USING NANO-SENSORS TO DIAGNOSE NEUROLOGICAL DISORDERS & FOR POWERFUL BRAIN-COMPUTER INTERFACES.
A team of scientists has developed a new kind of biosensor that can be injected straight into the bloodstream, and will then travel to your brain, where they will — according to the scientists behind the project — monitor your neural activity and even potentially thoughts.
The cell-sized nanosensors, aptly named NeuroSWARM3, can cross the blood-brain barrier to the brain, where they convert neural activity into electrical signals, allowing them to be read and interpreted by machinery, according to work by a team of University of California, Santa Cruz scientists that will be presented next week at a virtual Optical Society conference.
The tech could, the researchers say, help grant extra mobility to people with disabilities in addition to helping scientists understand human thoughtbetter than before. However, they haven’t yet been tested on humans or even animals.
“NeuroSWARM3 can convert the signals that accompany thoughts to remotely measurable signals for high precision brain-machine interfacing,” lead study author A. Ali Yanik said in a press release. “It will enable people suffering from physical disabilities to effectively interact with the external world and control wearable exoskeleton technology to overcome limitations of the body. It could also pick up early signatures of neural diseases.”
It’s also a notably different approach to the problem of brain-computer interfaces from most high profile attempts, including Elon Musk’s Neuralink, which are working on implant-based solutions instead of nanosensor swarms.
During tests, the team found that their nanosensor swarm is sensitive enough to pick up on the activity of individual brain cells. Single-neuron readings aren’t new, but the ability to detect them with free-floating sensors, and especially the ability to wirelessly broadcast them through a patient’s thick skull, is an impressive technological development. If further tests continue to pan out, those capabilities could make real-time neuroscientific research simpler and neurological medicine more sophisticated.
“We are just at the beginning stages of this novel technology, but I think we have a good foundation to build on,” Yanik added. “Our next goal is to start experiments in animals.”
Abnormal levels of stress hormones such as adrenaline and cortisol are linked to a variety of mental health disorders, including depression and posttraumatic stress disorder (PTSD). MIT researchers have now devised a way to remotely control the release of these hormones from the adrenal gland, using magnetic nanoparticles.
This approach could help scientists to learn more about how hormone release influences mental health, and could eventually offer a new way to treat hormone-linked disorders, the researchers say.
“We’re looking how can we study and eventually treat stress disorders by modulating peripheral organ function, rather than doing something highly invasive in the central nervous system,” says Polina Anikeeva, an MIT professor of materials science and engineering and of brain and cognitive sciences.
To achieve control over hormone release, Dekel Rosenfeld, an MIT-Technion postdoc in Anikeeva’s group, has developed specialized magnetic nanoparticles that can be injected into the adrenal gland. When exposed to a weak magnetic field, the particles heat up slightly, activating heat-responsive channels that trigger hormone release. This technique can be used to stimulate an organ deep in the body with minimal invasiveness.
Anikeeva and Alik Widge, an assistant professor of psychiatry at the University of Minnesota and a former research fellow at MIT’s Picower Institute for Learning and Memory, are the senior authors of the study. Rosenfeld is the lead author of the paper, which appears today in Science Advances.
Anikeeva’s lab has previously devised several novel magnetic nanomaterials, including particles that can release drugs at precise times in specific locations in the body.
In the new study, the research team wanted to explore the idea of treating disorders of the brain by manipulating organs that are outside the central nervous system but influence it through hormone release. One well-known example is the hypothalamic-pituitary-adrenal (HPA) axis, which regulates stress response in mammals. Hormones secreted by the adrenal gland, including cortisol and adrenaline, play important roles in depression, stress, and anxiety.
“Some disorders that we consider neurological may be treatable from the periphery, if we can learn to modulate those local circuits rather than going back to the global circuits in the central nervous system,” says Anikeeva, who is a member of MIT’s Research Laboratory of Electronics and McGovern Institute for Brain Research.
As a target to stimulate hormone release, the researchers decided on ion channels that control the flow of calcium into adrenal cells. Those ion channels can be activated by a variety of stimuli, including heat. When calcium flows through the open channels into adrenal cells, the cells begin pumping out hormones. “If we want to modulate the release of those hormones, we need to be able to essentially modulate the influx of calcium into adrenal cells,” Rosenfeld says.
Unlike previous research in Anikeeva’s group, in this study magnetothermal stimulation was applied to modulate the function of cells without artificially introducing any genes.
To stimulate these heat-sensitive channels, which naturally occur in adrenal cells, the researchers designed nanoparticles made of magnetite, a type of iron oxide that forms tiny magnetic crystals about 1/5000 the thickness of a human hair. In rats, they found these particles could be injected directly into the adrenal glands and remain there for at least six months. When the rats were exposed to a weak magnetic field—about 50 millitesla, 100 times weaker than the fields used for magnetic resonance imaging (MRI)—the particles heated up by about 6 degrees Celsius, enough to trigger the calcium channels to open without damaging any surrounding tissue.
The heat-sensitive channel that they targeted, known as TRPV1, is found in many sensory neurons throughout the body, including pain receptors. TRPV1 channels can be activated by capsaicin, the organic compound that gives chili peppers their heat, as well as by temperature. They are found across mammalian species, and belong to a family of many other channels that are also sensitive to heat.
This stimulation triggered a hormone rush—doubling cortisol production and boosting noradrenaline by about 25 percent. That led to a measurable increase in the animals’ heart rates.
Treating stress and pain
The researchers now plan to use this approach to study how hormone release affects PTSD and other disorders, and they say that eventually it could be adapted for treating such disorders. This method would offer a much less invasive alternative to potential treatments that involve implanting a medical device to electrically stimulate hormone release, which is not feasible in organs such as the adrenal glands that are soft and highly vascularized, the researchers say.
Another area where this strategy could hold promise is in the treatment of pain, because heat-sensitive ion channels are often found in pain receptors.
“Being able to modulate pain receptors with this technique potentially will allow us to study pain, control pain, and have some clinical applications in the future, which hopefully may offer an alternative to medications or implants for chronic pain,” Anikeeva says. With further investigation of the existence of TRPV1 in other organs, the technique can potentially be extended to other peripheral organs such as the digestive system and the pancreas.
” … What’s more, five minutes of monitoring electrical activity flowing through your brain, while you do nothing but let your mind wander, can reveal how your individual brain is wired.”
We need to figure out the ethical implications before they arrive
The ability to detect electrical activity in the brain through the scalp, and to control it, will soon transform medicine and change society in profound ways. Patterns of electrical activity in the brain can reveal a person’s cognition—normal and abnormal. New methods to stimulate specific brain circuits can treat neurological and mental illnesses and control behavior. In crossing this threshold of great promise, difficult ethical quandaries confront us.
The ability to interrogate and manipulate electrical activity in the human brain promises to do for the brain what biochemistry did for the body. When you go to the doctor, a chemical analysis of your blood is used to detect your body’s health and potential disease. Forewarned that your cholesterol level is high, and you are at risk of having a stroke, you can take action to avoid suffering one. Likewise, in experimental research destined to soon enter medical practice, just a few minutes of monitoring electrical activity in your brain using EEG and other methods can reveal not only neurological illness but also mental conditions like ADHD and schizophrenia. What’s more, five minutes of monitoring electrical activity flowing through your brain, while you do nothing but let your mind wander, can reveal how your individual brain is wired.
Tapping into your wandering mind can measure your IQ, identify your cognitive strengths and weaknesses, perceive your personality and determine your aptitude for learning specific types of information. Electrical activity in a preschooler’s brain be used to can predict, for example, how well that child will be able to read when they go to school. As I recount in my new book, Electric Brain (BenBella, 2020), after having brainwaves in my idling mind recorded using EEG for only five minutes, neuropsychologist Chantel Prat at the University of Washington, in Seattle, pronounced that learning a foreign language would be difficult for me because of weak beta waves in a particular part of my cerebral cortex processing language. (Don’t ask me to speak German or Spanish, languages that I studied but never mastered.) How will this ability to know a person’s mind change education and career choices?
Neuroscientist Marcel Just and colleagues at Carnegie Mellon University are using fMRI brain imaging to decipher what a person is thinking. By using machine learning to analyze complex patterns of activity in a person’s brain when they think of a specific number or object, read a sentence, experience a particular emotion or learn a new type of information, the researchers can read minds and know the person’s specific thoughts and emotions. “Nothing is more private than a thought,” Just says, but that privacy is no longer sacrosanct.
Armed with the ability to know what a person is thinking, scientists can do even more. They can predict what a person might do. Just and his team are able to tell if a person is contemplating suicide, simply by watching how the person’s brain responds to hearing words like “death” or “happiness.” As the tragic deaths of comedian Robin Williams and celebrity chef Anthony Bourdain show, suicide often comes as a shock because people tend to conceal their thoughts of suicide, even from loved ones and therapists.
Such “brain hacking” to uncover that someone is thinking of suicide could be lifesaving. The technique applied to the Columbine high school mass murderers might have prevented the horror of two troubled teens slaughtering their classmates and teachers, as well as their own suicides. But this insight into suicidal ideation is gleaned by judging that the pattern of brain activity in an individual’s brain deviates from what is considered “normal” as defined as the average response from a large population. At what point do we remove a person from society because their brain activity deviates from what is considered normal?
The ability to control electrical activity in brain circuits has the potential to do for brain disorders what electrical stimulation has accomplished in treating cardiac disorders. By beaming electrical or magnetic pulses through the scalp, and by implanting electrodes in the brain, researchers and doctors can treat a vast array of neurological and psychiatric disorders, from Parkinson’s disease to chronic depression.
But the prospect of “mind control” frightens many, and brain stimulation to modify behavior and treat mental illness has a sordid history. In the 1970s neuropsychologist Robert Heath at Tulane University inserted electrodes into a homosexual man’s brain to “cure” him of his homosexual nature by stimulating his brain’s pleasure center. Spanish neuroscientist José Delgado used brain stimulation in monkeys, people and even a charging bull to understand how, at a neural circuit level, specific behaviors and functions are controlled—and to control them at will by pushing buttons on his radio-controlled device energizing electrodes implanted in the brain. Controlling movements, altering thoughts, evoking memories, rage and passion were all at Delgado’s fingertips. Delgado’s goal was to relieve the world of deviant behavior through brain stimulation and produce a “psychocivilized” society.
The prospect of controlling a person’s brain by electrical stimulation is disturbing for many, but current methods of treating mental and neurological disorders are woefully inadequate and far too blunt. Neurological and psychoactive drugs affect many different neural circuits in addition to the one targeted, causing wide-ranging side effects. Not only the brain but every cell in the body that interacts with the drugs, such as SSRIs for treating chronic depression, will be affected.
At present, drugs available for treating mental illness and neurological conditions are not always effective, and they are often prescribed in a trial-and-error manner. Psychosurgery, notoriously prefrontal lobotomy, also has a tragic history of abuse. Moreover, while any surgeon faces the prospect of losing the patient on the operating table, neurosurgeons face the unique risk of saving a patient’s life but losing the person. Surgical removal of brain tissue can leave patients with physical, cognitive, personality or mood dysfunctions by damaging healthy tissue, or failing to remove all the dysfunctional tissue. Electroconvulsive stimulation (ECT), to treat chronic depression and other mental illnesses, rocks the entire brain with seizure; in the wake of the electrical firestorm, the brain somehow resets itself, and many patients are helped, but not all, and sometimes there are debilitating side effects or the method fails to work.
Rather than blasting the whole brain with bolts of electricity or saturating it with drugs, it makes far more sense to stimulate the precise neural circuit that is malfunctioning. Following the success of deep brain stimulation in treating Parkinson’s disorder, doctors are now applying the same method to treat a wide range of neurological and psychiatric illnesses, from dystonia to OCD. But they are often doing so without the requisite scientific understanding of the disorder at a neural circuit level. This is especially so for mental illnesses, which are poorly represented in nonhuman animals used in research. How electrical stimulation is working to help these conditions, including Parkinson’s disease, is not fully understood. The necessary knowledge of where to put the electrodes or what strength and pattern of electrical stimulation to use is not always available. Such doctors are in effect doing experiments on their patients, but they are doing so because it helps.
Noninvasive means of modifying brainwaves and patterns of electrical activity in specific brain circuits, such as neurofeedback, rhythmic sound or flashing light, ultrasonic and magnetic stimulation through the scalp, can modify neural activity without implanting electrodes in the brain to treat neurological and mental illnesses and improve mood and cognition. The FDA approved treating depression by transcranial magnetic stimulation in 2008, and subsequently expanded approval for treating pain and migraine. Electrical current can be applied by an electrode on the scalp to stimulate or inhibit neurons from firing in appropriate brain regions.
The military is using this method to speed learning and enhance cognitive performance in pilots. The method is so simple, brain stimulation devices can be purchased over the internet or you can make one yourself from nine-volt batteries. But the DIY approach renders the user an experimental guinea pig.
New methods of precision brain stimulation are being developed. Electrical stimulation is notoriously imprecise, following the path of least resistance through brain tissue and stimulating neurons from distant regions of the brain that extend axons past the electrode. In experimental animals, very precise stimulation or inhibition of neuronal firing can be achieved by optogenetics. This method uses genetic engineering to insert light sensitive ion channels into specific neurons to control their firing very precisely using laser light beamed into the brain through a fiber-optic cable. Applied to humans, optogenetic stimulation could relieve many neurological and psychiatric disorders by precision control of specific neural circuits, but using this approach in people is not considered ethical.
CROSSING THE THRESHOLD
Against the historical backdrop of ethical lapses and concerns that curtailed brain stimulation research for mental illnesses decades ago, we are reaching a point where it will become unethical to deny people suffering from severe mental or neurological illness treatments by optogenetic or electrical stimulation of their brain, or to withhold diagnosing their conditions objectively by reading their brain’s electrical activity. The new capabilities of being able to directly monitor and manipulate the brain’s electrical activity raise daunting ethical questions from technology that has not existed previously. But the genie is out of the bottle. We better get to know her.
Nanoparticles have the ability to make their way easily into cells. For the first time, high-resolution 3D microscopy images from BESSY II offer new insights about their distribution and function.
Nanoparticles easily penetrate cells. How they are distributed there and what they do is shown for the first time by high-resolution 3D microscopy images on BESSY II. For example, certain nanoparticles accumulate preferentially in certain organelles of the cell. This can increase the energy turnover in the cell. “The cell looks like a marathon, obviously it takes energy to absorb such nanoparticles,” says lead author James McNally.
Today, nanoparticles are not only in cosmetic products, but everywhere, in the air, in water, in the soil and in food. Because they are so tiny, they easily penetrate cells in our body. This is also of interest for medical applications: Nanoparticles coated with active ingredients could be specifically introduced into cells, for example to destroy cancer cells. However, a lot has hardly been researched: for example, how nanoparticles are distributed in the cells, what they do there and how this effect depends on their size and coating.
Overview of the entire cell
A study at BESSY II has now brought new insights, where Prof. Gerd Schneider’s team can carry out X-ray microscopy images with soft, intensive X-rays. A group around the HZB biophysicist Dr. James McNally has used X-ray microscopy to examine cells with differently coated nanoparticles. The nanoparticles were exactly the same size, but coated with different active ingredients. “X-ray microscopy offers significantly better resolutions than light microscopy and a much better overview than electron microscopy,” emphasizes Schneider.
The cell looks like it has just run a marathon, apparently, the cell requires energy to absorb such nanoparticles. – Dr James McNally, Study Lead Author and Biophysicist, Helmholtz-Zentrum Berlin
Energy storage is decreasing
“X-ray microscopy allows us to see the cell as a whole, so we were able to observe this peculiarity for the first time,” explains McNally. “We found that the uptake of nanoparticles increases the number of mitochondria and endosomes, while other organelles, namely lipid droplets and multivesicular bodies, decrease,” says Burcu Kepsutlu, who carried out the experiments for her doctorate.
“ When we go on a starvation diet or run a marathon, we see similar changes in the cell – namely an increase in mitochondria and a decrease in lipid droplets,” says McNally. “Apparently it takes energy for the cell to absorb the nanoparticles, and it feels like after a marathon.”
Accumulation in organelles
For the first time, they received complete, three-dimensional, high-resolution images of the cells with the organelles contained therein, including lipid droplets, multivesicular bodies, mitochondria and endosomes. Lipid droplets act as energy stores in the cell, while mitochondria metabolize this energy.
The analysis of the images showed: The nanoparticles accumulate preferentially in cell organelles and then change the number of certain organelles in favor of other organelles. These changes were almost independent of the respective coating of the nanoparticles. This suggests that different coatings could have similar effects.Further studies with other types of nanoparticles and in particular other cell types must show whether this effect can be generalized.
3D Image of the Cell and its Organelles
X-ray microscopy offers significantly better resolution than light microscopy, and a much better overview than electron microscopy. – Gerd Schneider, Professor, Helmholtz-Zentrum Berlin
The researchers acquired, for the first time, comprehensive, 3D, high-resolution images of the cells treated with the nanoparticles, where the organelles—including mitochondria, lipid droplets, endosomes, and multivesicular bodies—were contained within. Lipid droplets act as energy stores in the cell, while mitochondria metabolize this energy.
Accumulation of Nanoparticles
Investigation of the images revealed that the nanoparticles tend to build up preferentially within a subset of the cell organelles. Moreover, the nanoparticles alter the number of particular organelles at the cost of other organelles.
The variations in the numbers of organelles were identical irrespective of the nanoparticle coating. This shows that various different types of nanoparticle coatings may produce a similar effect. Further research with other cell types and with other nanoparticle coatings is necessary to assess how general this effect is.
Number of Lipid Droplets Decreases
“X-ray microscopy allows us to see the cell as a whole, so we were able to observe this behavior for the first time,” McNally explained.
We found that the absorption of such nanoparticles increases the number of mitochondria and endosomes, while other organelles, namely lipid droplets and multivesicular bodies, decrease. – Burcu Kepsutlu, Researcher, Helmholtz-Zentrum Berlin
Kepsutlu performed the experiments for her doctorate.
ACS Nano (2020): Cells Subject Major Changes in the Quantity of Cytoplasmic Organelles after Uptake of Gold Nanoparticles with Biologically Relevant Surface Coatings, Burcu Kepsutlu, Virginia Wycisk, Katharina Achazi, Sergey Kapishnikov, Ana Joaquina Pérez-Berná, Peter Guttmann, Antje Cossmer , Eva Pereiro, Helge Ewers, Matthias Ballauff, Gerd Schneider, James G. McNally
The cancer nanomedicine field is heading in two directions — debating whether the clinical translation of nanomaterials should be accelerated or whether some of the long-standing drug delivery paradigms have to be challenged first.
At the International Conference on Nanomedicine and Nanobiotechnology that was held in Munich, 16–18 October, the most striking talk was not given by a scientist, nor a clinician, but by Lora Kelly — a six-year pancreatic cancer survivor.
By telling her story of how it actually feels to receive chemotherapy, immunotherapy and radiation, she reminded everyone about the urgent need to improve cancer treatment regimes. The main goal remains to kill the cancer; however, it has become more evident how equally important it is to improve the quality of life of patients during treatment, that is, to reduce the often devastating side effects.
This is where nanomedicine comes in. Nanomaterials have the potential to direct drugs to specific tissues and to improve drug activity, as well as its transport in blood. Indeed, nanoparticles could ensure that therapeutic treatments act locally and not systemically, and thus improve anti-cancer efficacy while reducing damage to healthy tissues.
However, recent setbacks, including the bankruptcy of a prominent nanomedicine company1 and the less than 1% delivery efficiency claim2 (quoted at every cancer nanomedicine conference on at least one slide) have stirred discussions about the usefulness of nanomedicines for cancer treatment.
Some argue that the field is stuck in preclinical animal models owing to a lack of insight into the basics of nanomaterial–tissue interactions in the human body, from traversing biological barriers to clearance.
While less than 1% delivery efficiency might not be much, pharmacological parameters, such as peak drug concentration, clearance rate and elimination half-life, are often not as bad3, and these should be considered with equal importance.
Moreover, there are also clinical success stories of nanomedicines. Onpattro, a lipid nanoparticle-based short interfering RNA (siRNA) drug for the treatment of polyneuropathies, was approved by the US Food and Drug Administration in 2018, marking the first approved nanoparticle for nucleic acid delivery.
In a Comment in this issue, Akinc et al. report the endeavour of developing this nanomedicine, from the idea to preclinical and clinical testing4, to the final approval. There are further many opportunities for nanomaterials complementary to drug delivery, including bioimaging, modulation of the immune system and the tumour microenvironment, and, of course, local administration.
From an Editorial perspective, the ongoing discussion is reflected in the many manuscripts we receive, which often include both basic investigations and claims of clinical application. Naturally, this can lead to mixed peer-review reports echoing the disconnection between clinical vision and fundamental science.
Reviewers with a background in materials science or biomedical engineering often point out the gaps in the basic understanding of how a nanomaterial interacts with the biological environment, and clinicians would like to see more preclinical animal work. Indeed, a thorough fundamental study does not always need the claim of a specific application, as it might be exactly such overstatements that have precluded the field to deliver on the promise of revolutionizing drug delivery.
Along the same line, studies of nanoparticle transport through specific cells or nanomaterial–cell interactions at a molecular scale, do not necessarily require complex in vivo models; by contrast, applied studies claiming a therapeutic benefit need a robust in vivo validation in a relevant animal model — preferably with an intact immune system.
Going back to the goal of improving a patient’s life, possible side effects and impact on tissues other than tumours should also be reported. However, this data is often found, at best, somewhere in the supplementary information.
Regardless of the mouse model, the discussion rarely goes beyond the weight loss and the histology of organs. If the idea is to improve therapies, side effects need to be thoroughly investigated — even at an early preclinical stage. Similarly, we will make sure that studies claiming superiority of a therapeutic treatment compared to state-of-the-art treatment regimes are reviewed by clinical experts to ensure that clinical translation is — at least — possible and feasible.
Also, keeping regulatory requirements in mind, the more complex the new nanoparticle or nanoscale delivery agent, the more difficult it will be to get approval; and this is a valid criticism.
At Nature Nanotechnology, we consider both clinically relevant manuscripts and fundamental studies investigating the various barriers nanoparticles face on their journey through the body. We endeavour to assess the manuscripts we receive as fairly and consistently as possible, with the ongoing discussion in mind. We look forward to learning about possible alternative mechanisms and the heterogeneity of the enhanced permeability and retention (EPR) effect, nanoparticle interactions in the liver, spleen and kidneys during clearance, migration of nanomaterials through the tumour microenvironment, and nanoparticle uptake, lysosomal escape (or not) and transport in different cell types.
Such studies will shine a light on nanomaterial–tissue interactions, and also greatly contribute to the development of improved nanomedicines. Equally important, detailed investigations of nanoparticles in preclinical animal models as well as relevant organoid cultures will allow the optimization of treatment strategies and the reduction of side effects. Regardless of the aim, we urge authors to calibrate their claims in accordance with their data and scope of the investigation to preserve trust in cancer nanomedicine as a whole.
Florida Polytechnic University professor Dr. Ajeet Kaushik received the 2019 USERN Prize in biological sciences, an international award recognizing his work in the field of nanomaterials for the detection and treatment of diseases.
Florida Polytechnic University professor Dr. Ajeet Kaushik is determined to make detecting and treating diseases easy, accessible, and precise through the use of nanomaterials for biosensing and medicine.
His extensive work and resolute desire to improve the delivery of healthcare has earned Kaushik the prestigious Universal Scientific Education Research Network (USERN) Prize. He was named a laureate in the field of biological sciences during the group’s fourth annual congress on Nov. 8 in Budapest, Hungary.
USERN, a non-governmental, non-profit organization and network dedicated to non-military scientific advances, is committed to exploring science beyond international borders.
“I was speechless for a while,” said Kaushik, who is an assistant professor of chemistry at Florida Polytechnic University.
Kaushik did not attend the awards ceremony in person but did submit a video to be played at the event. He was among hundreds vying for the prize and one of five people who were recognized in different areas of study.
His submitted project, Nano-Bio-Technology for Personalized Health Care, focuses on using nanomaterials to create biosensors that will detect the markers of a disease at very low levels.
“Biosensing is not a new concept, but now we are making devices that are smarter and more capable,” Kaushik said.
He cited the recent zika virus epidemic that affected pregnant women and their fetuses, leading to significant health complications upon birth.
“There was a demand to have a system that could detect the virus protein at a very low level, but there was no device. There was no diagnostic system,” he said.
Kaushik worked on the development of a smart zika sensor that could detect the disease at these low levels.
“The kind of systems I’m focusing on can be customized in a way that we carry like a cell phone and do the tests wherever we need to do them,” he said.
In addition to using nanotechnology for the detection of diseases like zika, his research on nanoparticles is advancing efforts to precisely deliver medicine to a specific part of the body without affecting surrounding tissue or other parts of the body.
“The drugs we use now do not go only where they need to go, or sometimes they have side effects. We are treating one disease but creating other symptoms,” Kaushik said. “I’m exploring nanotechnology that can carry a drug, selectively go to a place, and release the drug so we avoid using excessive drugs.”
This nanomedicine could be used to precisely target brain tumors or other difficult-to-treat conditions.
He has published papers in scientific journals about this work and also holds multiple patents.
“My whole approach is using smart material science for better health for everybody, which is accessible to everybody everywhere,” Kaushik said.
In addition to his USERN prize, Kaushik was named a USERN junior ambassador for 2020 and will work to advance the organization’s mission in the United States.
About Florida Polytechnic University: Florida Polytechnic University is accredited by the Southern Association of Colleges and Schools Commission on Colleges and is a member of the State University System of Florida. It is the only state university dedicated exclusively to STEM and offers ABET accredited degrees. Florida Poly is a powerful economic engine within the state of Florida, blending applied research with industry partnerships to give students an academically rigorous education with real-world relevance. Connect with Florida Poly.
During embryonic development, the entire nervous system, the skin and the sensory organs emerge from a single sheet of cells known as the ectoderm. While there have been extensive studies of how this sheet forms all these derivatives, it hasn’t been possible to study the process in humans – until now.
Rice bioscientist Aryeh Warmflash, graduate student George Britton and their colleagues have created a system in which all of the major cell types of ectoderm are formed in a culture dish in a pattern similar to that seen in embryos.This technique, based on controlling the geometry of stem cell colonies with microscale patterns, has helped them make the most comprehensive analysis yet of signaling pathways that drive patterning of human ectoderm.
“There are very few possible signals the embryo uses to generate the wide variety of cell types that arise,” Britton said. “We want to understand the timing of these signals and how the cells interpret them in time to generate this variety.”
It revealed that the balance between two signaling pathways, BMP and Wnt, are both critical, and even a bit adaptable as they orchestrate patterning in the ectoderm. The logic they employ ultimately drives ectodermal cells to their fates, but the research showed they can take more than one road to get there.
Britton said the micro-patterned plates and a better understanding of how the signaling pathways work let them manipulate stem cell colonies to form unusual patterns at the start, but ultimately they always seemed to converge at the same place. “We found different trajectories of the signals that arrived at the same pattern,” he said. That suggested the system by which stem cells become neurons, neural crest cells, neurogenic placodes and epidermis cells is pretty robust.
“A lot of people are interested in the transcription factor network that directs neural crest emergence, so this is a powerful system to dissect the signals that contribute to that logic,” Britton said. “That was one thing we feel we contributed to the field.
“There’s also the idea that cells that have the ability to interpret relative levels of BMP and Wnt to incorporate the appropriate fate decision,” he said. “In the embryo, cells are moving around quite a bit in a space where signals and the ligands they’re exposed to are also moving around. It might be that cells are reading the relative levels to determine a certain fate.”
The researchers observed that the relative activity of BMP and Wnt signaling determines cells’ decisions to become either neural crest or placodal cells, while BMP alone initiates and controls the size of the surface ectoderm, all within about the first four days.
“Four days is about right in the sense that cells are starting to make decisions: ‘I’m going to be a placodal cell, I’m going to be a neural crest cell, I’m going to be neural fate and I’m going to an epidermal fate,” Britton said.
“We see that approximately a day or two after BMP treatment. But it’s hard to put a finger on whether these are the final patterns,” he said. “We’d have to do a more careful observation to make sure those placodal cells don’t change to neural crest cells, or vice versa. That will give us information on how these lineages and fates settle into a final pattern, maybe by day 6 or 7.”
He said future studies will further refine their understanding of how signaling patterns work, as well as how the development of all the germ layers collaborate.
“Until now, studies of human stem cells differentiating to ectodermal fates were mostly about how to get all the cells in your culture dish to become a particular cell type; for example, how to make a dish full of neurons,” Warmflash said. “We are interested in a different question: How do cells interact with each other to make patterns of different cell fates? The system we developed does this outside the embryo and is allowing us to begin to tackle this question.”
IMAGE: IN STUDYING THE EFFECTIVENESS OF THE NANOMESH, TWO ANTIBIOTICS, COLISTIN AND VANCOMYCIN, WERE ADDED TOGETHER WITH GOLD NANOPARTICLES TO THE MESH, BEFORE THEY WERE TESTED OVER A 14 DAY PERIOD CREDIT: FLINDERS UNIVERSITY … view more
The fight against global antibiotic resistance has taken a major step forward with scientists discovering a concept for fabricating nanomeshes as an effective drug delivery system for antibiotics.
Health experts are increasingly concerned about the rise in medication resistant bacteria.
Flinders University researchers and collaborators in Japan have produced a nanomesh that is capable of delivering drug treatments.
In studying the effectiveness of the nanomesh, two antibiotics, Colistin and Vancomycin, were added together with gold nanoparticles to the mesh, before they were tested over a 14 day period by PHD student Melanie Fuller.
Flinders Institute for Nanoscience and Technology Associate Professor Ingo Koeper says 20cm by 15cm pieces of mesh were produced which contain fibres 200 nm in diameter. These meshes are produced using a process called electrospinning with parameters being optimised to ensure the mesh material was consistent.
“In order to deliver the antibiotics to a specific area, the antibiotics were embedded into the mesh produced using a technique called electrospinning, which has gained considerable interest in the biomedical community as it offers promise in many applications including wound management, drug delivery and antibiotic coatings,” says Assoc Prof. Koeper
“A high voltage is then applied between the needle connected to the syringe, and the collector plate which causes the polymer solution to form a cone as it leaves the syringe, at which point the electrostatic forces release a jet of liquid.”
“Small charged nanoparticles altered the release of the antibiotics from the nanomesh. The addition of gold nanoparticles likely neutralised charge, causing the antibiotic to migrate toward the centre of the fibre, prolonging its release.”
The results also suggest dosages could be reduced when compared to traditional drugs which can also diminish potential side effects and complications.
“Although the dosage is reduced compared to an oral dosage, the concentration of antibiotics delivered to the infection site can still be higher, ensuring the bacteria cannot survive which will reduce instances of resistance.”
“This research, as a proof of concept, suggests an opportunity for fabricating nanomeshes which contain gold nanoparticles as a drug treatment for antibiotics.”
Working with Dr. Harriet Whiley, a Flinders environmental health scientists, the researchers studied how the release of the drugs affected the growth of E. Coli. The in vitro study confirmed Colistin with negatively charged gold nanoparticles produced the most efficient nanomesh, significantly affecting bacterial growth.
“Further investigation is needed to determine if other small charged particles affect the release of drugs and how it affects the release over time. As it is a pharmaceutical application, the stability of the mesh under different storage conditions as well as the toxicological properties also need to be evaluated.”
Just as the steam engine set the stage for the Industrial Revolution, and micro transistors sparked the digital age, nanoscale devices made from DNA are opening up a new era in bio-medical research and materials science.
The journal Science describes the emerging uses of DNA mechanical devices in a “Perspective” article by Khalid Salaita, a professor of chemistry at Emory University, and Aaron Blanchard, a graduate student in the Wallace H. Coulter Department of Biomedical Engineering, a joint program of Georgia Institute of Technology and Emory.
The article heralds a new field, which Blanchard dubbed “DNA mechanotechnology,” to engineer DNA machines that generate, transmit and sense mechanical forces at the nanoscale.
“For a long time,” Salaita says, “scientists have been good at making micro devices, hundreds of times smaller than the width of a human hair. It’s been more challenging to make functional nano devices, thousands of times smaller than that. But using DNA as the component parts is making it possible to build extremely elaborate nano devices because the DNA parts self-assemble.”
DNA, or deoxyribonucleic acid, stores and transmits genetic information as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C) and thymine (T). The DNA bases have a natural affinity to pair up with each other—A with T and C with G. Synthetic strands of DNA can be combined with natural DNA strands from bacteriophages. By moving around the sequence of letters on the strands, researchers can get the DNA strands to bind together in ways that create different shapes. The stiffness of DNA strands can also easily be adjusted, so they remain straight as a piece of dry spaghetti or bend and coil like boiled spaghetti.
The idea of using DNA as a construction material goes back to the 1980s, when biochemist Nadrian Seeman pioneered DNA nanotechnology. This field uses strands DNA to make functional devices at the nanoscale. The ability to make these precise, three-dimensional structures began as a novelty, nicknamed DNA origami, resulting in objects such as a microscopic map of the world and, more recently, the tiniest-ever game of tic-tac-toe, played on a DNA board.
Work on novelty objects continues to provide new insights into the mechanical properties of DNA. These insights are driving the ability to make DNA machines that generate, transmit and sense mechanical forces.
“If you put together these three main components of mechanical devices, you begin to get hammers and cogs and wheels and you can start building nano machines,” Salaita says. “DNA mechanotechnology expands the opportunities for research involving biomedicine and materials science. It’s like discovering a new continent and opening up fresh territory to explore.”
Potential uses for such devices include drug delivery devices in the form of nano capsules that open up when they reach a target site, nano computers and nano robots working on nanoscale assembly lines.
The use of DNA self-assembly by the genomics industry, for biomedical research and diagnostics, is further propelling DNA mechanotechnology, making DNA synthesis inexpensive and readily available. “Potentially anyone can dream up a nano-machine design and make it a reality,” Salaita says.
He gives the example of creating a pair of nano scissors. “You know that you need two rigid rods and that they need to be linked by a pivot mechanism,” he says. “By tinkering with some open-source software, you can create this design and then go onto a computer and place an order to custom synthesize your design. You’ll receive your order in a tube. You simply put the tube contents into a solution, let your device self-assemble, and then use a microscope to see if it works the way you thought that it would.”
Salaita’s lab is one of only about 100 around the world working at the forefront of DNA mechanotechnology. He and Blanchard developed the world’s strongest synthetic DNA-based motor, which was recently reported in Nano Letters.
A key focus of Salaita’s research is mapping and measuring how cells push and pull to learn more about the mechanical forces involved in the human immune system.
Salaita developed the first DNA force gauges for cells, providing the first detailed view of the mechanical forces that one molecule applies to another molecule across the entire surface of a living cell. Mapping such forces may help to diagnose and treat diseases related to cellular mechanics. Cancer cells, for instance, move differently from normal cells, and it is unclear whether that difference is a cause or an effect of the disease.
In 2016, Salaita used these DNA force gauges to provide the first direct evidence for the mechanical forces of T cells, the security guards of the immune system. His lab showed how T cells use a kind of mechanical “handshake” or tug to test whether a cell they encounter is a friend or foe. These mechanical tugs are central to a T cell’s decision for whether to mount an immune response.
“Your blood contains millions of different types of T cells, and each T cell is evolved to detect a certain pathogen or foreign agent,” Salaita explains. “T cells are constantly sampling cells throughout your body using these mechanical tugs. They bind and pull on proteins on a cell’s surface and, if the bond is strong, that’s a signal that the T cell has found a foreign agent.”
Salaita’s lab built on this discovery in a paper recently published in the Proceedings of the National Academy of Sciences (PNAS). Work led by Emory chemistry graduate student Rong Ma refined the sensitivity of the DNA force gauges. Not only can they detect these mechanical tugs at a force so slight that it is nearly one-billionth the weight of a paperclip, they can also capture evidence of tugs as brief as the blink of an eye.
The research provides an unprecedented look at the mechanical forces involved in the immune system. “We showed that, in addition to being evolved to detect certain foreign agents, T cells will also apply very brief mechanical tugs to foreign agents that are a near match,” Salaita says. “The frequency and duration of the tug depends on how closely the foreign agent is matched to the T cell receptor.”
The result provides a tool to predict how strong of an immune response a T cell will mount. “We hope this tool may eventually be used to fine tune immunotherapies for individual cancer patients,” Salaita says. “It could potentially help engineer T cells to go after particular cancer cells.”
Researchers have found a way to dispatch minute fragments of palladium—a key component in motor manufacture, electronics and the oil industry—inside cancerous cells.
Tiny extracts of a precious metal used widely in industry could play a vital role in new cancer therapies.
Scientists have long known that the metal, used in catalytic converters to detoxify exhaust, could be used to aid cancer treatment but, until now, have been unable to deliver it to affected areas.
A molecular shuttle system that targets specific cancer cells has been created by a team at the University of Edinburgh and the Universidad de Zaragoza in Spain.
The new method, which exploits palladium’s ability to accelerate—or catalyse—chemical reactions, mimics the process some viruses use to cross cell membranes and spread infection.
The team has used bubble-like pouches that resemble the biological carriers known as exosomes, which can transport essential proteins and genetic material between cells. These exosomes exit and enter cells, dump their content, and influence how the cells behave.
This targeted transport system, which is also exploited by some viruses to spread infection to other cells and tissues, inspired the team to investigate their use as shuttles of therapeutics.
The researchers have now shown that this complex communication network can be hijacked. The team created exosomes derived from lung cancer cells and cells associated with glioma—a tumour that occurs in the brain and spinal cord—and loaded them with palladium catalysts.
These artificial exosomes act as Trojan horses, taking the catalysts—which work in tandem with an existing cancer drug- straight to primary tumours and metastatic cells.
Having proved the concept in laboratory tests, the researchers have now been granted a patent that gives them exclusive rights to trial palladium-based therapies in medicine.
The study was funded by the Engineering and Physical Sciences Research Council and the European Research Council. It has been published in the journal, Nature Catalysis.
Professor Asier Unciti-Broceta, from the University of Edinburgh’s CRUK Edinburgh Centre, said: “We have tricked exosomes naturally released by cancer cells into taking up a metal that will activate chemotherapy drugs just inside the cancer cells, which could leave healthy cells untouched.”
Professor Jesús Santamaría, of the Universidad de Zaragoza, said: “This has the potential to be a very exciting technology. It could allow us to target the main tumour and metastatic cells, thus reducing the side effects of chemotherapy without compromising the treatment.”
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