magnetic challenge

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by Silviu “Silview” Costinescu

I can’t find the irony because I’m distracted by the facts.
The highlights in the text are mine, they are the key.

Flipping a Switch Inside the Head

With new technology, scientists are able to exert wireless control over brain cells of mice with just the push of a button. The first thing they did was make the mice hungry.

By W. Wayt Gibbs, APRIL 1, 2017

READY YOUR TINFOIL HATS—mind control is not as far-fetched an idea as it may seem. In Jeffrey M. Friedman’s laboratory, it happens all the time, though the subjects are mice, not people.

Friedman and his colleagues have demonstrated a radio-operated remote control for the appetite and glucose metabolism of mice—a sophisticated technique to wirelessly alter neurons in the animals’ brains. At the flick of a switch, they are able to make mice hungry—or suppress their appetite—while the mice go about their lives normally. It’s a tool they are using to unravel the neurological basis of eating, and it is likely to have applications for studies of other hard-wired behaviors.

Friedman, Marilyn M. Simpson Professor, has been working on the technique for several years with Sarah Stanley, a former postdoc in his lab who now is assistant professor at the Icahn School of Medicine at Mount Sinai, and collaborators at Rensselaer Polytechnic Institute. Aware of the limitations of existing methods for triggering brain cells in living animals, the group set out to invent a new way. An ideal approach, they reasoned, would be as noninvasive and non-damaging as possible. And it should work quickly and repeatedly.

Although there are other ways to deliver signals to neurons, each has its limitations. In deep-brain stimulation, for example, scientists thread a wire through the brain to place an electrode next to the target cells. But the implant can damage nearby cells and tissues in ways that interfere with normal behavior. Optogenetics, which works similarly but uses fiber optics and a pulse of light rather than electricity, has the same issue. A third strategy—using drugs to activate genetically modified cells bred into mice—is less invasive, but drugs are slow to take effect and wear off.

The solution that Friedman’s group hit upon, referred to as radiogenetics or magnetogenetics, avoids these problems. With their method, published last year in Nature, biologists can turn neurons on or off in a live animal at will—quickly, repeatedly, and without implants—by engineering the cells to make them receptive to radio waves or a magnetic field.

“In effect, we created a perceptual illusion that the animal had a drop in blood sugar.”

“We’ve combined molecules already used in cells for other purposes in a manner that allows an invisible force to take control of an instinct as primal as hunger,” Friedman says.

The method links five very different biological tools, which can look whimsically convoluted, like a Rube Goldberg contraption on a molecular scale. It relies on a green fluorescent protein borrowed from jellyfish, a peculiar antibody derived from camels, squishy bags of iron particles, and the cellular equivalent of a door made from a membrane-piercing protein—all delivered and installed by a genetically engineered virus. The remote control for this contraption is a modified welding tool (though a store-bought magnet also works).

The researchers’ first challenge was to find something in a neuron that could serve as an antenna to detect the incoming radio signal or magnetic field. The logical choice was ferritin, a protein that stores iron in cells in balloon-like particles just a dozen nanometers wide. Iron is essential to cells but can also be toxic, so it is sequestered in ferritin particles until it is needed. Each ferritin particle carries within it thousands of grains of iron that wiggle around in response to a radio signal, and shift and align when immersed in a magnetic field.
We all have these particles shimmying around inside our brain cells, but the motions normally have no effect on neurons.

Friedman and Stanley, with equipment they use to send radio waves.
Friedman and Stanley, with equipment they use to send radio waves. Photo by Zachary Veilleux

Friedman’s team realized that they could use a genetically engineered virus to create doorways into a neuron’s outer membrane. If they could then somehow attach each door to a ferritin particle, they reasoned, they might be able to wiggle the ferritin enough to jostle the door open. “The ‘door’ we chose is called TRPV1,” says Stanley. “Once TRPV1 is activated, calcium and sodium ions would next flow into the cell and trigger the neuron to fire.” The bits borrowed from camels and jellyfish provided what the scientists needed to connect the door to the ferritin (see How to outfit a brain sidebar, right).

Once the team had the new control mechanism working, they put it to the test. For Friedman and Stanley, whose goal is to unravel the biological causes of overeating and obesity, the first application was obvious: Try to identify specific neurons involved in appetite. The group modified glucose-sensing neurons—cells that are believed to monitor blood sugar levels in the brain and keep them within normal range—to put them under wireless control. To accomplish this, they inserted the TRPV1 and ferritin genes into a virus and—using yet another genetic trick—injected them into the glucose-sensing neurons. They could then fiddle with the cells to see whether they are involved, as suspected, in coordinating feeding and the release of hormones, such as insulin and glucagon, that keep blood glucose levels in check.

Illustration by Jasu Hu
HOW TO OUTFIT A BRAIN FOR RADIO CONTROL
Scientists have come up with a clever way to control neurons via radio by cobbling together genes from humans, camels, and jellyfish. They use an engineered virus to install a door into each target neuron’s outer membrane, then jostle the door open using ferritin particles that respond to strong radio signals. Once the door opens, calcium ions pour into the cell and trigger the neuron to fire.
1.
To install the radiogenetics system into neurons, the scientists equipped an adenovirus with the various genes needed to make the system work. Then they squirted the modified virus onto the brain cells they wanted to alter.
2.
One of the added genes produces TRPV1, a protein that normally helps cells detect heat and motion. Within each neuron, the TRPV1 protein (pink) embeds itself into the cell’s outer membrane. Like a door, it can change shape to open or shut an ion channel. To add a knob to the door, the researchers stitched TRPV1 to a “nanobody” (violet)—an unusually simple variety of antibody found in camels.
3.
Iron-filled ferritin particles (green) serve as the system’s sensor. To allow them to grab onto the nanobody doorknob, the researchers tacked on a gene for GFP—a jellyfish protein that glows green under ultraviolet light. By design, the nanobody and GFP stick together tightly.
The system is now connected. When exposed to strong radio waves or magnetic fields, the ferritin particles wiggle, the ion channel opens, and calcium ions (red) flow in to activate the cell.

Once the virus had enough time to infect and transform the target neurons, the researchers switched on a radio transmitter tuned to 465 kHz, a little below the band used for AM radio.

The neurons responded. They began to fire, signaling a shortage of glucose even though the animal’s blood sugar levels were normal. And other parts of the body responded just as they would to a real drop in blood sugar: insulin levels fell, the liver started pumping out more glucose, and the animals started eating more. “In effect,” Friedman says, “we created a perceptual illusion that the animal had low blood glucose even though the levels were normal.”

Inspired by these results, the researchers wondered if magnetism, like radio waves, might trigger ferritin to open the cellular doors. It did: When the team put the mice cages close to an MRI machine, or waved a rare-earth magnet over the animals, their glucose-sensing neurons were triggered.

Stimulating appetite is one thing. Could they also suppress it? The group tweaked the TRPV1 gene so it would pass chloride, which acts to inhibit neurons. Now when they inserted the modified TRPV1 into the neurons, the rush of chloride made the neurons behave as if the blood was overloaded with glucose. Insulin production surged in the animals, and they ate less. “This seems to indicate clearly that the brain as well as the pancreas is involved in glucose regulation,” Friedman says.

Friedman and Stanley hope that biologists will be able to use the remote-control system to tackle a range of neural processes other than appetite. And beyond being a basic research tool, the method could potentially lead to novel therapies for brain disorders.

For example, one could imagine using it to treat Parkinson’s disease or essential tremor—conditions that are sometimes treated by deep brain stimulation, via wires implanted into patients’ brains and connected to a battery pack tucked into the chest. Potentially, it would be less invasive to inject the crippled virus into the same spot of the brain and let it permanently modify the cells there, making them responsive to wireless control.

In theory, it might also be possible to make a patient’s own cells receptive to electromagnetic waves by removing them from the body, delivering TRPV1 and ferritin, and then putting the cells back, Friedman says. This would be a protocol not unlike those currently used in stem cell treatments and some cancer immunotherapies, in which patients’ own cells are engineered and reimplanted back into their bodies.

At this point, however, the system’s clinical usefulness is a question of speculation. “We are a long way from using it in humans for medical treatments,” Friedman says. “Much would need to be done before it could even be tested.”

Bench mouse illustration

To be continued?
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by Silviu “Silview” Costinescu

An editorial that stands by itself and speaks volumes for many of the incredible facts I’ve revealed in my own editorials. I don’t endorse all this, I just chew the meat on the bones.
Published in a journal called Expert Opinion on Drug Delivery

Manipulative magnetic nanomedicine: the future of COVID-19 pandemic/endemic therapy

By Ajeet Kaushik, Pages 531-534 | Received 06 Nov 2020, Accepted 03 Dec 2020, Published online: 14 Dec 2020

1. Introduction: COVID-19 pandemic or endemic as health emergency

Since the Spanish flu outbreak (1918), many pandemics and/or endemics related to a viral infection such as H1N1, H5N1, human immunodeficiency virus (HIV), Ebola, Zika, and coronavirus have surprised mankind time-to-time due to their sudden appearance, severe adverse health effect, loss of lives, socio-economic burden, and a damaged economy. Such deadly infectious viruses originated from natural reservoirs and then infect humans via spillover mechanism. During infection progression, viruses affect the human biological system and become a part of the host genome and then make structural changes in its structure to survive or infect longer. These infections can cause permanent disorders, may be death, if a patient is immunocompromised and could not fight against virus life-cycle associated pathways and viral infection progression.

One such pandemic and/or endemic is the recent COVID-19 infection associated with new server acute respiratory syndrome coronavirus (SARS-CoV-2), investigated by Chinese clinicians in Dec 2019. Chinese health agencies noticed a rapid increment in seasonal flu cases, and this emerged as a very serious health issue due to the ineffectiveness of prescribed therapies [1,2]. Systematic investigations conducted on this infectious disease by experts confirmed and claimed that SARS-CoV-2 virus infection is dramatically affecting the respiratory system of every age patient via affecting their lung function. Although SARS-CoV-2 virus protein exhibited 70% to 80% genomic profile like SARS-CoV-1 (2002 outbreak) and middle east respiratory syndrome (2012 outbreak), but its viral infection mechanism, pathogenesis, mortality per cent, and other risks are different, unknown, and serious than SARS and MERS [2]. Considering the severity of COVID-19 infection and variation in SARS-CoV-2 virus strains, this outbreak was first declared as an international health emergency; then, a pandemic due to global spread [2], and now experts are projecting this as an endemic due to post-infection effects and possibilities of reoccurrence like HIV [3]. This infection is emerging very challenging due to 1) human-to-human transmission via aerosolization, 2) ability to affect lung rapidly because of easy binding between Spike (S1) protein of SARS-COV-2 virus and host cell membrane receptors like angiotensin-converting enzyme 2 (ACE-2) and TMPRSS-2 protein, this makes virus replication easy [4].

A successful COVID-19 infection management is not the only issue to deal with the respiratory system as it affects lung function. But the SARS-CoV-2 virus infection also severely affects other important body organs including the heart, liver, eye, gut, and brain as well. This is the reason that recovery of a COVID-19 infected patient is slow and sometimes the patient exhibits permanent disorder in biological function due to weak organs and organ function [2]. Such scenarios have been investigated in asymptomatic patients as well. Keeping complete COVID-19 outbreak into consideration, health agencies were focused on 1) preparation and execution of safety guidelines, 2) exploring virus structure, genomic profiles, variability, and generate bioinformatics to understand pathogenesis, 3) developing rapid diagnostic kits, 4) optimizing available therapies, alone or in combination, 5) exploring methodologies to prevent SARS-CoV-2 transmission, 6) exploring novel therapeutics, 7) exploring aspects of therapeutic delivery at disease location, and 8) exploring combinational aspects of nanobiotechnology to support rapid testing, trapping of SARS-CoV-2, and delivery of therapeutics for not only to eradicate SARS-CoV-2 but provide long-term immunity for COVID-19 infected patient [4–6].

Based on the outcomes of big data analytics based on artificial intelligence (AI), it is suggested that recognition and eradication of the SARS-CoV-2 virus may be a time-taking procedure. Thus, all the focus is toward rapid infection diagnostics and viral infection management using state-of-the-art technologies, for example, 1) promoting physical distance and using of a mask to avoid virus transmission, 2) developing AI and internet-of-medical-things (IoMT) based strategies for rapid testing, tracking of patients, big data analytics, bioinformatics generation, developing a novel sensor for early-stage SARS-CoV-2 detection [2,5,7], and novel therapeutics and successful delivery using nanobiotechnology approach [8], the main focus of this editorial.

2. Manipulative magnetic nanomedicine: the future of COVID-19 therapy

Nanobiotechnology is emerging very promising to investigate novel methodologies for managing COVID-19 pandemic/endemic successfully [2,5]. In this direction, experts have explored the opto-electro-magnetic nanosystem to detect the SARS-CoV-2 virus using a biosensing approach. Such optical, electrical, or magnetic biosensors function based on geno-sensing and immune-sensing has detected the SARS-CoV-2 virus selectively at a very low level [7,8]. These efficient-miniaturized biosensors can be operated using a smartphone and promoted for clinical application for early-stage diagnostics of COVID-19 infection. The successful integration of these SARS-CoV-2 virus sensors with AI and IoMT enables virus detection at point-of-location and sharing of bioinformatics with the medical center at the same time for timely therapeutics decision. This approach is also useful for tracking tasks and managing COVID-19 infection according to patient infection profiling. To avoid human-to-human SARS-CoV-2 virus transmission, experts have developed stimuli-responsive nanotechnology enable which can not only trap aerosol of virus size but can eradicate viruses on applying external stimulation for example nanoenable photo-sensitive virus degradation. Various types of clothes containing nanoparticles have demonstrated SARS-CoV-2 virus trapping and eradication successfully [2,9]. However, significant attention is required to increase the production and distribution of these masks for public use.

Besides, the contribution of biotech-pharma companies is also of high significance in terms of investigating novel therapeutic agents of higher efficacy with least/acceptable adverse effects. Though the SARS-CoV-2 virus is new and has exhibited strain variation which is making treatment optimization challenging. But biotechnology experts are analyzing every aspect of bioinformatics to design and develop an effective therapy based on novel anti-viral agents, CRISPR-Cas, antibodies, and vaccines5. Another approach to manage COVID-19 infection is to introduce or boost immunity through nutrition, for example, nutraceuticals have acted as inhibitors to prevent binding between SARS-CoV-2 virus and ACE-2 enzyme [2,8].

Investigating a therapeutic agent against the SARS-CoV-2 virus infection seems possible now but the delivery of these agents is still a remaining challenge because this virus may have numerous reservoirs over the time. It is also demonstrated that COVID-19 infection patients may temporarily or permanently have immunocompromised biological systems. Such-related adverse effects include risk of cardiac arrest, vision issues, weak respiratory system, neurological disorders (one of the serious issues because SARS-CoV-2 virus crosses the blood-brain barrier), etc. Therefore, a single therapeutic agent designed against the SARS-CoV-2 virus may not be enough to treat COVID-19 infected patients completely [1,8].

Thus, a manipulative therapy, a combination of optimized therapeutic agents, consisting of an anti-SARS-CoV-2 virus agent and immune-supportive agents will require to be optimized based on the patient infection profiling. Experts have thought about it and raised/dealing the following concerns 1) drug-to-drug interaction, 2) delivery of drug/drugs at the targeted site, 3) control over the release of drug/drugs from a therapeutic formulation, and 4) immune-supporting long-acting therapies. These tasks are challenging but needed to be managed; therefore, exploring aspects of nanomedicine could be a promising approach to develop novel therapies to manage COVID-19 infection and support the immune system along with SARS-CoV-2 virus affected organs [8].

Nanomedicine (10 to 200 nm) is a therapeutic cargo designed using an appropriate drug nanocarrier and a therapeutic agent [9–15]. Nowadays magnetic nanomedicine has performed to manage viral infection at various reservoirs even in the brain because nanomedicine is capable to cross any barriers in the body via adopting the following approaches 1) functionalization of nanomedicine with barriers specific receptors, 2) applying external stimulation like ultrasound, and 3) noninvasive guided approach like magnetically guided drug delivery system [10–12].

Besides drug delivery, magnetic nanomedicine could be formulated to deliver multiple drugs at a targeted site to achieve desired therapeutic performance due to 1) control over the release by applying external stimulation like an ac-magnetic field, 2) formulating a magnetic cargo to load multiple drugs without drug-to-drug interaction, for example, layer-by-layer (LBL) approach, and 3) the sequence of drug release can be tuned and planned according to a stage/requirement of disease condition [13–15]. The performance of such nanomedicine mainly depends on the selection of a multi-functional stimuli-response drug nanocarrier such as magneto-electric nanoparticles (MENPs) [12], opto-magnetic, opto-electromagnetic, magneto-LBL, magneto-liposome, and magneto-plasmonics nanosystem. These advanced nanomedicines not only deliver the drug/drug but also help in the recognition of drug distribution and disease progression.

Combining above mentioned salient features, manipulative magnetic nanomedicine (MMN) as one of the potential future therapy wherein control over delivery and performance if required. Such MMN has the capabilities to recognize and eradicate the SARS-CoV-2 virus to manage COVID-19 infection and symptoms. Besides, due to the flexibility of using the therapeutic agent of choice, these manipulative nanomedicines can be designed and developed as long-acting therapy for COVID-19 infection where anti-virus and immune-supportive agents can stay longer in the body without causing any side-effects. Such personalized MMN (Figure 1) is an urgently required therapy and its development should be the focus of future research with the following aims

Figure 1. Systematic illustration of manipulative nanomedicine projected as future COVID-19 pandemic/endemic therapyDisplay full size

  1. Exploring stimuli-responsive magnetic nanosystems for on-demand-controlled delivery and release.
  2. Image-guided therapy to recognize the delivery site and confirm drug release.
  3. A magnetically guided approach to delivering drugs across the barriers like the gut, BBB, etc.
  4. Magneto-LBL/liposomal approach to delivering multiple drugs to avoid drug-to-drug interaction and control over the drug release sequence. For example, an anti-virus drug should be released first then an immune-protective agent.
  5. The MMN can be customized according to patient disease profile and medical history, for example, selection of anti-SARS-CoV-2 virus agent (antibody, ARV, CRISPR-Cas, etc.,) based on patient genomic profiling.
  6. The MMN can also be customized as long-acting therapeutics that allows drug-releasing for a longer time (2–3 months), as must require therapy to manage post-COVID-19 infection effects.
  7. The MMN can be explored as personalized precision therapy.

3. Expert opinion

Based on the experiences of developing MMN to eradicate neuroHIV/AIDS, under a project of getting into the brain, using MENPs as a drug nanocarrier, magnetically guided drug delivery, and ac-magnetic field stimulation dependent controlled drug release, my team and me believes that MMN can be a future therapy against COVID-19 infection pandemic/or endemic. As it is also known that the SARS-CoV-2 virus infection is a combination of several diseases and symptoms. During the infection treatment, even after the hospital discharge, the patient may have several diseases at the same time for a longer time. Such-complicated medical conditions are not easy to deal with using conventional antiviral drugs. Thus, experts feel the demand for a new therapy that can handle multiple tasks at the same time. Keeping advancements and potentials into consideration, manipulative nanomedicine can be one of the potential COVID-19 infection therapies.

Some of the advancements in this field has been reported, for example, micro-needle-based vaccine delivery to manage COVID-19 infection. Early outcomes are exciting, but a lot must be done in terms of animal model-based trials, and followed up with FDA approval, needed prior to suggest clinical implication. To promote MNM against COVID-19 successfully, a public-private involvement-based significant research needed to be conducted in this field to create a path from a lab (in-vitro) to in-vivo (appropriate animal model) to risk assessments to clinical trials to risk assessment to human trial to risk assessment to FDA approval for public utilization. In the process of developing an anti-COVID-19 infection therapy, careful and critical safety-related risk assessments will be a crucial factor to decide progression step-by-step. This introducing AI will be a good choice to gather bioinformatics, perform big data analysis, avoid unnecessary hit-&-trial approaches, establish a relation with a biological and pathological parameter, and projection of a potential approach. Besides AI, it is also suggested to design several projects focused on every aspect of pre/post-SARS-CoV-2 virus infection, and based on assessments and analytics a potential drug nanocarrier and therapeutics agents should be selected. Developing such an approach is a multidisciplinary research approach and experts of various expertise are needed to work on the same platform to investigate MMN to combat against SARS-CoV-2 virus infection. Projecting the above mention as a necessity, this editorial is a call to experts to join hands for investigating and promoting MMN as a potential future COVID-19 pandemic/endemic therapy. I believe that the MMN approach will be in more demand as new therapeutic agents, such BNT162b2, and mRNA1273 [16], vaccine as will be investigated over the time.

References

From author’s references, I want to highlight this study which shows that magnetism is also used to cross the Brain Blood Barrier -Silview

Magnetically guided non-invasive CRISPR-Cas9/gRNA delivery across blood-brain barrier to eradicate latent HIV-1 infection

Ajeet Kaushik 1, Adriana Yndart 1, Venkata Atluri 1, Sneham Tiwari 1, Asahi Tomitaka 1, Purnima Gupta 1, Rahul Dev Jayant 1, David Alvarez-Carbonell 2, Kamel Khalili 3, Madhavan Nair 4Affiliations expand

Free PMC article

Abstract

CRISPR-Cas9/gRNA exhibits therapeutic efficacy against latent human immunodeficiency virus (HIV) genome but the delivery of this therapeutic cargo to the brain remains as a challenge. In this research, for the first time, we demonstrated magnetically guided non-invasive delivery of a nano-formulation (NF), composed of Cas9/gRNA bound with magneto-electric nanoparticles (MENPs), across the blood-brain barrier (BBB) to inhibit latent HIV-1 infection in microglial (hμglia)/HIV (HC69) cells. An optimized ac-magnetic field of 60 Oe was applied on NF to release Cas9/gRNA from MENPs surface and to facilitate NF cell uptake resulting in intracellular release and inhibition of HIV. The outcomes suggested that developed NF reduced HIV-LTR expression significantly in comparison to unbound Cas9/gRNA in HIV latent hμglia/HIV (HC69) cells. These findings were also validated qualitatively using fluorescence microscopy to assess NF efficacy against latent HIV in the microglia cells. We believe that CNS delivery of NF (CRISPR/Cas9-gRNA-MENPs) across the BBB certainly will have clinical utility as future personalized nanomedicine to manage neuroHIV/AIDS.

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