potentials that elude other technologies.
With his new five-year, $2.4 million award, Gong will use this platform to monitor the collective activities of hundreds to thousands of neurons simultaneously rather than the minute workings of only a few. By genetically targeting different types of neurons with his sensor, Gong plans to investigate how these cell types oscillate together and contribute to various types of brainwaves. These insights could help reveal the neural origin of phenomena such as learning, remembering and decision-making.
For Michael Tadross, assistant professor of biomedical engineering at Duke, genetically targeting individual cell types in the brain has long been a hallmark of his research enterprise. His novel technology, dubbed DART (Drugs Acutely Restricted by Tethering), allows researchers to deliver pharmaceuticals to specific cell types.
The technology works by genetically programming a specific cell type to express a sort of GPS beacon, which is inert and does nothing more than attract drugs loaded with a special homing device. This allows Tadross to deliver drugs at concentrations that do not affect any cells other than those tagged with the GPS beacon, where it accumulates at levels 1,000 times higher than anywhere else.
In his new five-year, $2.4 million award, Tadross will use this technology to investigate the molecular underpinnings of addiction at a level never before possible. The DART system will deliver drugs targeted at excitatory and inhibitory receptors on dopaminergic neurons in mice in an attempt to gain a clearer picture of their roles in addiction and recovery.
As NIH Director’s New Innovator Awards, both grants are meant to support unusually innovative research from early career investigators who are within 10 years of their final degree or clinical residency and have not yet received a research project grant or equivalent NIH grant.
All told, the NIH issued 10 Pioneer awards, 58 New Innovator awards, 10 Transformative Research awards, and 11 Early Independence awards for 2018. Funding for the awards comes from the NIH Common Fund and other Office of the Director appropriations; National Cancer Institute; National Center for Complementary and Integrative Health; National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences; National Institute of Mental Health; and Office of Research Infrastructure Programs.
Source Publication: Pratt School of Engineering News
Source URL: https://pratt.duke.edu/about/news/nih-hrhr
Source Date: October 2, 2018
Summer Lab Outing
To celebrate the coming of summer, the Tadross lab chose to lock ourselves in a windowless room and attempt to escape!
This is the last known photograph of the lab. We may or may not be better at science than we are at escaping locked rooms.
July 3, 2018
Duke University News: Michael Tadross Receives Parkinson’s Foundation Award
Michael Tadross, assistant professor of biomedical engineering at Duke University, has been chosen as a recipient of the competitive 2017 Parkinson's Foundation Stanley Fahn Junior Faculty Award. Managed by the Parkinson's Foundation Grants Review Committee, the new program supports junior faculty at a critical time of career transition.
The three-year, $300,000 award will support Tadross’s continued work to explore the neurological and biomolecular roots of Parkinson’s disease using his novel drug targeting system. The system, named DART (Drugs Acutely Restricted by Tethering), allows researchers to deliver pharmaceuticals to specific types of neurons in the brain.
Many molecular targets of drugs are shared between different types of neurons. And because pharmaceuticals affect all of them, it has been impossible to disentangle the benefits certain drugs may provide by acting on one type of neuron from the adverse side-effects generated from effects on another.
In its recent inaugural study, DART revealed how movement difficulties in a mouse model of Parkinson's disease are controlled by the AMPA receptor (AMPAR)—a synaptic protein that enables neurons to receive fast incoming signals from other neurons in the brain. The results revealed why a recent clinical trial of an AMPAR-blocking drug failed, and offered a new approach to using the pharmaceutical.
"The insights we gained in studying Parkinson's mice were unexpected and could not have been obtained with any previous method,” said Tadross. “This grant will be instrumental in supporting my work to continue to unravel the intricacies of how pharmaceuticals treat the symptoms of Parkinson’s disease.”
Source Publication: Pratt School of Engineering News
Source URL: http://pratt.duke.edu/about/news/tadross-PDF-award
Source Date: Thursday, Apr 20, 2017
April 20, 2017
Homing system delivers drugs to specific neurons: New technique reveals synaptic contributions to Parkinson's Disease
Originally published in Science Daily
Biomedical engineers have developed a way to deliver drugs to specific types of neurons in the brain, providing an unprecedented ability to study neurological diseases while also promising a more targeted way to treat them.
Drugs are the tool of choice for studying the connections between neurons, and continue to be the mainstream treatment for neurological disease. But a major drawback in both endeavors is that the drugs affect all types of neurons, complicating the study of how cell receptors in the synapse -- the gap between neurons -- work in an intact brain, and how their manipulation can lead to clinical benefits and side effects.
A new method named DART (Drugs Acutely Restricted by Tethering) may overcome these limitations. Developed by researchers at Duke University and the Howard Hughes Medical Institute, DART offers researchers the first opportunity to test what happens when a drug is targeted exclusively to one cell type.
In its inaugural study, DART reveals how movement difficulties in a mouse model of Parkinson's Disease are controlled by the AMPA receptor (AMPAR) -- a synaptic protein that enables neurons to receive fast incoming signals from other neurons in the brain. The results reveal why a recent clinical trial of an AMPAR-blocking drug failed, and offer a new approach to using the pharmaceutical.
The paper appeared online on April 7, 2017 in the journal Science.
"This study marks a major milestone in behavioral neuropharmacology," said Michael Tadross, assistant professor of biomedical engineering, who is in the process of moving his laboratory from the HHMI Janelia Research Campus to Duke. "The insights we gained in studying Parkinson's mice were unexpected and could not have been obtained with any previous method."
DART works by genetically programming a specific cell type to express a sort of GPS beacon. The "beacon" is an enzyme borrowed from bacteria that is inert -- it does nothing more than sit on the cell surface. Nothing, that is, until researchers deliver drugs loaded with a special homing device.
Researchers administer these drugs at such low doses that they do not affect other cells. Because the homing system is so efficient, however, the drug is captured by the tagged cells' surface, accumulating within minutes to concentrations that are 100 to 1,000 times higher than anywhere else.
In an experiment using a mouse model of Parkinson's disease, Tadross and colleagues attached the homing signal beacon to two types of neurons found in the basal ganglia -- the region of the brain responsible for motor control. One type, referred to as D1 neurons, are believed to give a "go" command. The other, referred to as D2 neurons, are thought to do just the opposite, providing commands to stop movements.
Using DART, Tadross delivered an AMPAR-blocking pharmaceutical to only D1-neurons, only D2-neurons, or both. When delivered to both cell types simultaneously, the drugs improved only one of several components of motor dysfunction -- mirroring the lackluster results of recent human clinical trials. The team then found that delivering the drug to only the D1/"go" neurons did absolutely nothing. Surprisingly, however, by targeting the same drug to D2/"stop" neurons, the mice's movements became more frequent, faster, fluid and linear -- in other words, much closer to normal.
While the drug stops neurons from receiving certain incoming signals, it does not completely shut them down. This nuance is particularly important for a subset of the D2 neurons that have two prominent forms of firing. With DART, these components could be separately manipulated, providing the first evidence that Parkinson's motor deficits are attributable to the AMPAR-based component of firing in these cells. Tadross said this level of nuance could not have been obtained with prior cell type-specific methods that completely shut neurons down.
"Already in our first use of DART, we've learned something new about the synaptic basis of circuit dysfunction in Parkinson's disease," said Tadross. "We've discovered that targeting a specific receptor on specific types of neurons can lead to surprisingly potent improvements."
Tadross is already looking into how this discovery might translate into a new therapy by delivering drugs to these neurons through an emerging viral technique. He is also beginning work to develop a version of DART that does not need the genetically added homing beacon to work. Both efforts will require years of research before seeing fruition -- but that's not stopping Tadross.
"All too often in basic science, approaches are developed that may 'one day' make a difference to human health," he said. "At Duke, there's a palpable emphasis on providing new treatments to people as quickly as possible. I'm very excited that in this environment, my lab can work collaboratively with scientists, physicians, and biotech to solve the real-world challenges involved."
Brenda C. Shields, Elizabeth Kahuno, Charles Kim, Pierre F. Apostolides, Jennifer Brown, Sarah Lindo, Brett D. Mensh, Joshua T. Dudman, Luke D. Lavis, Michael R. Tadross. Deconstructing behavioral neuropharmacology with cellular specificity. Science, 2017; 356 (6333): eaaj2161 DOI: 10.1126/science.aaj2161
April 6, 2017
Michael Tadross: Targeting Neuropharmacology with Molecular GPS Technologies
New faculty member Michael Tadross brings to Duke an emerging technology to deliver drugs to specific cell types
Michael Tadross will join the Department of Biomedical Engineering at Duke University beginning July 1, 2017. Developer of a potentially revolutionary technology that can precisely deliver drugs to any specific cell type, Tadross will use his breakthrough to better understand how pharmaceuticals affect the human brain.
“Most of the neurologically active drugs prescribed today were discovered by chance,” said Tadross. “For example, monoaminergic drugs—including selective serotonin reuptake inhibitors, or SSRIs—are used to treat depression and are now the number one prescribed neuropsychiatric drug in the world. Their discovery can be traced back to a side-effect observed in a clinical trial for a tuberculosis treatment in the 1950’s, and we still don’t have a good understanding of how they work. We now know that they affect serotonin, but very little about how they affect neural circuits in the brain.”
In the past decade, a new technique called optogenetics—genetically programming cells to respond to light—has revolutionized how neural circuits are examined. In numerous studies, neurobiologists have used optogenetics to cause a precise group of neurons to fire or remain silent in an attempt to understand their roles in the greater network.
But according to Tadross, much more needs to be done. Though revolutionary, optogenetics has only scratched the surface of how neurons work. From the standpoint of the cells being manipulated, optogenetics can be thought of as a first-pass binary manipulation—a sledgehammer that completely silences or activates cells. But drugs can be a lot more nuanced in their effects – indeed they had to be.
“Drugs act simultaneously on all cells, and there would be little value in silencing or activating the entire brain,” said Tadross.
Tadross’s goal, then, is to bridge the gap between the cell-type-specific but binary nature of optogenetics and the molecularly nuanced, yet untargeted nature of pharmacology.
“We’ve developed a way to take traditional drugs and deliver them to particular cell types in the brain of a behaving animal,” said Tadross. “It’s a wonderful opportunity to connect the two worlds in a way that could give us new insights and lead to new targeted treatments.”
Tadross received his bachelor’s degree in electrical engineering from Rutgers University and his MD/PhD in biomedical engineering at the Johns Hopkins School of Medicine. He then completed a postdoc at Stanford University before moving to the Howard Hughes Medical Institute. There, a research-dedicated pre-faculty position allowed Tadross to focus entirely on developing his drug-targeting technique.
The technology works by genetically programming a specific cell type to express a sort of GPS beacon. An enzyme borrowed from bacteria, the beacon is inert and does nothing more than sit on the cell. Nothing, that is, except attract drugs loaded with a special homing device.
“We deliver drugs at such low doses that they might as well not be there,” said Tadross. “But the homing device and GPS beacon are so efficient that the concentration of the drug on the tagged cells’ surfaces rapidly accumulates to become 1,000 times higher than anywhere else within a few minutes.”
Tadross has already demonstrated the technology’s ability in two separate trials with mice and is now eager to put it to work in multiple collaborations on Duke’s campus.
“Duke is a perfect fit for this,” said Tadross. “It has one of the strongest biomedical engineering programs in the country. The potential collaborators are perfectly aligned for this project. And my laboratory will be situated close to my main users, the neurobiology community. We’ll be at the interface of both the technology’s development and its use in answering biological questions.”
Wasting no time, Tadross already has several collaborations under way with Duke faculty members. He is collaborating with Greg Fields, a neurobiologist working on retinal research; has submitted an R01 grant with neurobiology’s Kaf Dzirasa aimed at understanding depression; and is formulating a collaboration with Warren Grill, professor of biomedical engineering, on research related to Parkinson’s disease.
Aside from the numerous collaborators, Tadross said he chose to come to Duke because of its willingness to take risks—especially on him.
“I applied for positions well before this work was published,” said Tadross. “Nobody knew about it, and many places wanted to wait and see how successful it would become before investing. Duke really saw the vision right away and aggressively pursued it. It shows that they have great vision and are willing to take a few risks.”
Source Publication: Pratt School of Engineering News
Source URL: https://pratt.duke.edu/about/news/michael-tadross-targeting-neuropharmacology-molecular-gps-technologies
Source Date: October 27, 2016