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Monday, June 29th, 2020
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| 10:59a |
Producing a gaseous messenger molecule inside the body, on demand Nitric oxide is an important signaling molecule in the body, with a role in building nervous system connections that contribute to learning and memory. It also functions as a messenger in the cardiovascular and immune systems.
But it has been difficult for researchers to study exactly what its role is in these systems and how it functions. Because it is a gas, there has been no practical way to direct it to specific individual cells in order to observe its effects. Now, a team of scientists and engineers at MIT and elsewhere has found a way of generating the gas at precisely targeted locations inside the body, potentially opening new lines of research on this essential molecule’s effects.
The findings are reported today in the journal Nature Nanotechnology, in a paper by MIT professors Polina Anikeeva, Karthish Manthiram, and Yoel Fink; graduate student Jimin Park; postdoc Kyoungsuk Jin; and 10 others at MIT and in Taiwan, Japan, and Israel.
“It’s a very important compound,” Anikeeva says. But figuring out the relationships between the delivery of nitric oxide to particular cells and synapses, and the resulting higher-level effects on the learning process has been difficult. So far, most studies have resorted to looking at systemic effects, by knocking out genes responsible for the production of enzymes the body uses to produce nitric oxide where it’s needed as a messenger.
But that approach, she says, is “very brute force. This is a hammer to the system because you’re knocking it out not just from one specific region, let’s say in the brain, but you essentially knock it out from the entire organism, and this can have other side effects.”
Others have tried introducing compounds into the body that release nitric oxide as they decompose, which can produce somewhat more localized effects, but these still spread out, and it is a very slow and uncontrolled process.
The team’s solution uses an electric voltage to drive the reaction that produces nitric oxide. This is similar to what is happening on a much larger scale with some industrial electrochemical production processes, which are relatively modular and controllable, enabling local and on-demand chemical synthesis. “We've taken that concept and said, you know what? You can be so local and so modular with an electrochemical process that you can even do this at the level of the cell,” Manthiram says. “And I think what’s even more exciting about this is that if you use electric potential, you have the ability to start production and stop production in a heartbeat.”
The team’s key achievement was finding a way for this kind of electrochemically controlled reaction to be operated efficiently and selectively at the nanoscale. That required finding a suitable catalyst material that could generate nitric oxide from a benign precursor material. They found that nitrite offered a promising precursor for electrochemical nitric oxide generation.
“We came up with the idea of making a tailored nanoparticle to catalyze the reaction,” Jin says. They found that the enzymes that catalyze nitric oxide generation in nature contain iron-sulfur centers. Drawing inspiration from these enzymes, they devised a catalyst that consisted of nanoparticles of iron sulfide, which activates the nitric oxide-producing reaction in the presence of an electric field and nitrite. By further doping these nanoparticles with platinum, the team was able to enhance their electrocatalytic efficiency.
To miniaturize the electrocatalytic cell to the scale of biological cells, the team has created custom fibers containing the positive and negative microelectrodes, which are coated with the iron sulfide nanoparticles, and a microfluidic channel for the delivery of sodium nitrite, the precursor material. When implanted in the brain, these fibers direct the precursor to the specific neurons. Then the reaction can be activated at will electrochemically, through the electrodes in the same fiber, producing an instant burst of nitric oxide right at that spot so that its effects can be recorded in real-time.
As a test, they used the system in a rodent model to activate a brain region that is known to be a reward center for motivation and social interaction, and that plays a role in addiction. They showed that it did indeed provoke the expected signaling responses, demonstrating its effectiveness.
Anikeeva says this “would be a very useful biological research platform, because finally, people will have a way to study the role of nitric oxide at the level of single cells, in whole organisms that are performing tasks.” She points out that there are certain disorders that are associated with disruptions of the nitric oxide signaling pathway, so more detailed studies of how this pathway operates could help lead to treatments.
The method could be generalizable, Park says, as a way of producing other molecules of biological interest within an organism. “Essentially we can now have this really scalable and miniaturized way to generate many molecules, as long as we find the appropriate catalyst, and as long as we find an appropriate starting compound that is also safe.” This approach to generating signaling molecules in situ could have wide applications in biomedicine, he says.
“One of our reviewers for this manuscript pointed out that this has never been done — electrolysis in a biological system has never been leveraged to control biological function,” Anikeeva says. “So, this is essentially the beginning of a field that could potentially be very useful” to study molecules that can be delivered at precise locations and times, for studies in neurobiology or any other biological functions. That ability to make molecules on demand inside the body could be useful in fields such as immunology or cancer research, she says.
The project got started as a result of a chance conversation between Park and Jin, who were friends working in different fields — neurobiology and electrochemistry. Their initial casual discussions ended up leading to a full-blown collaboration between several departments. But in today’s locked-down world, Jin says, such chance encounters and conversations have become less likely. “In the context of how much the world has changed, if this were in this era in which we’re all apart from each other, and not in 2018, there is some chance that this collaboration may just not ever have happened.”
“This work is a milestone in bioelectronics,” says Bozhi Tian, an associate professor of chemistry at the University of Chicago, who was not connected to this work. “It integrates nanoenabled catalysis, microfluidics, and traditional bioelectronics … and it solves a longstanding challenge of precise neuromodulation in the brain, by in situ generation of signaling molecules. This approach can be widely adopted by the neuroscience community and can be generalized to other signaling systems, too.”
Besides MIT, the team included researchers at National Chiao Tung University in Taiwan, NEC Corporation in Japan, and the Weizman Institute of Science in Israel. The work was supported by the National Institute for Neurological Disorders and Stroke, the National Institutes of Health, the National Science Foundation, and MIT’s Department of Chemical Engineering. | | 11:00a |
Engineers use “DNA origami” to identify vaccine design rules By folding DNA into a virus-like structure, MIT researchers have designed HIV-like particles that provoke a strong immune response from human immune cells grown in a lab dish. Such particles might eventually be used as an HIV vaccine.
The DNA particles, which closely mimic the size and shape of viruses, are coated with HIV proteins, or antigens, arranged in precise patterns designed to provoke a strong immune response. The researchers are now working on adapting this approach to develop a potential vaccine for SARS-CoV-2, and they anticipate it could work for a wide variety of viral diseases.
“The rough design rules that are starting to come out of this work should be generically applicable across disease antigens and diseases,” says Darrell Irvine, who is the Underwood-Prescott Professor with appointments in the departments of Biological Engineering and Materials Science and Engineering; an associate director of MIT’s Koch Institute for Integrative Cancer Research; and a member of the Ragon Institute of MGH, MIT, and Harvard.
Irvine and Mark Bathe, an MIT professor of biological engineering and an associate member of the Broad Institute of MIT and Harvard, are the senior authors of the study, which appears today in Nature Nanotechnology. The paper’s lead authors are former MIT postdocs Rémi Veneziano and Tyson Moyer.
DNA design
Because DNA molecules are highly programmable, scientists have been working since the 1980s on methods to design DNA molecules that could be used for drug delivery and many other applications, most recently using a technique called DNA origami that was invented in 2006 by Paul Rothemund of Caltech.
In 2016, Bathe’s lab developed an algorithm that can automatically design and build arbitrary three-dimensional virus-like shapes using DNA origami. This method offers precise control over the structure of synthetic DNA, allowing researchers to attach a variety of molecules, such as viral antigens, at specific locations.
“The DNA structure is like a pegboard where the antigens can be attached at any position,” Bathe says. “These virus-like particles have now enabled us to reveal fundamental molecular principles of immune cell recognition for the first time.”
Natural viruses are nanoparticles with antigens arrayed on the particle surface, and it is thought that the immune system (especially B cells) has evolved to efficiently recognize such particulate antigens. Vaccines are now being developed to mimic natural viral structures, and such nanoparticle vaccines are believed to be very effective at producing a B cell immune response because they are the right size to be carried to the lymphatic vessels, which send them directly to B cells waiting in the lymph nodes. The particles are also the right size to interact with B cells and can present a dense array of viral particles.
However, determining the right particle size, spacing between antigens, and number of antigens per particle to optimally stimulate B cells (which bind to target antigens through their B cell receptors) has been a challenge. Bathe and Irvine set out to use these DNA scaffolds to mimic such viral and vaccine particle structures, in hopes of discovering the best particle designs for B cell activation.
“There is a lot of interest in the use of virus-like particle structures, where you take a vaccine antigen and array it on the surface of a particle, to drive optimal B-cell responses,” Irvine says. “However, the rules for how to design that display are really not well-understood.”
Other researchers have tried to create subunit vaccines using other kinds of synthetic particles, such as polymers, liposomes, or self-assembling proteins, but with those materials, it is not possible to control the placement of viral proteins as precisely as with DNA origami.
For this study, the researchers designed icosahedral particles with a similar size and shape as a typical virus. They attached an engineered HIV antigen related to the gp120 protein to the scaffold at a variety of distances and densities. To their surprise, they found that the vaccines that produced the strongest response B cell responses were not necessarily those that packed the antigens as closely as possible on the scaffold surface.
“It is often assumed that the higher the antigen density, the better, with the idea that bringing B cell receptors as close together as possible is what drives signaling. However, the experimental result, which was very clear, was that actually the closest possible spacing we could make was not the best. And, and as you widen the distance between two antigens, signaling increased,” Irvine says.
The findings from this study have the potential to guide HIV vaccine development, as the HIV antigen used in these studies is currently being tested in a clinical trial in humans, using a protein nanoparticle scaffold.
Based on their data, the MIT researchers worked with Jayajit Das, a professor of immunology and microbiology at Ohio State University, to develop a model to explain why greater distances between antigens produce better results. When antigens bind to receptors on the surface of B cells, the activated receptors crosslink with each other inside the cell, enhancing their response. However, the model suggests that if the antigens are too close together, this response is diminished.
Beyond HIV
In recent months, Bathe’s lab has created a variant of this vaccine with the Aaron Schmidt and Daniel Lingwood labs at the Ragon Institute, in which they swapped out the HIV antigens for a protein found on the surface of the SARS-CoV-2 virus. They are now testing whether this vaccine will produce an effective response against the coronavirus SARS-CoV-2 in isolated B cells, and in mice.
“Our platform technology allows you to easily swap out different subunit antigens and peptides from different types of viruses to test whether they may potentially be functional as vaccines,” Bathe says.
Because this approach allows for antigens from different viruses to be carried on the same DNA scaffold, it could be possible to design variants that target multiple types of coronaviruses, including past and potentially future variants that may emerge, the researchers say.
Bathe was recently awarded a grant from the Fast Grants Covid-19 fund to develop their SARS-CoV-2 vaccine. The HIV research presented in the Nature Nanotechnology paper was funded by the Human Frontier Science Program, the U.S. Office of Naval Research, the U.S. Army Research Office through MIT’s Institute for Soldier Nanotechnologies, the Ragon Institute, and the U.S. National Institutes of Health. | | 3:35p |
The MIT Press and UC Berkeley launch Rapid Reviews: COVID-19 The MIT Press has announced the launch of Rapid Reviews: COVID-19 (RR:C19), an open access, rapid-review overlay journal that will accelerate peer review of Covid-19-related research and deliver real-time, verified scientific information that policymakers and health leaders can use.
Scientists and researchers are working overtime to understand the SARS-CoV-2 virus and are producing an unprecedented amount of preprint scholarship that is publicly available online but has not been vetted yet by peer review for accuracy. Traditional peer review can take four or more weeks to complete, but RR:C19’s editorial team, led by Editor-in-Chief Stefano M. Bertozzi, professor of health policy and management and dean emeritus of the School of Public Health at the University of California at Berkeley, will produce expert reviews in a matter of days.
Using artificial intelligence tools, a global team will identify promising scholarship in preprint repositories, commission expert peer reviews, and publish the results on an open access platform in a completely transparent process. The journal will strive for disciplinary and geographic breadth, sourcing manuscripts from all regions and across a wide variety of fields, including medicine; public health; the physical, biological, and chemical sciences; the social sciences; and the humanities. RR:C19 will also provide a new publishing option for revised papers that are positively reviewed.
Amy Brand, director of the MIT Press sees the no-cost open access model as a way to increase the impact of global research and disseminate high-quality scholarship. “Offering a peer-reviewed model on top of preprints will bring a level of diligence that clinicians, researchers, and others worldwide rely on to make sound judgments about the current crisis and its amelioration,” says Brand. “The project also aims to provide a proof-of-concept for new models of peer-review and rapid publishing for broader applications.”
Made possible by a $350,000 grant from the Patrick J. McGovern Foundation and hosted on PubPub, an open-source publishing platform from the Knowledge Futures Group for collaboratively editing and publishing journals, monographs, and other open access scholarly content, RR:C19 will limit the spread of misinformation about Covid-19, according to Bertozzi.
“There is an urgent need to validate — or debunk — the rapidly growing volume of Covid-19-related manuscripts on preprint servers,” explains Bertozzi. “I'm excited to be working with the MIT Press, the Patrick J. McGovern Foundation, and the Knowledge Futures Group to create a novel publishing model that has the potential to more efficiently translate important scientific results into action. We are also working with COVIDScholar, an initiative of UC Berkeley and Lawrence Berkeley National Lab, to create unique AI/machine learning tools to support the review of hundreds of preprints per week.”
“This project signals a breakthrough in academic publishing, bringing together urgency and scientific rigor so the world’s researchers can rapidly disseminate new discoveries that we can trust,” says Vilas Dhar, trustee of the Patrick J. McGovern Foundation. “We are confident the RR:C19 journal will quickly become an invaluable resource for researchers, public health officials, and healthcare providers on the frontline of this pandemic. We’re also excited about the potential for a long-term transformation in how we evaluate and share research across all scientific disciplines.”
On the collaboration around this new journal, Travis Rich, executive director of the Knowledge Futures Group notes, “At a moment when credibility is increasingly crucial to the well-being of society, we’re thrilled to be partnering with this innovative journal to expand the idea of reviews as first-class research objects, both on PubPub and as a model for others.
RR:C19 will publish its first reviews in July 2020 and is actively recruiting potential reviewers and contributors. To learn more about this project and its esteemed editorial board, visit rapidreviewscovid19.mitpress.mit.edu. |
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