Category Archives: medicine

Could CRISPR (clustered regularly interspaced short palindromic repeats) be weaponized?

On the occasion of an American team’s recent publication of research where they edited the germline (embryos), I produced a three-part series about CRISPR (clustered regularly interspaced short palindromic repeats), sometimes referred to as CRISPR/Cas9, (links offered at end of this post).

Somewhere in my series, there’s a quote about how CRISPR could be used as a ‘weapon of mass destruction’ and it seems this has been a hot topic for the last year or so as James Revill, research fellow at the University of Sussex, references in his August 31, 2017 essay on theconversation.com (h/t phys.org August 31, 2017 news item), Note: Links have been removed,

The gene editing technique CRISPR has been in the limelight after scientists reported they had used it to safely remove disease in human embryos for the first time. This follows a “CRISPR craze” over the last couple of years, with the number of academic publications on the topic growing steadily.

There are good reasons for the widespread attention to CRISPR. The technique allows scientists to “cut and paste” DNA more easily than in the past. It is being applied to a number of different peaceful areas, ranging from cancer therapies to the control of disease carrying insects.

Some of these applications – such as the engineering of mosquitoes to resist the parasite that causes malaria – effectively involve tinkering with ecosystems. CRISPR has therefore generated a number of ethical and safety concerns. Some also worry that applications being explored by defence organisations that involve “responsible innovation in gene editing” may send worrying signals to other states.

Concerns are also mounting that gene editing could be used in the development of biological weapons. In 2016, Bill Gates remarked that “the next epidemic could originate on the computer screen of a terrorist intent on using genetic engineering to create a synthetic version of the smallpox virus”. More recently, in July 2017, John Sotos, of Intel Health & Life Sciences, stated that gene editing research could “open up the potential for bioweapons of unimaginable destructive potential”.

An annual worldwide threat assessment report of the US intelligence community in February 2016 argued that the broad availability and low cost of the basic ingredients of technologies like CRISPR makes it particularly concerning.

A Feb. 11, 2016 news item on sciencemagazine.org offers a précis of some of the reactions while a February 9, 2016 article by Antonio Regalado for the Massachusetts Institute of Technology’s MIT Technology Review delves into the matter more deeply,

Genome editing is a weapon of mass destruction.

That’s according to James Clapper, [former] U.S. director of national intelligence, who on Tuesday, in the annual worldwide threat assessment report of the U.S. intelligence community, added gene editing to a list of threats posed by “weapons of mass destruction and proliferation.”

Gene editing refers to several novel ways to alter the DNA inside living cells. The most popular method, CRISPR, has been revolutionizing scientific research, leading to novel animals and crops, and is likely to power a new generation of gene treatments for serious diseases (see “Everything You Need to Know About CRISPR’s Monster Year”).

It is gene editing’s relative ease of use that worries the U.S. intelligence community, according to the assessment. “Given the broad distribution, low cost, and accelerated pace of development of this dual-use technology, its deliberate or unintentional misuse might lead to far-reaching economic and national security implications,” the report said.

The choice by the U.S. spy chief to call out gene editing as a potential weapon of mass destruction, or WMD, surprised some experts. It was the only biotechnology appearing in a tally of six more conventional threats, like North Korea’s suspected nuclear detonation on January 6 [2016], Syria’s undeclared chemical weapons, and new Russian cruise missiles that might violate an international treaty.

The report is an unclassified version of the “collective insights” of the Central Intelligence Agency, the National Security Agency, and half a dozen other U.S. spy and fact-gathering operations.

Although the report doesn’t mention CRISPR by name, Clapper clearly had the newest and the most versatile of the gene-editing systems in mind. The CRISPR technique’s low cost and relative ease of use—the basic ingredients can be bought online for $60—seems to have spooked intelligence agencies.

….

However, one has to be careful with the hype surrounding new technologies and, at present, the security implications of CRISPR are probably modest. There are easier, cruder methods of creating terror. CRISPR would only get aspiring biological terrorists so far. Other steps, such as growing and disseminating biological weapons agents, would typically be required for it to become an effective weapon. This would require additional skills and places CRISPR-based biological weapons beyond the reach of most terrorist groups. At least for the time being.

A July 5, 2016 opinion piece by Malcolm Dando for Nature argues for greater safeguards,

In Geneva next month [August 2016], officials will discuss updates to the global treaty that outlaws the use of biological weapons. The 1972 Biological Weapons Convention (BWC) was the first agreement to ban an entire class of weapons, and it remains a crucial instrument to stop scientific research on viruses, bacteria and toxins from being diverted into military programmes.

The BWC is the best route to ensure that nations take the biological-weapons threat seriously. Most countries have struggled to develop and introduce strong and effective national programmes — witness the difficulty the United States had in agreeing what oversight system should be applied to gain-of-function experiments that created more- dangerous lab-grown versions of common pathogens.

As scientific work advances — the CRISPR gene-editing system has been flagged as the latest example of possible dual-use technology — this treaty needs to be regularly updated. This is especially important because it has no formal verification system. Proposals for declarations, monitoring visits and inspections were vetoed by the United States in 2001, on the grounds that such verification threatened national security and confidential business information.

Even so, issues such as the possible dual-use threat from gene-editing systems will not be easily resolved. But we have to try. Without the involvement of the BWC, codes of conduct and oversight systems set up at national level are unlikely to be effective. The stakes are high, and after years of fumbling, we need strong international action to monitor and assess the threats from the new age of biological techniques.

Revill notes the latest BWC agreement and suggests future directions,

This convention is imperfect and lacks a way to ensure that states are compliant. Moreover, it has not been adequately “tended to” by its member states recently, with the last major meeting unable to agree a further programme of work. Yet it remains the cornerstone of an international regime against the hostile use of biology. All 178 state parties declared in December of 2016 their continued determination “to exclude completely the possibility of the use of (biological) weapons, and their conviction that such use would be repugnant to the conscience of humankind”.

These states therefore need to address the hostile potential of CRISPR. Moreover, they need to do so collectively. Unilateral national measures, such as reasonable biological security procedures, are important. However, preventing the hostile exploitation of CRISPR is not something that can be achieved by any single state acting alone.

As such, when states party to the convention meet later this year, it will be important to agree to a more systematic and regular review of science and technology. Such reviews can help with identifying and managing the security risks of technologies such as CRISPR, as well as allowing an international exchange of information on some of the potential benefits of such technologies.

Most states supported the principle of enhanced reviews of science and technology under the convention at the last major meeting. But they now need to seize the opportunity and agree on the practicalities of such reviews in order to prevent the convention being left behind by developments in science and technology.

Experts (military, intelligence, medical, etc.) are not the only ones concerned about CRISPR according to a February 11, 2016 article by Sharon Begley for statnews.com (Note: A link has been removed),

Most Americans oppose using powerful new technology to alter the genes of unborn babies, according to a new poll — even to prevent serious inherited diseases.

They expressed the strongest disapproval for editing genes to create “designer babies” with enhanced intelligence or looks.

But the poll, conducted by STAT and Harvard T.H. Chan School of Public Health, found that people have mixed, and apparently not firm, views on emerging genetic techniques. US adults are almost evenly split on whether the federal government should fund research on editing genes before birth to keep children from developing diseases such as cystic fibrosis or Huntington’s disease.

“They’re not against scientists trying to improve [genome-editing] technologies,” said Robert Blendon, professor of health policy and political analysis at Harvard’s Chan School, perhaps because they recognize that one day there might be a compelling reason to use such technologies. An unexpected event, such as scientists “eliminating a terrible disease” that a child would have otherwise inherited, “could change people’s views in the years ahead,” Blendon said.

But for now, he added, “people are concerned about editing the genes of those who are yet unborn.”

A majority, however, wants government regulators to approve gene therapy to treat diseases in children and adults.

The STAT-Harvard poll comes as scientists and policy makers confront the ethical, social, and legal implications of these revolutionary tools for changing DNA. Thanks to a technique called CRISPR-Cas9, scientists can easily, and with increasing precision, modify genes through the genetic analog of a computer’s “find and replace” function.

I find it surprising that there’s resistance to removing diseases found in the germline (embryos). When they were doing public consultations on nanotechnology, the one area where people tended to be quite open to research was health and medicine. Where food was concerned however, people had far more concerns.

If you’re interested in the STAT-Harvard poll, you can find it here. As for James Revill, he has written a more substantive version of this essay as a paper, which is available here.

On a semi-related note, I found STAT (statnews.com) to be a quite interesting and accessibly written online health science journal. Here’s more from the About Us page (Note: A link has been removed),

What’s STAT all about?
STAT is a national publication focused on finding and telling compelling stories about health, medicine, and scientific discovery. We produce daily news, investigative articles, and narrative projects in addition to multimedia features. We tell our stories from the places that matter to our readers — research labs, hospitals, executive suites, and political campaigns.

Why did you call it STAT?
In medical parlance, “stat” means important and urgent, and that’s what we’re all about — quickly and smartly delivering good stories. Read more about the origins of our name here.

Who’s behind the new publication?
STAT is produced by Boston Globe Media. Our headquarters is located in Boston but we have bureaus in Washington, New York, Cleveland, Atlanta, San Francisco, and Los Angeles. It was started by John Henry, the owner of Boston Globe Media and the principal owner of the Boston Red Sox. Rick Berke is executive editor.

So is STAT part of The Boston Globe?
They’re distinct properties but the two share content and complement one another.

Is it free?
Much of STAT is free. We also offer STAT Plus, a premium subscription plan that includes exclusive reporting about the pharmaceutical and biotech industries as well as other benefits. Learn more about it here.

Who’s working for STAT?
Some of the best-sourced science, health, and biotech journalists in the country, as well as motion graphics artists and data visualization specialists. Our team includes talented writers, editors, and producers capable of the kind of explanatory journalism that complicated science issues sometimes demand.

Who’s your audience?
You. Even if you don’t work in science, have never stepped foot in a hospital, or hated high school biology, we’ve got something for you. And for the lab scientists, health professionals, business leaders, and policy makers, we think you’ll find coverage here that interests you, too. The world of health, science, and medicine is booming and yielding fascinating stories. We explore how they affect us all.

….

As promised, here are the links to my three-part series on CRISPR,

Part 1 opens the series with a basic description of CRISPR and the germline research that occasioned the series along with some of the other (non-weapon) ethical issues and patent disputes that are arising from this new technology. CRISPR and editing the germline in the US (part 1 of 3): In the beginning

Part 2 covers three critical responses to the reporting and between them describe the technology in more detail and the possibility of ‘designer babies’.  CRISPR and editing the germline in the US (part 2 of 3): ‘designer babies’?

Part 3 is all about public discussion or, rather, the lack of and need for according to a couple of social scientists. Informally, there is some discussion via pop culture and Joelle Renstrom notes although she is focused on the larger issues touched on by the television series, Orphan Black and as I touch on in my final comments. CRISPR and editing the germline in the US (part 3 of 3): public discussions and pop culture

Finally, I hope to stumble across studies from other countries about how they are responding to the possibilities presented by CRISPR/Cas9 so that I can offer a more global perspective than this largely US perspective. At the very least, it would be interesting to find it if there differences.

What helps you may hurt you (titanium dioxide nanoparticles and orthopedic implants)

From a Sept. 16, 2017 news item on Nanotechnology Now,

Researchers from the Mayo Clinic have proposed that negative cellular responses to titanium-based nanoparticles released from metal implants interfere in bone formation and resorption at the site of repair, resulting in implant loosening and joint pain. [emphasis mine]Their review of recent scientific evidence and call for further research to characterize the biological, physical, and chemical interactions between titanium dioxide nanoparticles and bone-forming cells is published in BioResearch Open Access, a peer-reviewed open access journal from Mary Ann Liebert, Inc., publishers. The article is available free on theBioResearch Open Access website.

A Sept. 14, 2017 Mary Anne Liebert (Publishing) news release, which originated the news item,  mentions the authors,

Jie Yao, Eric Lewallen, PhD, David Lewallen, MD, Andre van Wijnen, PhD, and colleagues from the Mayo Clinic, Rochester, MN and Second Affiliated Hospital of Soochow University, China, coauthored the article entitled “Local Cellular Responses to Titanium Dioxide from Orthopedic Implants The authors examined the results of recently published studies of titanium-based implants, focusing on the direct and indirect effects of titanium dioxide nanoparticles on the viability and behavior of multiple bone-related cell types. They discuss the impact of particle size, aggregation, structure, and the specific extracellular and intracellular (if taken up by the cells) effects of titanium particle exposure.

“The adverse effects of metallic orthopedic particles generated from implants are of significant clinical interest given the large number of procedures carried out each year. This article reviews our current understanding of the clinical issues and highlights areas for future research,” says BioResearch Open Access Editor Jane Taylor, PhD, MRC Centre for Regenerative Medicine, University of Edinburgh, Scotland.

Before getting to the abstract, here’s a link to and a citation for the paper,

Local Cellular Responses to Titanium Dioxide from Orthopedic Implants by Yao, Jie J.; Lewallen, Eric A.; Trousdale, William H.; Xu, Wei; Thaler, Roman; Salib, Christopher G.; Reina, Nicolas; Abdel, Matthew P.; Lewallen, David G.; and van Wijnenm, Andre J.. BioResearch Open Access. July 2017, 6(1): 94-103. https://doi.org/10.1089/biores.2017.0017 Published July 1, 2017

This paper is open access.

Melting body fat with a microneedle patch

For many people this may seem like a dream come true but there is a proviso. So far researchers have gotten to the in vivo testing (mice)  with no word about human clinical trials, which means it could be quite a while, assuming human clinical trials go well, before any product comes to market. With that in mind, here’s more from a Sept.15, 2017 news item on Nanowerk,

Researchers have devised a medicated skin patch that can turn energy-storing white fat into energy-burning brown fat locally while raising the body’s overall metabolism. The patch could be used to burn off pockets of unwanted fat such as “love handles” and treat metabolic disorders like obesity and diabetes, according to researchers at Columbia University Medical Center (CUMC) and the University of North Carolina.

A Sept. 15, 2017 Columbia University Medical Center news release on EurekAlert, which originated the news item, describes the research further,

Humans have two types of fat. White fat stores excess energy in large triglyceride droplets. Brown fat has smaller droplets and a high number of mitochondria that burn fat to produce heat. Newborns have a relative abundance of brown fat, which protects against exposure to cold temperatures. But by adulthood, most brown fat is lost.

For years, researchers have been searching for therapies that can transform an adult’s white fat into brown fat–a process named browning–which can happen naturally when the body is exposed to cold temperatures–as a treatment for obesity and diabetes.

“There are several clinically available drugs that promote browning, but all must be given as pills or injections,” said study co-leader Li Qiang, PhD, assistant professor of pathology and cell biology at CUMC. “This exposes the whole body to the drugs, which can lead to side effects such as stomach upset, weight gain, and bone fractures. Our skin patch appears to alleviate these complications by delivering most drugs directly to fat tissue.”

To apply the treatment, the drugs are first encased in nanoparticles, each roughly 250 nanometers (nm) in diameter–too small to be seen by the naked eye. (In comparison, a human hair is about 100,000 nm wide.) The nanoparticles are then loaded into a centimeter-square skin patch containing dozens of microscopic needles. When applied to skin, the needles painlessly pierce the skin and gradually release the drug from nanoparticles into underlying tissue.

“The nanoparticles were designed to effectively hold the drug and then gradually collapse, releasing it into nearby tissue in a sustained way instead of spreading the drug throughout the body quickly,” said patch designer and study co-leader Zhen Gu, PhD, associate professor of joint biomedical engineering at the University of North Carolina at Chapel Hill and North Carolina State University.

The new treatment approach was tested in obese mice by loading the nanoparticles with one of two compounds known to promote browning: rosiglitazone (Avandia) or beta-adrenergic receptor agonist (CL 316243) that works well in mice but not in humans. Each mouse was given two patches–one loaded with drug-containing nanoparticles and another without drug–that were placed on either side of the lower abdomen. New patches were applied every three days for a total of four weeks. Control mice were also given two empty patches.

Mice treated with either of the two drugs had a 20 percent reduction in fat on the treated side compared to the untreated side. They also had significantly lower fasting blood glucose levels than untreated mice.

Tests in normal, lean mice revealed that treatment with either of the two drugs increased the animals’ oxygen consumption (a measure of overall metabolic activity) by about 20 percent compared to untreated controls.

Genetic analyses revealed that the treated side contained more genes associated with brown fat than on the untreated side, suggesting that the observed metabolic changes and fat reduction were due to an increase in browning in the treated mice.

“Many people will no doubt be excited to learn that we may be able to offer a noninvasive alternative to liposuction for reducing love handles,” says Dr. Qiang. “What’s much more important is that our patch may provide a safe and effective means of treating obesity and related metabolic disorders such as diabetes.” [emphasis mine]

The patch has not been tested in humans. The researchers are currently studying which drugs, or combination of drugs, work best to promote localized browning and increase overall metabolism.

The study was supported by grants from the North Carolina Translational and Clinical Sciences Institute and the National Institutes of Health (1UL1TR001111, R00DK97455, and P30DK063608).

Notice the emphasis on health and that the funding does not seem to be from industry (the National Institutes of Health is definitely a federal US agency but I’m not familiar with the North Carolina Translational and Clinical Sciences Institute).

Getting back to the research, here’s an animation featuring the work,

Here’s a link and a citation for the paper,

Locally Induced Adipose Tissue Browning by Microneedle Patch for Obesity Treatment by Yuqi Zhang†, Qiongming Liu, Jicheng Yu†, Shuangjiang Yu, Jinqiang Wang, Li Qiang, and Zhen Gu. ACS Nano, Article ASAP DOI: 10.1021/acsnano.7b04348 Publication Date (Web): September 15, 2017

Copyright © 2017 American Chemical Society

This paper is behind a paywall.

I would imagine that Qiang and his colleagues will find a number of business entities will be lining up to fund their work. While the researchers may be focused primarily on health issues, I imagine business types will be seeing dollar signs (very big ones with many zeroes).

A flexible, organic battery from Northern Ireland

A team from Northern Ireland seems to have made a splash in the race to develop a flexible, environmentally friendly battery. From a Sept. 13, 2017 news item on phys.org,

Experts at Queen’s University Belfast have designed a flexible and organic alternative to the rigid batteries that power up medical implants.

Currently, devices such as pacemakers and defibrillators are fitted with rigid and metal based batteries, which can cause patient discomfort.

Dr Geetha Srinivasan and a team of young researchers from Queen’s University Ionic Liquid Laboratories (QUILL) Research Centre, have now developed a flexible supercapacitor with a longer cycle life, which could power body sensors.

Courtesy: Queen’s University Belfast

A Sept. 13, 2017 Queen’s University Belfast press release (also on EurekAlert), which originated the news item, delves further,

The flexible device is made up of non-flammable electrolytes and organic composites, which are safe to the human body. It can also be easily decomposed without incurring the major costs associated with recycling or disposing off metal based batteries.

The findings, which have been published in Energy Technology and Green Chemistry, show that the device could be manufactured using readily available natural feedstock, rather than sophisticated and expensive metals or semiconductors.

Dr Srinivasan explains: “In modern society, we all increasingly depend on portable electronics such as smartphones and laptops in our everyday lives and this trend has spread to other important areas such as healthcare devices.

“In medical devices such as pacemakers and defibrillators there are two implants, one which is fitted in the heart and another which holds the metal based, rigid batteries – this is implanted under the skin.

“The implant under the skin is wired to the device and can cause patients discomfort as it is rubs against the skin. For this reason batteries need to be compatible to the human body and ideally we would like them to be flexible so that they can adapt to body shapes.”

Dr Srinivasan adds: “At Queen’s University Belfast we have designed a flexible energy storage device, which consists of conducting polymer – biopolymer composites as durable electrodes and ionic liquids as safer electrolytes.

“The device we have created has a longer life-cycle, is non-flammable, has no leakage issues and above all, it is more flexible for placing within the body.”

Environmentally friendly

While the findings show that there are many advantages in the medical world, the organic storage device could also provide solutions in wearable electronics and portable electronic devices, making these more flexible.

Ms Marta Lorenzo, PhD researcher on the project at Queen’s University Belfast, commented: “Although this research could be a potential solution to a global problem, the actual supercapacitor assembly is a straightforward process.”

Dr Srinivasan says: “There is also opportunity to fabricate task-specific supercapacitors. This means that their properties can be tuned and also manufactured using environmentally friendly methods, which is important if they are to be produced on a large scale, for example in powering portable personal electronic devices.”

Here are links and citations to the two papers mentioned in the press release,

Durable Flexible Supercapacitors Utilizing the Multifunctional Role of Ionic Liquids by Marta Lorenzo and Dr Geetha Srinivasan. Energy Technology. DOI: 10.1002/ente.201700407 First published: 23 August 2017

Intrinsically flexible electronic materials for smart device applications by Marta Lorenzo, Biyun Zhu, and Geetha Srinivasan. Green Chem., 2016,18, 3513-3517 DOI: 10.1039/C6GC00826G First published on 20 May 2016

The first paper is open access and the second paper is behind a paywall.

Vampire nanogenerators: 2017

Researchers have been working on ways to harvest energy from bloodstreams. I last wrote about this type of research in an April 3, 2009 posting about ‘vampire batteries ‘(for use in pacemakers). The latest work according to a Sept. 8, 2017 news item on Nanowerk comes from China,

Men build dams and huge turbines to turn the energy of waterfalls and tides into electricity. To produce hydropower on a much smaller scale, Chinese scientists have now developed a lightweight power generator based on carbon nanotube fibers suitable to convert even the energy of flowing blood in blood vessels into electricity. They describe their innovation in the journal Angewandte Chemie (“A One-Dimensional Fluidic Nanogenerator with a High Power Conversion Efficiency”)

A Sept. 8, 2017 Wiley Publishing news release (also on EurekAlert), which originated the news item, expands on the theme,

For thousands of years, people have used the energy of flowing or falling water for their purposes, first to power mechanical engines such as watermills, then to generate electricity by exploiting height differences in the landscape or sea tides. Using naturally flowing water as a sustainable power source has the advantage that there are (almost) no dependencies on weather or daylight. Even flexible, minute power generators that make use of the flow of biological fluids are conceivable. How such a system could work is explained by a research team from Fudan University in Shanghai, China. Huisheng Peng and his co-workers have developed a fiber with a thickness of less than a millimeter that generates electrical power when surrounded by flowing saline solution—in a thin tube or even in a blood vessel.

The construction principle of the fiber is quite simple. An ordered array of carbon nanotubes was continuously wrapped around a polymeric core. Carbon nanotubes are well known to be electroactive and mechanically stable; they can be spun and aligned in sheets. In the as-prepared electroactive threads, the carbon nanotube sheets coated the fiber core with a thickness of less than half a micron. For power generation, the thread or “fiber-shaped fluidic nanogenerator” (FFNG), as the authors call it, was connected to electrodes and immersed into flowing water or simply repeatedly dipped into a saline solution. “The electricity was derived from the relative movement between the FFNG and the solution,” the scientists explained. According to the theory, an electrical double layer is created around the fiber, and then the flowing solution distorts the symmetrical charge distribution, generating an electricity gradient along the long axis.

The power output efficiency of this system was high. Compared with other types of miniature energy-harvesting devices, the FFNG was reported to show a superior power conversion efficiency of more than 20%. Other advantages are elasticity, tunability, lightweight, and one-dimensionality, thus offering prospects of exciting technological applications. The FFNG can be made stretchable just by spinning the sheets around an elastic fiber substrate. If woven into fabrics, wearable electronics become thus a very interesting option for FFNG application. Another exciting application is the harvesting of electrical energy from the bloodstream for medical applications. First tests with frog nerves proved to be successful.

Here’s a link to and a citation for the paper,

A One-Dimensional Fluidic Nanogenerator with a High Power Conversion Efficiency by Yifan Xu, Dr. Peining Chen, Jing Zhang, Songlin Xie, Dr. Fang Wan, Jue Deng, Dr. Xunliang Cheng, Yajie Hu, Meng Liao, Dr. Bingjie Wang, Dr. Xuemei Sun, and Prof. Dr. Huisheng Peng. Angewandte Chemie International Edition DOI: 10.1002/anie.201706620 Version of Record online: 7 SEP 2017

© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

Hallucinogenic molecules and the brain

Psychedelic drugs seems to be enjoying a ‘moment’. After decades of being vilified and  declared illegal (in many jurisdictions), psychedelic (or hallucinogenic) drugs are once again being tested for use in therapy. A Sept. 1, 2017 article by Diana Kwon for The Scientist describes some of the latest research (I’ve excerpted the section on molecules; Note: Links have been removed),

Mind-bending molecules

© SEAN MCCABE

All the classic psychedelic drugs—psilocybin, LSD, and N,N-dimethyltryptamine (DMT), the active component in ayahuasca—activate serotonin 2A (5-HT2A) receptors, which are distributed throughout the brain. In all likelihood, this receptor plays a key role in the drugs’ effects. Krähenmann [Rainer Krähenmann, a psychiatrist and researcher at the University of Zurich]] and his colleagues in Zurich have discovered that ketanserin, a 5-HT2A receptor antagonist, blocks LSD’s hallucinogenic properties and prevents individuals from entering a dreamlike state or attributing personal relevance to the experience.12,13

Other research groups have found that, in rodent brains, 2,5-dimethoxy-4-iodoamphetamine (DOI), a highly potent and selective 5-HT2A receptor agonist, can modify the expression of brain-derived neurotrophic factor (BDNF)—a protein that, among other things, regulates neuronal survival, differentiation, and synaptic plasticity. This has led some scientists to hypothesize that, through this pathway, psychedelics may enhance neuroplasticity, the ability to form new neuronal connections in the brain.14 “We’re still working on that and trying to figure out what is so special about the receptor and where it is involved,” says Katrin Preller, a postdoc studying psychedelics at the University of Zurich. “But it seems like this combination of serotonin 2A receptors and BDNF leads to a kind of different organizational state in the brain that leads to what people experience under the influence of psychedelics.”

This serotonin receptor isn’t limited to the central nervous system. Work by Charles Nichols, a pharmacology professor at Louisiana State University, has revealed that 5-HT2A receptor agonists can reduce inflammation throughout the body. Nichols and his former postdoc Bangning Yu stumbled upon this discovery by accident, while testing the effects of DOI on smooth muscle cells from rat aortas. When they added this drug to the rodent cells in culture, it blocked the effects of tumor necrosis factor-alpha (TNF-α), a key inflammatory cytokine.

“It was completely unexpected,” Nichols recalls. The effects were so bewildering, he says, that they repeated the experiment twice to convince themselves that the results were correct. Before publishing the findings in 2008,15 they tested a few other 5-HT2A receptor agonists, including LSD, and found consistent anti-inflammatory effects, though none of the drugs’ effects were as strong as DOI’s. “Most of the psychedelics I have tested are about as potent as a corticosteroid at their target, but there’s something very unique about DOI that makes it much more potent,” Nichols says. “That’s one of the mysteries I’m trying to solve.”

After seeing the effect these drugs could have in cells, Nichols and his team moved on to whole animals. When they treated mouse models of system-wide inflammation with DOI, they found potent anti-inflammatory effects throughout the rodents’ bodies, with the strongest effects in the small intestine and a section of the main cardiac artery known as the aortic arch.16 “I think that’s really when it felt that we were onto something big, when we saw it in the whole animal,” Nichols says.

The group is now focused on testing DOI as a potential therapeutic for inflammatory diseases. In a 2015 study, they reported that DOI could block the development of asthma in a mouse model of the condition,17 and last December, the team received a patent to use DOI for four indications: asthma, Crohn’s disease, rheumatoid arthritis, and irritable bowel syndrome. They are now working to move the treatment into clinical trials. The benefit of using DOI for these conditions, Nichols says, is that because of its potency, only small amounts will be required—far below the amounts required to produce hallucinogenic effects.

In addition to opening the door to a new class of diseases that could benefit from psychedelics-inspired therapy, Nichols’s work suggests “that there may be some enduring changes that are mediated through anti-inflammatory effects,” Griffiths [Roland Griffiths, a psychiatry professor at Johns Hopkins University] says. Recent studies suggest that inflammation may play a role in a number of psychological disorders, including depression18 and addiction.19

“If somebody has neuroinflammation and that’s causing depression, and something like psilocybin makes it better through the subjective experience but the brain is still inflamed, it’s going to fall back into the depressed rut,” Nichols says. But if psilocybin is also treating the inflammation, he adds, “it won’t have that rut to fall back into.”

If it turns out that psychedelics do have anti-inflammatory effects in the brain, the drugs’ therapeutic uses could be even broader than scientists now envision. “In terms of neurodegenerative disease, every one of these disorders is mediated by inflammatory cytokines,” says Juan Sanchez-Ramos, a neuroscientist at the University of South Florida who in 2013 reported that small doses of psilocybin could promote neurogenesis in the mouse hippocampus.20 “That’s why I think, with Alzheimer’s, for example, if you attenuate the inflammation, it could help slow the progression of the disease.”

For anyone who was never exposed to the anti-hallucinogenic drug campaigns, this turn of events is mindboggling. There was a great deal of concern especially with LSD in the 1960s and it was not entirely unfounded. In my own family, a distant cousin, while under the influence of the drug, jumped off a building believing he could fly.  So, Kwon’s story opening with a story about someone being treated successfully for depression with a psychedelic drug was surprising to me . Why these drugs are being used successfully for psychiatric conditions when so much damage was apparently done under the influence in decades past may have something to do with taking the drugs in a controlled environment and, possibly, smaller dosages.

Alan Copperman and Amanda Marcotte have a very US-centric discussion about CRISPR and germline editing (designer babies?)

For anyone who needs more information, I ran a three part series on CRISPR germline editing on August 15, 2017:

Part 1 opens the series with a basic description of CRISPR and the germline research that occasioned the series along with some of the ethical issues and patent disputes that are arising from this new technology. CRISPR and editing the germline in the US (part 1 of 3): In the beginning

Part 2 covers three critical responses to the reporting and between them describe the technology in more detail and the possibility of ‘designer babies’.  CRISPR and editing the germline in the US (part 2 of 3): ‘designer babies’?

Part 3 is all about public discussion or, rather, the lack of and need for according to a couple of social scientists. Informally, there is some discussion via pop culture and Joelle Renstrom notes although she is focused on the larger issues touched on by the television series, Orphan Black and as I touch on in my final comments. CRISPR and editing the germline in the US (part 3 of 3): public discussions and pop culture

The news about CRISPR and germline editing by a US team made a bit of a splash even being mentioned on Salon.com, which hardly ever covers any science news (except for some occasional climate change pieces). In a Sept. 4, 2017 salon.com item (an excerpt from the full interview) Amanda Marcotte talks with Dr. Alan Copperman director of the division of reproductive endocrinology and infertility at Mount Sinai Medical Center about the technology and its implications.  As noted in the headline, it’s a US-centric discussion where assumptions are made about who will be leading discussions about the future of the technology.

It’s been a while since I’ve watched it but I believe they do mention in passing that Chinese scientists published two studies about using CRISPR to edit the germline (i think there’s a third Chinese paper in the pipeline) before the American team announced its accomplishment in August 2017. By the way, the first paper by the Chinese caused quite the quandary in April 2015. (My May 14, 2015 posting covers some of the ethical issues; scroll down about 50% of the way for more about the impact of the published Chinese research.)

Also, you might want notice just how smooth Copperman’s responses are almost always emphasizing the benefits of the technology before usually answering the question. He’s had media training and he’s good at this.

They also talk about corn and CRISPR just about the time that agricultural research was announced. Interesting timing, non? (See my Oct. 11, 2017 posting about CRISPR edited corn coming to market in 2020.)

For anyone who wants to skip to the full Marcotte/Cooperman interview, go here on Facebook.

Hit and run gene therapy?

The approach looks promising but there’s a still long way to go before this ‘simpler, gentler’ approach to gene therapy will make its way into any treatments. From an August 30, 2017 news item on Nanowerk,

A new biomedical tool using nanoparticles that deliver transient gene changes to targeted cells could make therapies for a variety of diseases — including cancer, diabetes and HIV — faster and cheaper to develop, and more customizable.

The tool, developed by researchers at Fred Hutchinson Cancer Research Center and tested in preclinical models, is described in a paper published August 30 [2017] in Nature Communications.

This animation demonstrates the approach,

Biodegradable nanoparticles (orange) carry short-lived gene therapy to specific cells (light teal). Animation by Kimberly Carney / Fred Hutch News Service

An August 30, 2017 Fred Hutchinson Cancer Research Center (Fred Hutch) news release (from news release received via email; also on EurekAlert) by Sabrina Richards, which originated the news item, elucidates further (Note: Some links and notes have been removed),

“Our goal is to streamline the manufacture of cell-based therapies,” said lead author DR. MATTHIAS STEPHAN [6], a faculty member in the Fred Hutch Clinical Research Division and an expert in developing biomaterials. “In this study, we created a product where you just add it to cultured cells and that’s it — no additional manufacturing steps.”

Stephan and his colleagues developed a nanoparticle delivery system to extend the therapeutic potential of messenger RNA, which delivers molecular instructions from DNA to cells in the body, directing them to make proteins to prevent or fight disease.

The researchers’ approach was designed to zero in on specific cell types — T cells of the immune system and blood stem cells — and deliver mRNA directly to the cells, triggering short-term gene expression. It’s called “hit-and-run” genetic programming because the transient effect of mRNA does not change the DNA, but it is enough to make a permanent impact on the cells’ therapeutic potential.

Stephan and colleagues used three examples in the Nature Communications paper to demonstrate their technology:

* Nanoparticles carried a gene-editing tool to T cells of the immune system that snipped out their natural T-cell receptors, and then was paired with genes encoding a “chimeric antigen receptor” or CAR, a synthetic molecule designed to attack cancer.
* Targeted to blood stem cells, nanoparticles were equipped with mRNA that enabled the stem cells to multiply and replace blood cancer cells with healthy cells when used in bone marrow transplants.
* Nanoparticles targeted to CAR-T cells and containing foxo1 mRNA, which signals the anti-cancer T cells to develop into a type of “memory” cell that is more aggressive and destroys tumor cells more effectively and maintains anti-tumor activity longer.

Other attempts to engineer mRNA into disease-fighting cells have been tricky. The large messenger molecule degrades quickly before it can have an effect, and the body’s immune system recognizes it as foreign — not coming from DNA in the nucleus of the cell — and destroys it.

Stephan and his Fred Hutch collaborators devised a workaround to those hurdles.

“We developed a nanocarrier that binds and condenses synthetic mRNA and protects it from degradation,” Stephan said. The researchers surrounded the nanoparticle with a negatively charged envelope with a targeting ligand attached to the surface so that the particle selectively homes in and binds to a particular cell type.

The cells swallow up the tiny carrier, which can be loaded with different types of manmade mRNA. “If you know from the scientific literature that a signaling pathway works in synergy, you could co-deliver mRNA in a single nanoparticle,” Stephan said. “Every cell that takes up the nanoparticle can express both.”

The approach involves mixing the freeze-dried nanoparticles with water and a sample of cells. Within four hours, cells start showing signs that the editing has taken effect. Boosters can be given if needed. Made from a dissolving biomaterial, the nanoparticles are removed from the body like other cell waste.

“Just add water to our freeze-dried product,” Stephan said. Since it’s built on existing technologies and doesn’t require knowledge of nanotechnology, he intends for it to be an off-the-shelf way for cell-therapy engineers to develop new approaches to treating a variety of diseases.

The approach could replace labor-intensive electroporation, a multistep cell-manufacturing technique that requires specialized equipment and clean rooms. All the handling ends up destroying many of the cells, which limits the amount that can be used in treatments for patients.

Gentler to cells, the nanoparticle system developed by the Fred Hutch team showed that up to 60 times more cells survive the process compared with electroporation. This is a critical feature for ensuring enough cells are viable when transferred to patients.

“You can imagine taking the nanoparticles, injecting them into a patient and then you don’t have to culture cells at all anymore,” he said.

Stephan has tested the technology is cultured cells in the lab, and it’s not yet available as a treatment. Stephan is looking for commercial partners to move the technology toward additional applications and into clinical trials where it could be developed into a therapy.

Here’s a link to and a citation for the paper,

Hit-and-run programming of therapeutic cytoreagents using mRNA nanocarriers by H. F. Moffett, M. E. Coon, S. Radtke, S. B. Stephan, L. McKnight, A. Lambert, B. L. Stoddard, H. P. Kiem, & M. T. Stephan. Nature Communications 8, Article number: 389 (2017) doi:10.1038/s41467-017-00505-8 Published online: 30 August 2017

This paper is open access.

Predicting drug side effects with guts-on-a-chip

It’s been a while since I’ve featured a story about a technology that could drastically reduce (or even eliminate) animal testing. Researchers in the Netherlands have announced some guts-on-a-chip research that may do just that. From an Aug. 22, 2017 news item on ScienceDaily,

Research conducted at Leiden has established that guts-on-chips respond in the same way to aspirin as real human organs do. This is a sign that these model organs are good predictors of the effect of medical drugs on the human body.

A method to test medical drugs for efficacy and potential side-effects, but then much cheaper and using the fewest possible lab animals: this is likely to be possible in future thanks to organs-on-chips, miniature model organs on microchips. In these model organs, which are equipped with human organ cells and microfluidic channels, researchers and pharmacists can mimic the working of an organ.

An Aug. 17, 2017 University of Leiden (Universiteit Leiden) press release, which originated the news item, provides more detail,

Leiden researchers, their spin-off company Mimetas and pharmaceutical company Roche have now shown that one type of organ chip experiences the same side-effects from the drug aspirin as the same organ in the human body. This is good news, because it is a sign that these miniature model organs are good predictors of the effect of medical drugs in the human body.

Aspirin

The researchers exposed 357 guts-on-chips for a significant period to the substance acetylsalicylic acid, better known as the analgesic aspirin. It has been known for a long time already that this substance can lead to gastrointestinal perforation, a complication that can be fatal if untreated. ‘We saw exactly the same side-effects occur in our guts-on-chips,’ says Professor of Analytical Biosciences Thomas Hankemeier. ‘In our model guts the gut wall also became more permeable after the drug had been administered.’

Effectiveness of candidate drugs

According to Hankemeier, the research shows that organs-on-chips are suited to testing a medical drug for efficacy and side-effects. This is good news for pharmacists, because the model organs make it easier for them to evaluate whether candidate drugs are effective or harmful. Many substances would be excluded from futher research before a drug entered the lab animal phase. This would help reduce the cost of drug production and mean less animal testing.

Diagnosing diseases

Organs-on-chips have taken off in recent years. They will be increasingly important in the near future, not just in drug development but also in the diagnosis of disease. Leiden researchers are at the forefront of this development. Hankemeier and a number of other groups (Erasmus MC, VUmc, RU Groningen) have been awared a 1.5 million ZonMW grant to research the effect of the body’s micro-organisms in the gut on the development of dementia. Organ-on-a-chip technology will play an important role here. Mimetas is the first company in the world to produce and sell organ chips on a large scale.

Here’s a link to and a citation for the paper,

Membrane-free culture and real-time barrier integrity assessment of perfused intestinal epithelium tubes by Sebastiaan J. Trietsch, Elena Naumovska, Dorota Kurek, Meily C. Setyawati, Marianne K. Vormann, Karlijn J. Wilschut, Henriëtte L. Lanz, Arnaud Nicolas, Chee Ping Ng, Jos Joore, Stefan Kustermann, Adrian Roth, Thomas Hankemeier, Annie Moisan, & Paul Vulto. Nature Communications 8, Article number: 262 (2017) doi:10.1038/s41467-017-00259-3 Published online: 15 August 2017

This paper is open access.

You can find Mimetas here.

Nanomesh for hypoallergenic wearable electronics

It stands to reason that sensors and monitoring devices held against the skin (wearable electronics) for long periods of time could provoke an allergic reaction. Scientists at the University of Tokyo have devised a possible solution according to a July 17, 2017 news item on ScienceDaily,

A hypoallergenic electronic sensor can be worn on the skin continuously for a week without discomfort, and is so light and thin that users forget they even have it on, says a Japanese group of scientists. The elastic electrode constructed of breathable nanoscale meshes holds promise for the development of noninvasive e-skin devices that can monitor a person’s health continuously over a long period.

Here’s an image illustrating the hypoallergenic electronics,

Caption: The electric current from a flexible battery placed near the knuckle flows through the conductor and powers the LED just below the fingernail. Credit: 2017 Someya Laboratory.

A University of Tokyo press release on EurekAlert, which originated the news item, expands on the theme,

Wearable electronics that monitor heart rate and other vital health signals have made headway in recent years, with next-generation gadgets employing lightweight, highly elastic materials attached directly onto the skin for more sensitive, precise measurements. However, although the ultrathin films and rubber sheets used in these devices adhere and conform well to the skin, their lack of breathability is deemed unsafe for long-term use: dermatological tests show the fine, stretchable materials prevent sweating and block airflow around the skin, causing irritation and inflammation, which ultimately could lead to lasting physiological and psychological effects.

“We learned that devices that can be worn for a week or longer for continuous monitoring were needed for practical use in medical and sports applications,” says Professor Takao Someya at the University of Tokyo’s Graduate School of Engineering whose research group had previously developed an on-skin patch that measured oxygen in blood.

In the current research, the group developed an electrode constructed from nanoscale meshes containing a water-soluble polymer, polyvinyl alcohol (PVA), and a gold layer–materials considered safe and biologically compatible with the body. The device can be applied by spraying a tiny amount of water, which dissolves the PVA nanofibers and allows it to stick easily to the skin–it conformed seamlessly to curvilinear surfaces of human skin, such as sweat pores and the ridges of an index finger’s fingerprint pattern.

The researchers next conducted a skin patch test on 20 subjects and detected no inflammation on the participants’ skin after they had worn the device for a week. The group also evaluated the permeability, with water vapor, of the nanomesh conductor–along with those of other substrates like ultrathin plastic foil and a thin rubber sheet–and found that its porous mesh structure exhibited superior gas permeability compared to that of the other materials.

Furthermore, the scientists proved the device’s mechanical durability through repeated bending and stretching, exceeding 10,000 times, of a conductor attached on the forefinger; they also established its reliability as an electrode for electromyogram recordings when its readings of the electrical activity of muscles were comparable to those obtained through conventional gel electrodes.

“It will become possible to monitor patients’ vital signs without causing any stress or discomfort,” says Someya about the future implications of the team’s research. In addition to nursing care and medical applications, the new device promises to enable continuous, precise monitoring of athletes’ physiological signals and bodily motion without impeding their training or performance.

Here’s a link to and a citation for the paper,

Inflammation-free, gas-permeable, lightweight, stretchable on-skin electronics with nanomeshes by Akihito Miyamoto, Sungwon Lee, Nawalage Florence Cooray, Sunghoon Lee, Mami Mori, Naoji Matsuhisa, Hanbit Jin, Leona Yoda, Tomoyuki Yokota, Akira Itoh, Masaki Sekino, Hiroshi Kawasaki, Tamotsu Ebihara, Masayuki Amagai, & Takao Someya. Nature Nanotechnology (2017) doi:10.1038/nnano.2017.125 Published online 17 July 2017

This paper is behind a paywall.