Category Archives: health and safety

Food nanoparticles and their effect on intestinal flora (i.e., your gut microbiome)

This work from Germany is largely speculative. The scientists seem to be interested in exploring how engineered nanoparticles and naturally occurring nanoparticles in food affect your gut. From a January 29, 2019 news item on ScienceDaily,

The intestinal microbiome is not only key for food processing but an accepted codeterminant for various diseases. Researchers led by the University Medical Center of Johannes Gutenberg University Mainz (JGU) identified effects of nanoparticles on intestinal microorganisms. The ultra-small particles adhere to intestinal microorganisms, thereby affecting their life cycle as well as cross talk with the host. One of the researchers’ observations was that nanoparticles’ binding inhibits the infection with Helicobacter pylori, a pathogen implicated in gastric cancer. The findings will stimulate further epidemiological studies and pave the way for the development of potential ‘probiotic’ nanoparticles for food. The discoveries were published in Science of Food.

A January 29, 2019 Johannes Gutenberg University Mainz (JGU) press release (also on EurekAlert), which originated the news item, provides more detail,

Due to their minute size, nanoparticles have unique characteristics and capabilities, such as adhering to microstructures. Nanotechnology is as an important driver of innovation for both consumer industry and medicine. In medicine, the focus is on improving diagnostics and therapeutics, while industry addresses mainly product optimization. Hence, synthetic nanoparticles are already used as additives to improve the characteristics of food. But how can we use nanotechnology more efficiently and safely in food? And are there unknown effects of nanoparticles, which need to be further exploited?

Nutrition strongly influences the diversity and composition of our microbiome. ‘Microbiome’ describes all colonizing microorganisms present in a human being, in particular, all the bacteria in the gut. In other words, your microbiome includes your intestinal flora as well as the microorganisms that colonize your skin, mouth, and nasal cavity.

Scientists and clinicians are interested in microbiomes because of their positive or negative effects on the host. These include modulation of our immune system, metabolism, vascular aging, cerebral functioning, and our hormonal system. The composition of the microbiome seems to play an important role for the development of various disorders, such as cardiovascular diseases, cancer, allergies, obesity, and even mental disorders. “Hence, nutrition and its containing nanoparticulates may affect the microbiome-host balance, finally influencing human health. In order to reduce potential risks and, ideally, promote health, the impact of dietary nanoparticles needs to be understood,” emphasized Professor David J. McClements from the Department of Food Science at the University of Massachusetts in Amherst, USA.

“Prior to our studies, nobody really looked whether and how nano-additives directly influence the gastrointestinal flora,” commented Professor Roland Stauber of the Department of Otolaryngology, Head, and Neck Surgery at the Mainz University Medical Center. “Hence, we studied at a wide range of technical nanoparticles with clearly defined properties in order to mimic what happens to currently used or potential future nanosized food additives. By simulating the journey of particles through the different environments of the digestive tract in the laboratory, we found that the all tested nanomaterials were indeed able to bind to bacteria.” explained Stauber.

The scientists discovered that these binding processes can have different outcomes. On the one hand, nanoparticle-bound microorganisms were less efficiently recognized by the immune system, which may lead to increased inflammatory responses. On the other hand, ‘nano-food’ showed beneficial effects. In cell culture models, silica nanoparticles inhibited the infectivity of Helicobacter pylori, which is considered to be one of the main agents involved in gastric cancer.

‘It was puzzling that we were able to also isolate naturally occurring nanoparticles from food, like beer, which showed similar effects. Nanoparticles in our daily food are not just those added deliberately but can also be generated naturally during preparation. Nanoparticulates are already omnipresent,” concluded Stauber.

The insights of the study will allow to derive strategies for developing and utilizing synthetic or natural nanoparticles to modulate the microbiome as beneficial ingredients in functional foods. “The challenge is to identify nanoparticles that fit the desired purpose, perhaps even as probiotic food supplements in the future. Challenge accepted,” emphasized Stauber and his team.

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

Nanosized food additives impact beneficial and pathogenic bacteria in the human gut: a simulated gastrointestinal study by Svenja Siemer, Angelina Hahlbrock, Cecilia Vallet, David Julian McClements, Jan Balszuweit, Jens Voskuhl, Dominic Docter, Silja Wessler, Shirley K. Knauer, Dana Westmeier, & Roland H. Stauber. npj Science of Foodvolume 2, Article number: 22 (2018) DOI: https://doi.org/10.1038/s41538-018-0030-8 Published 04 December 2018

This paper is open access.

Iron oxide nanoparticles for artificial skin with super powers

A January 28, 2019 news item on ScienceDaily describes the possibilities for a skin replacement material,

A new type of sensor could lead to artificial skin that someday helps burn victims ‘feel’ and safeguards the rest of us, University of Connecticut researchers suggest in a paper in Advanced Materials.

Our skin’s ability to perceive pressure, heat, cold, and vibration is a critical safety function that most people take for granted. But burn victims, those with prosthetic limbs, and others who have lost skin sensitivity for one reason or another, can’t take it for granted, and often injure themselves unintentionally.

Chemists Islam Mosa from UConn [University of Connecticut], and James Rusling from UConn and UConn Health, along with University of Toronto engineer Abdelsalam Ahmed, wanted to create a sensor that can mimic the sensing properties of skin. Such a sensor would need to be able to detect pressure, temperature, and vibration. But perhaps it could do other things too, the researchers thought.

“It would be very cool if it had abilities human skin does not; for example, the ability to detect magnetic fields, sound waves, and abnormal behaviors,” said Mosa.

A January 22, 2019 UConn news release (also on EurekAlert but dated January 28, 2019), which originated the news item, give more detail about the work,

Mosa and his colleagues created such a sensor with a silicone tube wrapped in a copper wire and filled with a special fluid made of tiny particles of iron oxide just one billionth of a meter long, called nanoparticles. The nanoparticles rub around the inside of the silicone tube and create an electric current. The copper wire surrounding the silicone tube picks up the current as a signal. When this tube is bumped by something experiencing pressure, the nanoparticles move and the electric signal changes. Sound waves also create waves in the nanoparticle fluid, and the electric signal changes in a different way than when the tube is bumped.

The researchers found that magnetic fields alter the signal too, in a way distinct from pressure or sound waves. Even a person moving around while carrying the sensor changes the electrical current, and the team found they could distinguish between the electrical signals caused by walking, running, jumping, and swimming.

Metal skin might sound like a superhero power, but this skin wouldn’t make the wearer Colossus from the X-men. Rather, Mosa and his colleagues hope it could help burn victims “feel” again, and perhaps act as an early warning for workers exposed to dangerously high magnetic fields. Because the rubber exterior is completely sealed and waterproof, it could also serve as a wearable monitor to alert parents if their child fell into deep water in a pool, for example.

“The inspiration was to make something durable that would last for a very long time, and could detect multiple hazards,” Mosa says. The team has yet to test the sensor for its response to heat and cold, but they suspect it will work for those as well. The next step is to make the sensor in a flat configuration, more like skin, and see if it still works.

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

An Ultra‐Shapeable, Smart Sensing Platform Based on a Multimodal Ferrofluid‐Infused Surface by Abdelsalam Ahmed, Islam Hassan, Islam M. Mosa, Esraa Elsanadidy, Mohamed Sharafeldin, James F. Rusling, Shenqiang Ren. Advanced Materials DOI: https://doi.org/10.1002/adma.201807201 First published: 28 January 2019

This paper is behind a paywall.

How do nanoparticles interact with the environment and with humans over time?

I meant to get this piece published sooner but good intentions don’t get you far.

At Northwestern University, scientists have researched the impact engineered nanoparticles (ENPs) might have as they enter the food chain. An October 18, 2019 Northwestern University news release (also on EurekAlert) by Megan Fellman describes research on an investigation of ENPs and their interaction with living organisms,

Personal electronic devices — smartphones, computers, TVs, tablets, screens of all kinds — are a significant and growing source of the world’s electronic waste. Many of these products use nanomaterials, but little is known about how these modern materials and their tiny particles interact with the environment and living things.

Now a research team of Northwestern University chemists and colleagues from the national Center for Sustainable Nanotechnology has discovered that when certain coated nanoparticles interact with living organisms it results in new properties that cause the nanoparticles to become sticky. Fragmented lipid coronas form on the particles, causing them to stick together and grow into long kelp-like strands. Nanoparticles with 5-nanometer diameters form long structures that are microns in size in solution. The impact on cells is not known.

“Why not make a particle that is benign from the beginning?” said Franz M. Geiger, professor of chemistry in Northwestern’s Weinberg College of Arts and Sciences. He led the Northwestern portion of the research.

“This study provides insight into the molecular mechanisms by which nanoparticles interact with biological systems,” Geiger said. “This may help us understand and predict why some nanomaterial/ligand coating combinations are detrimental to cellular organisms while others are not. We can use this to engineer nanoparticles that are benign by design.”

Using experiments and computer simulations, the research team studied how gold nanoparticles wrapped in strings having positively charged beads interact with a variety of bilayer membrane models. The researchers found that a nearly circular layer of lipids forms spontaneously around the particles. Formation of these “fragmented lipid coronas” have never been seen before to form from membranes.

The study points to solving problems with chemistry. Scientists can use the findings to design a better ligand coating for nanoparticles that avoids the ammonium-phosphate interaction, which causes the aggregation. (Ligands are used in nanomaterials for layering.)

The results will be published Oct. 18 [2018] in the journal Chem.

Geiger is the study’s corresponding author. Other authors include scientists from the Center for Sustainable Nanotechnology’s other institutional partners. Based at the University of Wisconsin-Madison, the center studies engineered nanomaterials and their interaction with the environment, including biological systems — both the negative and positive aspects.

“The nanoparticles pick up parts of the lipid cellular membrane like a snowball rolling in a snowfield, and they become sticky,” Geiger said. “This unintended effect happens because of the presence of the nanoparticle. It can bring lipids to places in cells where lipids are not meant to be.”

The experiments were conducted in idealized laboratory settings that nevertheless are relevant to environments found during the late summer in a landfill — at 21-22 degrees Celsius and a couple feet below ground, where soil and groundwater mix and the food chain begins.

By pairing spectroscopic and imaging experiments with atomistic and coarse-grain simulations, the researchers identified that ion pairing between the lipid head groups of biological membranes and the polycations’ ammonium groups in the nanoparticle wrapping leads to the formation of fragmented lipid coronas. These coronas engender new properties, including composition and stickiness, to the particles with diameters below 10 nanometers.

The study’s insights help predict the impact that the increasingly widespread use of engineered nanomaterials has on the nanoparticles’ fate once they enter the food chain, which many of them may eventually do.

“New technologies and mass consumer products are emerging that feature nanomaterials as critical operational components,” Geiger said. “We can upend the existing paradigm in nanomaterial production towards one in which companies design nanomaterials to be sustainable from the beginning, as opposed to risking expensive product recalls — or worse — down the road.” [emphases mine]

Here’s an image illustrating the work,

Caption: This is a computer simulation of a lipid corona around a 5-nanometer nanoparticle showing ammonium-phosphate ion pairing. Credit: Northwestern University

The curious can find the paper here,

Lipid Corona Formation from Nanoparticle Interactions with Bilayers by Laura L. Olenick, Julianne M. Troiano, Ariane Vartanian, Eric S. Melby, Arielle C. Mensch, Leili Zhang, Jiewei Hong, Oluwaseun Mesele, Tian Qiu, Jared Bozich, Samuel Lohse, Xi Zhang, Thomas R. Kuech, Augusto Millevolte, Ian Gunsolus, Alicia C. McGeachy, Merve Doğangün, Tianzhe Li, Dehong Hu, Stephanie R. Walter, Aurash Mohaimani, Angela Schmoldt, Marco D. Torelli, Katherine R. Hurley, Joe Dalluge, Gene Chong, Z. Vivian Feng, Christy L. Haynes, Robert J. Hamers, Joel A. Pedersen, Qiang Cui, Rigoberto Hernandez, Rebecca Klaper, Galya Orr, Catherine J. Murphy, Franz M. Geiger. Chem Volume 4, ISSUE 11, P2709-2723, November 08, 2018 DOI:https://doi.org/10.1016/j.chempr.2018.09.018 Published:October 18, 2018

This paper is behind a paywall.

Human lung enzyme can degrade graphene

Caption: A human lung enzyme can biodegrade graphene. Credit: Fotolia Courtesy: Graphene Flagship

The big European Commission research programme, Grahene Flagship, has announced some new work with widespread implications if graphene is to be used in biomedical implants. From a August 23, 2018 news item on ScienceDaily,

Myeloperoxidase — an enzyme naturally found in our lungs — can biodegrade pristine graphene, according to the latest discovery of Graphene Flagship partners in CNRS, University of Strasbourg (France), Karolinska Institute (Sweden) and University of Castilla-La Mancha (Spain). Among other projects, the Graphene Flagship designs based like flexible biomedical electronic devices that will interfaced with the human body. Such applications require graphene to be biodegradable, so our body can be expelled from the body.

An August 23, 2018 Grapehene Flagship press release (mildly edited version on EurekAlert), which originated the news item, provides more detail,

To test how graphene behaves within the body, researchers analysed how it was broken down with the addition of a common human enzyme – myeloperoxidase or MPO. If a foreign body or bacteria is detected, neutrophils surround it and secrete MPO, thereby destroying the threat. Previous work by Graphene Flagship partners found that MPO could successfully biodegrade graphene oxide.

However, the structure of non-functionalized graphene was thought to be more resistant to degradation. To test this, the team looked at the effects of MPO ex vivo on two graphene forms; single- and few-layer.

Alberto Bianco, researcher at Graphene Flagship Partner CNRS, explains: “We used two forms of graphene, single- and few-layer, prepared by two different methods in water. They were then taken and put in contact with myeloperoxidase in the presence of hydrogen peroxide. This peroxidase was able to degrade and oxidise them. This was really unexpected, because we thought that non-functionalized graphene was more resistant than graphene oxide.”

Rajendra Kurapati, first author on the study and researcher at Graphene Flagship Partner CNRS, remarks how “the results emphasize that highly dispersible graphene could be degraded in the body by the action of neutrophils. This would open the new avenue for developing graphene-based materials.”

With successful ex-vivo testing, in-vivo testing is the next stage. Bengt Fadeel, professor at Graphene Flagship Partner Karolinska Institute believes that “understanding whether graphene is biodegradable or not is important for biomedical and other applications of this material. The fact that cells of the immune system are capable of handling graphene is very promising.”

Prof. Maurizio Prato, the Graphene Flagship leader for its Health and Environment Work Package said that “the enzymatic degradation of graphene is a very important topic, because in principle, graphene dispersed in the atmosphere could produce some harm. Instead, if there are microorganisms able to degrade graphene and related materials, the persistence of these materials in our environment will be strongly decreased. These types of studies are needed.” “What is also needed is to investigate the nature of degradation products,” adds Prato. “Once graphene is digested by enzymes, it could produce harmful derivatives. We need to know the structure of these derivatives and study their impact on health and environment,” he concludes.

Prof. Andrea C. Ferrari, Science and Technology Officer of the Graphene Flagship, and chair of its management panel added: “The report of a successful avenue for graphene biodegradation is a very important step forward to ensure the safe use of this material in applications. The Graphene Flagship has put the investigation of the health and environment effects of graphene at the centre of its programme since the start. These results strengthen our innovation and technology roadmap.”

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

Degradation of Single‐Layer and Few‐Layer Graphene by Neutrophil Myeloperoxidase by Dr. Rajendra Kurapati, Dr. Sourav P. Mukherjee, Dr. Cristina Martín, Dr. George Bepete, Prof. Ester Vázquez, Dr. Alain Pénicaud, Prof. Dr. Bengt Fadeel, Dr. Alberto Bianco. Angewandte Chemie https://doi.org/10.1002/anie.201806906 First published: 13 July 2018

This paper is behind a paywall.

Nanoparticles in combination could be more toxic

It seems that one set of nanoparticles, e.g., silver nanoparticles, in combination with another material, e.g., cadmium ions, are more dangerous than either one separately according to an August 17, 2018 University of Southern Denmark press release by Birgitte Svennevig (also on EurekAlert but dated August 20, 2018),

Researchers warn that a combination of nanoparticles and contaminants may form a cocktail that is harmful to our cells. In their study, 72 pct. of cells died after exposure to a cocktail of nano-silver and cadmium ions.

Nanoparticles are becoming increasingly widespread in our environment. Thousands of products contain nanoparticles because of their unique properties. Silver nanoparticles are one example: They have an effective antibacterial effect and can be found in refrigerators, sports clothes, cosmetics, tooth brushes, water filters, etc.

There is a significant difference between how the cells react when exposed to nanosilver alone and when they are exposed to a cocktail of nanosilver and cadmium ions. Cadmium ions are naturally found everywhere around us on Earth.

In the study, 72 pct. of the cells died, when exposed to both nanosilver and cadmiun ions. When exposed to nanosilver only, 25 pct. died. When exposed to cadmium ions only, 12 pct. died.

The study was conducted on human liver cancer cells.

  • This study indicates, that we should not look at nanoparticles isolated when we investigate and discuss the effects, they may have on our health. We need to take cocktail effects into account, said Professor Frank Kjeldsen, Dept of Biochemistry and Molecular Biology, SDU, adding:
  • Products with nano particles are being developed and manufactured every day, but in most countries there are no regulations, so there is no way of knowing what and how many nanoparticles are being released into the environment. In my opinion, this should be stopped.

Other studies, led by Professor Kjeldsen have previously shown that human cells interact with metal nanoparticles.

One study showed that nano-silver leads to the formation free radicals in cells and changes in the form and amount of proteins. Many serious diseases are characterized by an overproduction of free radicals in cells. This applies to cancer and neurological diseases such as Alzheimer’s and Parkinson’s.

This is not great news but there are a few things to note about this research. First, it was conducted on cells and therefore not subject to some of the defensive systems found in complete biological organisms such as a mouse or a dandelion plant for example.

Also, since they were cancer cells one might suspect their reactions might differ from those of healthy cells. As for how the cells were exposed to the contaminants, I think (???) they were sitting in a solution of contaminants and most of us do not live in that kind of environment.. Finally, with regard to the concentrations, I have no idea if they are greater than one might expect to encounter in one’s lifecycle but it’s always worth questioning just how much exposure you might expect during yours or a mouse’s or a dandelion’s life.

These caveats aside, Professor Frank Kjeldsen’s work raises some very concerning issues and his work adds to a growing body of evidence.

Here’s a video featuring Dr. Kjeldsen talking about his work,

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

Co-exposure to silver nanoparticles and cadmium induce metabolic adaptation in HepG2 cells by Renata Rank Miranda, Vladimir Gorshkov, Barbara Korzeniowska, Stefan J. Kempf, Francisco Filipak Neto, & Frank Kjeldsen. Nanotoxicology DOI: https://doi.org/10.1080/17435390.2018.1489987 Published online: 11 Jul 2018

This paper is open access.

Artificial intelligence (AI) brings together International Telecommunications Union (ITU) and World Health Organization (WHO) and AI outperforms animal testing

Following on my May 11, 2018 posting about the International Telecommunications Union (ITU) and the 2018 AI for Good Global Summit in mid- May, there’s an announcement. My other bit of AI news concerns animal testing.

Leveraging the power of AI for health

A July 24, 2018 ITU press release (a shorter version was received via email) announces a joint initiative focused on improving health,

Two United Nations specialized agencies are joining forces to expand the use of artificial intelligence (AI) in the health sector to a global scale, and to leverage the power of AI to advance health for all worldwide. The International Telecommunication Union (ITU) and the World Health Organization (WHO) will work together through the newly established ITU Focus Group on AI for Health to develop an international “AI for health” standards framework and to identify use cases of AI in the health sector that can be scaled-up for global impact. The group is open to all interested parties.

“AI could help patients to assess their symptoms, enable medical professionals in underserved areas to focus on critical cases, and save great numbers of lives in emergencies by delivering medical diagnoses to hospitals before patients arrive to be treated,” said ITU Secretary-General Houlin Zhao. “ITU and WHO plan to ensure that such capabilities are available worldwide for the benefit of everyone, everywhere.”

The demand for such a platform was first identified by participants of the second AI for Good Global Summit held in Geneva, 15-17 May 2018. During the summit, AI and the health sector were recognized as a very promising combination, and it was announced that AI-powered technologies such as skin disease recognition and diagnostic applications based on symptom questions could be deployed on six billion smartphones by 2021.

The ITU Focus Group on AI for Health is coordinated through ITU’s Telecommunications Standardization Sector – which works with ITU’s 193 Member States and more than 800 industry and academic members to establish global standards for emerging ICT innovations. It will lead an intensive two-year analysis of international standardization opportunities towards delivery of a benchmarking framework of international standards and recommendations by ITU and WHO for the use of AI in the health sector.

“I believe the subject of AI for health is both important and useful for advancing health for all,” said WHO Director-General Tedros Adhanom Ghebreyesus.

The ITU Focus Group on AI for Health will also engage researchers, engineers, practitioners, entrepreneurs and policy makers to develop guidance documents for national administrations, to steer the creation of policies that ensure the safe, appropriate use of AI in the health sector.

“1.3 billion people have a mobile phone and we can use this technology to provide AI-powered health data analytics to people with limited or no access to medical care. AI can enhance health by improving medical diagnostics and associated health intervention decisions on a global scale,” said Thomas Wiegand, ITU Focus Group on AI for Health Chairman, and Executive Director of the Fraunhofer Heinrich Hertz Institute, as well as professor at TU Berlin.

He added, “The health sector is in many countries among the largest economic sectors or one of the fastest-growing, signalling a particularly timely need for international standardization of the convergence of AI and health.”

Data analytics are certain to form a large part of the ITU focus group’s work. AI systems are proving increasingly adept at interpreting laboratory results and medical imagery and extracting diagnostically relevant information from text or complex sensor streams.

As part of this, the ITU Focus Group for AI for Health will also produce an assessment framework to standardize the evaluation and validation of AI algorithms — including the identification of structured and normalized data to train AI algorithms. It will develop open benchmarks with the aim of these becoming international standards.

The ITU Focus Group for AI for Health will report to the ITU standardization expert group for multimedia, Study Group 16.

I got curious about Study Group 16 (from the Study Group 16 at a glance webpage),

Study Group 16 leads ITU’s standardization work on multimedia coding, systems and applications, including the coordination of related studies across the various ITU-T SGs. It is also the lead study group on ubiquitous and Internet of Things (IoT) applications; telecommunication/ICT accessibility for persons with disabilities; intelligent transport system (ITS) communications; e-health; and Internet Protocol television (IPTV).

Multimedia is at the core of the most recent advances in information and communication technologies (ICTs) – especially when we consider that most innovation today is agnostic of the transport and network layers, focusing rather on the higher OSI model layers.

SG16 is active in all aspects of multimedia standardization, including terminals, architecture, protocols, security, mobility, interworking and quality of service (QoS). It focuses its studies on telepresence and conferencing systems; IPTV; digital signage; speech, audio and visual coding; network signal processing; PSTN modems and interfaces; facsimile terminals; and ICT accessibility.

I wonder which group deals with artificial intelligence and, possibly, robots.

Chemical testing without animals

Thomas Hartung, professor of environmental health and engineering at Johns Hopkins University (US), describes in his July 25, 2018 essay (written for The Conversation) on phys.org the situation where chemical testing is concerned,

Most consumers would be dismayed with how little we know about the majority of chemicals. Only 3 percent of industrial chemicals – mostly drugs and pesticides – are comprehensively tested. Most of the 80,000 to 140,000 chemicals in consumer products have not been tested at all or just examined superficially to see what harm they may do locally, at the site of contact and at extremely high doses.

I am a physician and former head of the European Center for the Validation of Alternative Methods of the European Commission (2002-2008), and I am dedicated to finding faster, cheaper and more accurate methods of testing the safety of chemicals. To that end, I now lead a new program at Johns Hopkins University to revamp the safety sciences.

As part of this effort, we have now developed a computer method of testing chemicals that could save more than a US$1 billion annually and more than 2 million animals. Especially in times where the government is rolling back regulations on the chemical industry, new methods to identify dangerous substances are critical for human and environmental health.

Having written on the topic of alternatives to animal testing on a number of occasions (my December 26, 2014 posting provides an overview of sorts), I was particularly interested to see this in Hartung’s July 25, 2018 essay on The Conversation (Note: Links have been removed),

Following the vision of Toxicology for the 21st Century, a movement led by U.S. agencies to revamp safety testing, important work was carried out by my Ph.D. student Tom Luechtefeld at the Johns Hopkins Center for Alternatives to Animal Testing. Teaming up with Underwriters Laboratories, we have now leveraged an expanded database and machine learning to predict toxic properties. As we report in the journal Toxicological Sciences, we developed a novel algorithm and database for analyzing chemicals and determining their toxicity – what we call read-across structure activity relationship, RASAR.

This graphic reveals a small part of the chemical universe. Each dot represents a different chemical. Chemicals that are close together have similar structures and often properties. Thomas Hartung, CC BY-SA

To do this, we first created an enormous database with 10 million chemical structures by adding more public databases filled with chemical data, which, if you crunch the numbers, represent 50 trillion pairs of chemicals. A supercomputer then created a map of the chemical universe, in which chemicals are positioned close together if they share many structures in common and far where they don’t. Most of the time, any molecule close to a toxic molecule is also dangerous. Even more likely if many toxic substances are close, harmless substances are far. Any substance can now be analyzed by placing it into this map.

If this sounds simple, it’s not. It requires half a billion mathematical calculations per chemical to see where it fits. The chemical neighborhood focuses on 74 characteristics which are used to predict the properties of a substance. Using the properties of the neighboring chemicals, we can predict whether an untested chemical is hazardous. For example, for predicting whether a chemical will cause eye irritation, our computer program not only uses information from similar chemicals, which were tested on rabbit eyes, but also information for skin irritation. This is because what typically irritates the skin also harms the eye.

How well does the computer identify toxic chemicals?

This method will be used for new untested substances. However, if you do this for chemicals for which you actually have data, and compare prediction with reality, you can test how well this prediction works. We did this for 48,000 chemicals that were well characterized for at least one aspect of toxicity, and we found the toxic substances in 89 percent of cases.

This is clearly more accurate that the corresponding animal tests which only yield the correct answer 70 percent of the time. The RASAR shall now be formally validated by an interagency committee of 16 U.S. agencies, including the EPA [Environmental Protection Agency] and FDA [Food and Drug Administration], that will challenge our computer program with chemicals for which the outcome is unknown. This is a prerequisite for acceptance and use in many countries and industries.

The potential is enormous: The RASAR approach is in essence based on chemical data that was registered for the 2010 and 2013 REACH [Registration, Evaluation, Authorizations and Restriction of Chemicals] deadlines [in Europe]. If our estimates are correct and chemical producers would have not registered chemicals after 2013, and instead used our RASAR program, we would have saved 2.8 million animals and $490 million in testing costs – and received more reliable data. We have to admit that this is a very theoretical calculation, but it shows how valuable this approach could be for other regulatory programs and safety assessments.

In the future, a chemist could check RASAR before even synthesizing their next chemical to check whether the new structure will have problems. Or a product developer can pick alternatives to toxic substances to use in their products. This is a powerful technology, which is only starting to show all its potential.

It’s been my experience that these claims having led a movement (Toxicology for the 21st Century) are often contested with many others competing for the title of ‘leader’ or ‘first’. That said, this RASAR approach seems very exciting, especially in light of the skepticism about limiting and/or making animal testing unnecessary noted in my December 26, 2014 posting.it was from someone I thought knew better.

Here’s a link to and a citation for the paper mentioned in Hartung’s essay,

Machine learning of toxicological big data enables read-across structure activity relationships (RASAR) outperforming animal test reproducibility by Thomas Luechtefeld, Dan Marsh, Craig Rowlands, Thomas Hartung. Toxicological Sciences, kfy152, https://doi.org/10.1093/toxsci/kfy152 Published: 11 July 2018

This paper is open access.

Sound-absorbing nanofoam

In these increasingly noisy days (there’s construction going on around me), news of a cheaper, easier way to dull the noise is very attractive. From a June 25, 2018 Far Eastern Federal University (Russia) press release on EurekAlert,

The breakthrough material reduces a noise level by 100% more efficient comparing to standard analogs, cutting the level of noise transmission by 20-22 dB. The new foam reacts to sound waves not only of high but also of low frequencies, which can damage human health. A young scientist from the Far Eastern Federal University (FEFU) took part in the development.

PARTNERSHIP DEVELOPMENT

Alexey Zavjalov, postdoc, researcher at the Academic Department of Nuclear Technologies School of Natural Science, FEFU, worked as a part of the international team of Russian and South Korean scientists under professor S.P. Bardakhanov. Alexey’s research performance led to the creation of nanofoam – the new noise-absorbing composite material. The results of the work are published in ‘Applied Acoustics’.

‘The problem of noise is the problem of modern technogenic civilization. In South Korea, cities are equipped with round-the-clock working stationary and mobile networks for noise levels monitoring. The urbanization level of such territorially small countries as South Korea is much higher than in Russia. However, in our country this problem is still crucial for big cities,’ – explained Alexey Zavjalov. – ‘The development of new noise-absorbing materials is especially interesting for the automotive industry. Modern people spend a lot of time driving cars and the noise level inside the vehicles’ directly determines the quality of life. For East Asian countries, the issue of noise control is relevant for high-speed rail lines.’ Porous materials are excellent sound absorbers but their noise-absorbing properties can be significantly enhanced by nanoporous grit injected into the foam structure and formed internal channels in it. Alexey Zavjalov has developed approaches for saturation of macroporous foam material with nanoporous grit.

HARMFULNESS OF THE LOW FREQUENCIES NOISES.

Along with the rapid development of nanotechnology, there have been many attempts to mix nano- and microsized materials to create a modified material with enhanced strength, elastic, dynamical and vibrational properties. The acoustic parameters of such materials could not be fundamentally enhanced thus far.

Foam materials are most often used for soundproofing purposes. They provide the proper quality at a reasonable cost, but until today have been effective against high-frequency noise only. At the same time, low frequencies can be much more harmful to human health.

Infra- and low-frequency vibrations and noise (less than 0.4 kHz) are most harmful and dangerous for human health and life. Especially unfavorable is their long-lasting impact, since leads to serious diseases and pathologies. Complaints on such oppressions exceed 35% of the sum total of complaints on harmful environmental conditions.

The foam material, developed by Russian and Korean scientists, demonstrated promising results at medium frequencies and, therefore, more specialized low-frequency noise tests are needed.

CHEAPER AND EASIER FOR APPLICATION THAN AEROGEL.

The improved acoustic characteristics of the newest hybrid nanofoam were obtained by additional impregnation of the standard off-the-shelf sound-absorbing foam with porous granules of silica and magnetite nanoparticles. The porous foam was immersed in nanopowder suspensions in the liquid, subjected to ultrasonic treatment and dried.

The nanoparticles granules formed in the result can be compared structurally to a widely known class of materials – aerogel. It has not only excellent thermal insulation properties but also has a good noise-proof. However, aerogels are quite expensive and complex when used in structures. The new material, created according to the scheme developed by the FEFU researcher, is structurally similar to aerogel but is free of such shortcomings as a high price and engineering problems.

COMPOSITE TECHNOLOGY

The mechanism of sound absorption of a new foam is based on the fact that its sound-absorbing surface is significantly scaled due to the presence of a large number of nanopores in the particles injected, as well as the location of these particles in the foam matrix in the form of distinct channels. Nanoparticles dissipate the energy of a sound wave transforming it into heat. The soundproof properties of the material increase.

Scientists found out that the composite structure is most effective for noise reduction. Thin layers of foam impregnated with nanoparticles are connected to each other in a “sandwich”-construction. This design significantly improves the soundproof properties of the resulting material. The outcome of the study also suggests that the more foamy material is impregnated with nanoparticles, the better it’s sound absorption is.

‘In some approximation, any material can be represented as a network of weights connected by springs. Such a mechanical system always has its own frequency bands, in which the oscillations propagate in the system relatively freely. There are also forbidden frequency bands in which the oscillations rapidly fade out in the system. To effectively extinguish the transmission of oscillations, including sound waves, the materials should be alternated in such a way that the fluctuations that propagate freely in the first material would be in the forbidden band for the second layer,’- commented Alexey Zavjalov. – ‘Of course, for our foam material, this idealization is too crude. However, it allows us to clearly illustrate the fundamentally conditioned necessity of creating a “sandwich” structure.’

RESEARCH OUTCOME

The study showed the effectiveness of the method of foams impregnation with nanosilica or nanomagnetite, which form granules up to several hundred micrometers (in accordance with the pore sizes of the modified foam material) and having pores about 15 nm. This small addition provided a more complex and branched 3D network of nanochannels which led to an additional absorption of noise energy.

Due to the method used, the noise absorption efficiency was achieved in the range of 2.0-6.3 kHz and at lower frequencies 0.5-1.6 kHz. The degree of absorption was increased by 60-100% and the sound transmission was reduced by 20-22 dB, regardless of the type of nanofiller.

‘There is room to further improve the sound absorbing properties of the new material for medium and low frequencies using the” active control” strategy’. – Alexey Zavjalov comments on the plans for further development of such an important scientific topic. – ‘First of all, this refers to the materials obtained by using a magnetite nanopowder. Active noise protection systems have long been used in the world. The main idea is to detect the noise acoustic fields “online” and to generate sound waves in antiphase by means of loudspeakers. That allows achieving a significant reduction of noise in a given area. Concerning the nanofoam, it’s proposed to adapt this approach and to actively exert on a material saturated with granules of magnetite nanoparticles by magnetic fields. This will achieve even better noise reduction.’

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

Hybrid sound-absorbing foam materials with nanostructured grit-impregnated pores by S.P.Bardakhanov, C.M.Lee, V.N.Goverdovskiy, A.P.Zavjalov, K.V.Zobov, M.Chen, Z.H.Xu, I.K.Chakin, D.Yu.Trufanov. Applied Acoustics Volume 139, October 2018, Pages 69-74
https://doi.org/10.1016/j.apacoust.2018.04.024 Available online 23 April 2018.

This paper is behind a paywall.

If you have difficulty seeing the press release on EurekAlert, there is a June 26, 2018 news item on a Russian news site, RSF News and there is an edited version in a June 26, 2018 news item on Azonano.

Australian scientists say that sunscreens with zinc oxide nanoparticles aren’t toxic to you

The Australians have had quite the struggle over whether or not to use nanotechnology-enabled sunscreens (see my Feb. 9, 2012 posting about an Australian nanosunscreen debacle and I believe the reverberations continue even ’til today). This latest research will hopefully help calm the waters. From a Dec. 4, 2018 news item on ScienceDaily,

Zinc oxide (ZnO) has long been recognized as an effective sunscreen agent. However, there have been calls for sunscreens containing ZnO nanoparticles to be banned because of potential toxicity and the need for caution in the absence of safety data in humans. An important new study provides the first direct evidence that intact ZnO nanoparticles neither penetrate the human skin barrier nor cause cellular toxicity after repeated application to human volunteers under in-use conditions. This confirms that the known benefits of using ZnO nanoparticles in sunscreens clearly outweigh the perceived risks, reports the Journal of Investigative Dermatology.

A December 4, 2018 Elsevier (Publishing) press release (also on EurekAlert), which originated the news item, provides international context for the safety discussion while providing more details about this latest research,

The safety of nanoparticles used in sunscreens has been a highly controversial international issue in recent years, as previous animal exposure studies found much higher skin absorption of zinc from application of ZnO sunscreens to the skin than in human studies. Some public advocacy groups have voiced concern that penetration of the upper layer of the skin by sunscreens containing ZnO nanoparticles could gain access to the living cells in the viable epidermis with toxic consequences, including DNA damage. A potential danger, therefore, is that this concern may also result in an undesirable downturn in sunscreen use. A 2017 National Sun Protection Survey by the Cancer Council Australia found only 55 percent of Australians believed it was safe to use sunscreen every day, down from 61 per cent in 2014.

Investigators in Australia studied the safety of repeated application of agglomerated ZnO nanoparticles applied to five human volunteers (aged 20 to 30 years) over five days. This mimics normal product use by consumers. They applied ZnO nanoparticles suspended in a commercial sunscreen base to the skin of volunteers hourly for six hours and daily for five days. Using multiphoton tomography with fluorescence lifetime imaging microscopy, they showed that the nanoparticles remained within the superficial layers of the stratum corneum and in the skin furrows. The fate of ZnO nanoparticles was also characterized in excised human skin in vitro. They did not penetrate the viable epidermis and no cellular toxicity was seen, even after repeated hourly or daily applications typically used for sunscreens.

“The terrible consequences of skin cancer and photoaging are much greater than any toxicity risk posed by approved sunscreens,” stated lead investigator Michael S. Roberts, PhD, of the Therapeutics Research Centre, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, and School of Pharmacy and Medical Sciences, University of South Australia, Sansom Institute, Adelaide, QLD, Australia.

“This study has shown that sunscreens containing nano ZnO can be repeatedly applied to the skin with minimal risk of any toxicity. We hope that these findings will help improve consumer confidence in these products, and in turn lead to better sun protection and reduction in ultraviolet-induced skin aging and cancer cases,” he concluded.

“This study reinforces the important public health message that the known benefits of using ZnO nano sunscreens clearly outweigh the perceived risks of using nano sunscreens that are not supported by the scientific evidence,” commented Paul F.A. Wright, PhD, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia, in an accompanying editorial. “Of great significance is the investigators’ finding that the slight increase in zinc ion concentrations in viable epidermis was not associated with cellular toxicity under conditions of realistic ZnO nano sunscreen use.

A November 21, 2018 University of South Australia press release (also on EurekAlert) provides some additional insight into the Australian situation,, Note: Links have been removed,

It’s safe to slap on the sunscreen this summer – in repeated doses – despite what you have read about the potential toxicity of sunscreens.

A new study led by the University of Queensland (UQ) and University of South Australia (UniSA) provides the first direct evidence that zinc oxide nanoparticles used in sunscreen neither penetrate the skin nor cause cellular toxicity after repeated applications.

The research, published this week in the Journal of Investigative Dermatology, refutes widespread claims among some public advocacy groups – and a growing belief among consumers – about the safety of nanoparticulate-based sunscreens.

UQ and UniSA lead investigator, Professor Michael Roberts, says the myth about sunscreen toxicity took hold after previous animal studies found much higher skin absorption of zinc-containing sunscreens than in human studies.

“There were concerns that these zinc oxide nanoparticles could be absorbed into the epidermis, with toxic consequences, including DNA damage,” Professor Roberts says.

The toxicity link was picked up by consumers, sparking fears that Australians could reduce their sunscreen use, echoed by a Cancer Council 2017 National Sun Protection Survey showing a drop in the number of people who believed it was safe to use sunscreens every day.

Professor Roberts and his co-researchers in Brisbane, Adelaide, Perth and Germany studied the safety of repeated applications of zinc oxide nanoparticles applied to five volunteers aged 20-30 years.

Volunteers applied the ZnO nanoparticles every hour for six hours on five consecutive days.

“Using superior imaging methods, we established that the nanoparticles remained within the superficial layers of the skin and did not cause any cellular damage,” Professor Roberts says.

“We hope that these findings help improve consumer confidence in these products and in turn lead to better sun protection. The terrible consequences of skin cancer and skin damage caused by prolonged sun exposure are much greater than any toxicity posed by approved sunscreens.”

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

Support for the Safe Use of Zinc Oxide Nanoparticle Sunscreens: Lack of Skin Penetration or Cellular Toxicity after Repeated Application in Volunteers by Yousuf H. Mohammed, Amy Holmes, Isha N. Haridass, Washington Y. Sanchez, Hauke Studier, Jeffrey E. Grice, Heather A.E. Benson, Michael S. Roberts. Jurnal of Investigative Dermatology. DOI: https://doi.org/10.1016/j.jid.2018.08.024 Article in Press Published online (Dec. 4, 2018?)

As of Dec. 11, 2018, this article is open access.

First CRISPR gene-edited babies? Ethics and the science story

Scientists, He Jiankui and Michael Deem, may have created the first human babies born after being subjected to CRISPR (clustered regularly interspaced short palindromic repeats) gene editing.  At this point, no one is entirely certain that these babies  as described actually exist since the information was made public in a rather unusual (for scientists) fashion.

The news broke on Sunday, November 25, 2018 through a number of media outlets none of which included journals associated with gene editing or high impact journals such as Cell, Nature, or Science.The news broke in MIT Technology Review and in Associated Press. Plus, this all happened just before the Second International Summit on Human Genome Editing (Nov. 27 – 29, 2018) in Hong Kong. He Jiankui was scheduled to speak today, Nov. 27, 2018.

Predictably, this news has caused quite a tizzy.

Breaking news

Antonio Regalado broke the news in a November 25, 2018  article for MIT [Massachusetts Institute of Technology] Technology Review (Note: Links have been removed),

According to Chinese medical documents posted online this month (here and here), a team at the Southern University of Science and Technology, in Shenzhen, has been recruiting couples in an effort to create the first gene-edited babies. They planned to eliminate a gene called CCR5 in hopes of rendering the offspring resistant to HIV, smallpox, and cholera.

The clinical trial documents describe a study in which CRISPR is employed to modify human embryos before they are transferred into women’s uteruses.

The scientist behind the effort, He Jiankui, did not reply to a list of questions about whether the undertaking had produced a live birth. Reached by telephone, he declined to comment.

However, data submitted as part of the trial listing shows that genetic tests have been carried out on fetuses as late as 24 weeks, or six months. It’s not known if those pregnancies were terminated, carried to term, or are ongoing.

Apparently He changed his mind because Marilynn Marchione in a November 26, 2018 article for the Associated Press confirms the news,

A Chinese researcher claims that he helped make the world’s first genetically edited babies — twin girls born this month whose DNA he said he altered with a powerful new tool capable of rewriting the very blueprint of life.

If true, it would be a profound leap of science and ethics.

A U.S. scientist [Dr. Michael Deem] said he took part in the work in China, but this kind of gene editing is banned in the United States because the DNA changes can pass to future generations and it risks harming other genes.

Many mainstream scientists think it’s too unsafe to try, and some denounced the Chinese report as human experimentation.

There is no independent confirmation of He’s claim, and it has not been published in a journal, where it would be vetted by other experts. He revealed it Monday [November 26, 2018] in Hong Kong to one of the organizers of an international conference on gene editing that is set to begin Tuesday [November 27, 2018], and earlier in exclusive interviews with The Associated Press.

“I feel a strong responsibility that it’s not just to make a first, but also make it an example,” He told the AP. “Society will decide what to do next” in terms of allowing or forbidding such science.

Some scientists were astounded to hear of the claim and strongly condemned it.

It’s “unconscionable … an experiment on human beings that is not morally or ethically defensible,” said Dr. Kiran Musunuru, a University of Pennsylvania gene editing expert and editor of a genetics journal.

“This is far too premature,” said Dr. Eric Topol, who heads the Scripps Research Translational Institute in California. “We’re dealing with the operating instructions of a human being. It’s a big deal.”

However, one famed geneticist, Harvard University’s George Church, defended attempting gene editing for HIV, which he called “a major and growing public health threat.”

“I think this is justifiable,” Church said of that goal.

h/t Cale Guthrie Weissman’s Nov. 26, 2018 article for Fast Company.

Diving into more detail

Ed Yong in a November 26, 2018 article for The Atlantic provides more details about the claims (Note: Links have been removed),

… “Two beautiful little Chinese girls, Lulu and Nana, came crying into the world as healthy as any other babies a few weeks ago,” He said in the first of five videos, posted yesterday {Nov. 25, 2018] to YouTube [link provided at the end of this section of the post]. “The girls are home now with their mom, Grace, and dad, Mark.” The claim has yet to be formally verified, but if true, it represents a landmark in the continuing ethical and scientific debate around gene editing.

Late last year, He reportedly enrolled seven couples in a clinical trial, and used their eggs and sperm to create embryos through in vitro fertilization. His team then used CRISPR to deactivate a single gene called CCR5 in the embryos, six of which they then implanted into mothers. CCR5 is a protein that the HIV virus uses to gain entry into human cells; by deactivating it, the team could theoretically reduce the risk of infection. Indeed, the fathers in all eight couples were HIV-positive.

Whether the experiment was successful or not, it’s intensely controversial. Scientists have already begun using CRISPR and other gene-editing technologies to alter human cells, in attempts to treat cancers, genetic disorders, and more. But in these cases, the affected cells stay within a person’s body. Editing an embryo [it’s often called, germline editing] is very different: It changes every cell in the body of the resulting person, including the sperm or eggs that would pass those changes to future generations. Such work is banned in many European countries, and prohibited in the United States. “I understand my work will be controversial, but I believe families need this technology and I’m willing to take the criticism for them,” He said.

“Was this a reasonable thing to do? I would say emphatically no,” says Paula Cannon of the University of Southern California. She and others have worked on gene editing, and particularly on trials that knock out CCR5 as a way to treat HIV. But those were attempts to treat people who were definitively sick and had run out of other options. That wasn’t the case with Nana and Lulu.

“The idea that being born HIV-susceptible, which is what the vast majority of humans are, is somehow a disease state that requires the extraordinary intervention of gene editing blows my mind,” says Cannon. “I feel like he’s appropriating this potentially valuable therapy as a shortcut to doing something in the sphere of gene editing. He’s either very naive or very cynical.”

“I want someone to make sure that it has happened,” says Hank Greely, an ethicist at Stanford University. If it hasn’t, that “would be a pretty bald-faced fraud,” but such deceptions have happened in the past. “If it is true, I’m disappointed. It’s reckless on safety grounds, and imprudent and stupid on social grounds.” He notes that a landmark summit in 2015 (which included Chinese researchers) and a subsequent major report from the National Academies of Science, Engineering, and Medicine both argued that “public participation should precede any heritable germ-line editing.” That is: Society needs to work out how it feels about making gene-edited babies before any babies are edited. Absent that consensus, He’s work is “waving a red flag in front of a bull,” says Greely. “It provokes not just the regular bio-Luddites, but also reasonable people who just wanted to talk it out.”

Societally, the creation of CRISPR-edited babies is a binary moment—a Rubicon that has been crossed. But scientifically, the devil is in the details, and most of those are still unknown.

CRISPR is still inefficient. [emphasis mine] The Chinese teams who first used it to edit human embryos only did so successfully in a small proportion of cases, and even then, they found worrying levels of “off-target mutations,” where they had erroneously cut parts of the genome outside their targeted gene. He, in his video, claimed that his team had thoroughly sequenced Nana and Lulu’s genomes and found no changes in genes other than CCR5.

That claim is impossible to verify in the absence of a peer-reviewed paper, or even published data of any kind. “The paper is where we see whether the CCR5 gene was properly edited, what effect it had at the cellular level, and whether [there were] any off-target effects,” said Eric Topol of the Scripps Research Institute. “It’s not just ‘it worked’ as a binary declaration.”

In the video, He said that using CRISPR for human enhancement, such as enhancing IQ or selecting eye color, “should be banned.” Speaking about Nana and Lulu’s parents, he said that they “don’t want a designer baby, just a child who won’t suffer from a disease that medicine can now prevent.”

But his rationale is questionable. Huang [Junjiu Huang of Sun Yat-sen University ], the first Chinese researcher to use CRISPR on human embryos, targeted the faulty gene behind an inherited disease called beta thalassemia. Mitalipov, likewise, tried to edit a gene called MYBPC3, whose faulty versions cause another inherited disease called hypertrophic cardiomyopathy (HCM). Such uses are still controversial, but they rank among the more acceptable applications for embryonic gene editing as ways of treating inherited disorders for which treatments are either difficult or nonexistent.

In contrast, He’s team disableda normal gene in an attempt to reduce the risk of a disease that neither child had—and one that can be controlled. There are already ways of preventing fathers from passing HIV to their children. There are antiviral drugs that prevent infections. There’s safe-sex education. “This is not a plague for which we have no tools,” says Cannon.

As Marilynn Marchione of the AP reports, early tests suggest that He’s editing was incomplete [emphasis mine], and at least one of the twins is a mosaic, where some cells have silenced copies of CCR5 and others do not. If that’s true, it’s unlikely that they would be significantly protected from HIV. And in any case, deactivating CCR5 doesn’t confer complete immunity, because some HIV strains can still enter cells via a different protein called CXCR4.

Nana and Lulu might have other vulnerabilities. …

It is also unclear if the participants in He’s trial were fully aware of what they were signing up for. [emphasis mine] The team’s informed-consent document describes their work as an “AIDS vaccine development project,” and while it describes CRISPR gene editing, it does so in heavily technical language. It doesn’t mention any of the risks of disabling CCR5, and while it does note the possibility of off-target effects, it also says that the “project team is not responsible for the risk.”

He owns two genetics companies, and his collaborator, Michael Deem of Rice University,  [emphasis mine] holds a small stake in, and sits on the advisory board of, both of them. The AP’s Marchione reports, “Both men are physics experts with no experience running human clinical trials.” [emphasis mine]

Yong’s article is well worth reading in its entirety. As for YouTube, here’s The He Lab’s webpage with relevant videos.

Reactions

Gina Kolata, Sui-Lee Wee, and Pam Belluck writing in a Nov. 26, 2018 article for the New York Times chronicle some of the response to He’s announcement,

It is highly unusual for a scientist to announce a groundbreaking development without at least providing data that academic peers can review. Dr. He said he had gotten permission to do the work from the ethics board of the hospital Shenzhen Harmonicare, but the hospital, in interviews with Chinese media, denied being involved. Cheng Zhen, the general manager of Shenzhen Harmonicare, has asked the police to investigate what they suspect are “fraudulent ethical review materials,” according to the Beijing News.

The university that Dr. He is attached to, the Southern University of Science and Technology, said Dr. He has been on no-pay leave since February and that the school of biology believed that his project “is a serious violation of academic ethics and academic norms,” according to the state-run Beijing News.

In a statement late on Monday, China’s national health commission said it has asked the health commission in southern Guangdong province to investigate Mr. He’s claims.

“I think that’s completely insane,” said Shoukhrat Mitalipov, director of the Center for Embryonic Cell and Gene Therapy at Oregon Health and Science University. Dr. Mitalipov broke new ground last year by using gene editing to successfully remove a dangerous mutation from human embryos in a laboratory dish. [I wrote a three-part series about CRISPR, which included what was then the latest US news, Mitalipov’s announcement, along with a roundup of previous work in China. Links are at the end of this section.’

Dr. Mitalipov said that unlike his own work, which focuses on editing out mutations that cause serious diseases that cannot be prevented any other way, Dr. He did not do anything medically necessary. There are other ways to prevent H.I.V. infection in newborns.

Just three months ago, at a conference in late August on genome engineering at Cold Spring Harbor Laboratory in New York, Dr. He presented work on editing the CCR₅ gene in the embryos of nine couples.

At the conference, whose organizers included Jennifer Doudna, one of the inventors of Crispr technology, Dr. He gave a careful talk about something that fellow attendees considered squarely within the realm of ethically approved research. But he did not mention that some of those embryos had been implanted in a woman and could result in genetically engineered babies.

“What we now know is that as he was talking, there was a woman in China carrying twins,” said Fyodor Urnov, deputy director of the Altius Institute for Biomedical Sciences and a visiting researcher at the Innovative Genomics Institute at the University of California. “He had the opportunity to say ‘Oh and by the way, I’m just going to come out and say it, people, there’s a woman carrying twins.’”

“I would never play poker against Dr. He,” Dr. Urnov quipped.

Richard Hynes, a cancer researcher at the Massachusetts Institute of Technology, who co-led an advisory group on human gene editing for the National Academy of Sciences and the National Academy of Medicine, said that group and a similar organization in Britain had determined that if human genes were to be edited, the procedure should only be done to address “serious unmet needs in medical treatment, it had to be well monitored, it had to be well followed up, full consent has to be in place.”

It is not clear why altering genes to make people resistant to H.I.V. is “a serious unmet need.” Men with H.I.V. do not infect embryos. …

Dr. He got his Ph.D., from Rice University, in physics and his postdoctoral training, at Stanford, was with Stephen Quake, a professor of bioengineering and applied physics who works on sequencing DNA, not editing it.

Experts said that using Crispr would actually be quite easy for someone like Dr. He.

After coming to Shenzhen in 2012, Dr. He, at age 28, established a DNA sequencing company, Direct Genomics, and listed Dr. Quake on its advisory board. But, in a telephone interview on Monday, Dr. Quake said he was never associated with the company.

Deem, the US scientist who worked in China with He is currently being investigated (from a Nov. 26, 2018 article by Andrew Joseph in STAT),

Rice University said Monday that it had opened a “full investigation” into the involvement of one of its faculty members in a study that purportedly resulted in the creation of the world’s first babies born with edited DNA.

Michael Deem, a bioengineering professor at Rice, told the Associated Press in a story published Sunday that he helped work on the research in China.

Deem told the AP that he was in China when participants in the study consented to join the research. Deem also said that he had “a small stake” in and is on the scientific advisory boards of He’s two companies.

Megan Molteni in a Nov. 27, 2018 article for Wired admits she and her colleagues at the magazine may have dismissed CRISPR concerns about designer babies prematurely while shedding more light on this  latest development (Note: Links have been removed),

We said “don’t freak out,” when scientists first used Crispr to edit DNA in non-viable human embryos. When they tried it in embryos that could theoretically produce babies, we said “don’t panic.” Many years and years of boring bench science remain before anyone could even think about putting it near a woman’s uterus. Well, we might have been wrong. Permission to push the panic button granted.

Late Sunday night, a Chinese researcher stunned the world by claiming to have created the first human babies, a set of twins, with Crispr-edited DNA….

What’s perhaps most strange is not that He ignored global recommendations on conducting responsible Crispr research in humans. He also ignored his own advice to the world—guidelines that were published within hours of his transgression becoming public.

On Monday, He and his colleagues at Southern University of Science and Technology, in Shenzhen, published a set of draft ethical principles “to frame, guide, and restrict clinical applications that communities around the world can share and localize based on religious beliefs, culture, and public-health challenges.” Those principles included transparency and only performing the procedure when the risks are outweighed by serious medical need.

The piece appeared in the The Crispr Journal, a young publication dedicated to Crispr research, commentary, and debate. Rodolphe Barrangou, the journal’s editor in chief, where the peer-reviewed perspective appeared, says that the article was one of two that it had published recently addressing the ethical concerns of human germline editing, the other by a bioethicist at the University of North Carolina. Both papers’ authors had requested that their writing come out ahead of a major gene editing summit taking place this week in Hong Kong. When half-rumors of He’s covert work reached Barrangou over the weekend, his team discussed pulling the paper, but ultimately decided that there was nothing too solid to discredit it, based on the information available at the time.

Now Barrangou and his team are rethinking that decision. For one thing, He did not disclose any conflicts of interest, which is standard practice among respectable journals. It’s since become clear that not only is He at the helm of several genetics companies in China, He was actively pursuing controversial human research long before writing up a scientific and moral code to guide it.“We’re currently assessing whether the omission was a matter of ill-management or ill-intent,” says Barrangou, who added that the journal is now conducting an audit to see if a retraction might be warranted. …

“There are all sorts of questions these issues raise, but the most fundamental is the risk-benefit ratio for the babies who are going to be born,” says Hank Greely, an ethicist at Stanford University. “And the risk-benefit ratio on this stinks. Any institutional review board that approved it should be disbanded if not jailed.”

Reporting by Stat indicates that He may have just gotten in over his head and tried to cram a self-guided ethics education into a few short months. The young scientist—records indicate He is just 34—has a background in biophysics, with stints studying in the US at Rice University and in bioengineer Stephen Quake’s lab at Stanford. His resume doesn’t read like someone steeped deeply in the nuances and ethics of human research. Barrangou says that came across in the many rounds of edits He’s framework went through.

… China’s central government in Beijing has yet to come down one way or another. Condemnation would make He a rogue and a scientific outcast. Anything else opens the door for a Crispr IVF cottage industry to emerge in China and potentially elsewhere. “It’s hard to imagine this was the only group in the world doing this,” says Paul Knoepfler, a stem cell researcher at UC Davis who wrote a book on the future of designer babies called GMO Sapiens. “Some might say this broke the ice. Will others forge ahead and go public with their results or stop what they’re doing and see how this plays out?”

Here’s some of the very latest information with the researcher attempting to explain himself.

What does He have to say?

After He’s appearance at the Second International Summit on Human Genome Editing today, Nov. 27, 2018, David Cyranoski produced this article for Nature,

He Jiankui, the Chinese scientist who claims to have helped produce the first people born with edited genomes — twin girls — appeared today at a gene-editing summit in Hong Kong to explain his experiment. He gave his talk amid threats of legal action and mounting questions, from the scientific community and beyond, about the ethics of his work and the way in which he released the results.

He had never before presented his work publicly outside of a handful of videos he posted on YouTube. Scientists welcomed the fact that he appeared at all — but his talk left many hungry for more answers, and still not completely certain that He has achieved what he claims.

“There’s no reason not to believe him,” says Robin Lovell-Badge, a developmental biologist at the Francis Crick Institute in London. “I’m just not completely convinced.”

Lovell-Badge, like others at the conference, says that an independent body should confirm the test results by performing an in-depth comparison of the parents’ and childrens’ genes.

Many scientists faulted He for a lack of transparency and the seemingly cavalier nature in which he embarked on such a landmark, and potentially risky, project.

“I’m happy he came but I was really horrified and stunned when he described the process he used,” says Jennifer Doudna, a biochemist at the University of California, Berkeley and a pioneer of the CRISPR/Cas-9 gene-editing technique that He used. “It was so inappropriate on so many levels.”

He seemed shaky approaching the stage and nervous during the talk. “I think he was scared,” says Matthew Porteus, who researches genome-editing at Stanford University in California and co-hosted a question-and-answer session with He after his presentation. Porteus attributes this either to the legal pressures that He faces or the mounting criticism from the scientists and media he was about to address.

He’s talk leaves a host of other questions unanswered, including whether the prospective parents were properly informed of the risks; why He selected CCR5 when there are other, proven ways to prevent HIV; why he chose to do the experiment with couples in which the fathers have HIV, rather than mothers who have a higher chance of passing the virus on to their children; and whether the risks of knocking out CCR5 — a gene normally present in people, which could have necessary but still unknown functions — outweighed the benefits in this case.

In the discussion following He’s talk, one scientist asked why He proceeded with the experiments despite the clear consensus among scientists worldwide that such research shouldn’t be done. He didn’t answer the question.

He’s attempts to justify his actions mainly fell flat. In response to questions about why the science community had not been informed of the experiments before the first women were impregnated, he cited presentations that he gave last year at meetings at the University of California, Berkeley, and at the Cold Spring Harbor Laboratory in New York. But Doudna, who organized the Berkeley meeting, says He did not present anything that showed he was ready to experiment in people. She called his defence “disingenuous at best”.

He also said he discussed the human experiment with unnamed scientists in the United States. But Porteus says that’s not enough for such an extraordinary experiment: “You need feedback not from your two closest friends but from the whole community.” …

Pressure was mounting on He ahead of the presentation. On 27 November, the Chinese national health commission ordered the Guangdong health commission, in the province where He’s university is located, to investigate.

On the same day, the Chinese Academy of Sciences issued a statement condemning his work, and the Genetics Society of China and the Chinese Society for Stem Cell Research jointly issued a statement saying the experiment “violates internationally accepted ethical principles regulating human experimentation and human rights law”.

The hospital cited in China’s clinical-trial registry as the that gave ethical approval for He’s work posted a press release on 27 November saying it did not give any approval. It questioned the signatures on the approval form and said that the hospital’s medical-ethics committee never held a meeting related to He’s research. The hospital, which itself is under investigation by the Shenzhen health authorities following He’s revelations, wrote: “The Company does not condone the means of the Claimed Project, and has reservations as to the accuracy, reliability and truthfulness of its contents and results.”

He has not yet responded to requests for comment on these statements and investigations, nor on why the hospital was listed in the registry and the claim of apparent forged signatures.

Alice Park’s Nov. 26, 2018 article for Time magazine includes an embedded video of He’s Nov. 27, 2018 presentation at the summit meeting.

What about the politics?

Mara Hvistendahl’s Nov. 27, 2018 article about this research for Slate.com poses some geopolitical questions (Note: Links have been removed),

The informed consent agreement for He Jiankui’s experiment describes it as an “AIDS vaccine development project” and used highly technical language to describe the procedure that patients would undergo. If the reality for some Chinese patients is that such agreements are glossed over, densely written, or never read, the reality for some researchers working in the country is that the appeal of cutting-edge trials is too great to resist. It is not just Chinese scientists who can be blinded by the lure of quick breakthroughs. Several of the most notable breaches of informed consent on the mainland have involved Western researchers or co-authors. … When people say that the usual rules don’t apply in China, they are really referring to authoritarian science, not some alternative communitarian ethics.

For the many scientists in China who adhere to recognized international standards, the incident comes as a disgrace. He Jiankui now faces an ethics investigation from provincial health authorities, and his institution, Southern University of Science and Technology, was quick to issue a statement noting that He was on unpaid leave. …

It would seem that US [and from elsewhere]* scientists wanting to avoid pesky ethics requirements in the US have found that going to China could be the answer to their problems. I gather it’s not just big business that prefers deregulated environments.

Guillaume Levrier’s  (he’ studying for a PhD at the Universté Sorbonne Paris Cité) November 16, 2018 essay for The Conversation sheds some light on political will and its impact on science (Note: Links have been removed),

… China has entered a “genome editing” race among great scientific nations and its progress didn’t come out of nowhere. China has invested heavily in the natural-sciences sector over the past 20 years. The Ninth Five-Year Plan (1996-2001) mentioned the crucial importance of biotechnologies. The current Thirteenth Five-Year Plan is even more explicit. It contains a section dedicated to “developing efficient and advanced biotechnologies” and lists key sectors such as “genome-editing technologies” intended to “put China at the bleeding edge of biotechnology innovation and become the leader in the international competition in this sector”.

Chinese embryo research is regulated by a legal framework, the “technical norms on human-assisted reproductive technologies”, published by the Science and Health Ministries. The guidelines theoretically forbid using sperm or eggs whose genome have been manipulated for procreative purposes. However, it’s hard to know how much value is actually placed on this rule in practice, especially in China’s intricate institutional and political context.

In theory, three major actors have authority on biomedical research in China: the Science and Technology Ministry, the Health Ministry, and the Chinese Food and Drug Administration. In reality, other agents also play a significant role. Local governments interpret and enforce the ministries’ “recommendations”, and their own interpretations can lead to significant variations in what researchers can and cannot do on the ground. The Chinese National Academy of Medicine is also a powerful institution that has its own network of hospitals, universities and laboratories.

Another prime actor is involved: the health section of the People’s Liberation Army (PLA), which has its own biomedical faculties, hospitals and research labs. The PLA makes its own interpretations of the recommendations and has proven its ability to work with the private sector on gene editing projects. …

One other thing from Levrier’s essay,

… And the media timing is just a bit too perfect, …

Do read the essay; there’s a twist at the end.

Final thoughts and some links

If I read this material rightly, there are suspicions there may be more of this work being done in China and elsewhere. In short, we likely don’t have the whole story.

As for the ethical issues, this is a discussion among experts only, so far. The great unwashed (thee and me) are being left at the wayside. Sure, we’ll be invited to public consultations, one day,  after the big decisions have been made.

Anyone who’s read up on the history of science will tell you this kind of breach is very common at the beginning. Richard Holmes’  2008 book, ‘The Age of Wonder: How the Romantic Generation Discovered the Beauty and Terror of Science’ recounts stories of early scientists (European science) who did crazy things. Some died, some shortened their life spans; and, some irreversibly damaged their health.  They also experimented on other people. Informed consent had not yet been dreamed up.

In fact, I remember reading somewhere that the largest human clinical trial in history was held in Canada. The small pox vaccine was highly contested in the US but the Canadian government thought it was a good idea so they offered US scientists the option of coming here to vaccinate Canadian babies. This was in the 1950s and the vaccine seems to have been administered almost universally. That was a lot of Canadian babies. Thankfully, it seems to have worked out but it does seem mind-boggling today.

For all the indignation and shock we’re seeing, this is not the first time nor will it be the last time someone steps over a line in order to conduct scientific research. And, that is the eternal problem.

Meanwhile I think some of the real action regarding CRISPR and germline editing is taking place in the field (pun!) of agriculture:

My Nov. 27, 2018 posting titled: ‘Designer groundcherries by CRISPR (clustered regularly interspaced short palindromic repeats)‘ and a more disturbing Nov. 27, 2018 post titled: ‘Agriculture and gene editing … shades of the AquAdvantage salmon‘. That second posting features a company which is trying to sell its gene-editing services to farmers who would like cows that  never grow horns and pigs that never reach puberty.

Then there’s this ,

The Genetic Revolution‘, a documentary that offers relatively up-to-date information about gene editing, which was broadcast on Nov. 11, 2018 as part of The Nature of Things series on CBC (Canadian Broadcasting Corporation).

My July 17, 2018 posting about research suggesting that scientists hadn’t done enough research on possible effects of CRISPR editing titled: ‘The CRISPR ((clustered regularly interspaced short palindromic repeats)-CAS9 gene-editing technique may cause new genetic damage kerfuffle’.

My 2017 three-part series on CRISPR and germline editing:

CRISPR and editing the germline in the US (part 1 of 3): In the beginning

CRISPR and editing the germline in the US (part 2 of 3): ‘designer babies’?

CRISPR and editing the germline in the US (part 3 of 3): public discussions and pop culture

There you have it.

Added on November 30, 2018: David Cyanowski has written one final article (Nov. 30, 2018 for Nature) about He and the Second International Summit on Human Genome Editing. He did not make his second scheduled appearance at the summit, returning to China before the summit concluded. He was rebuked in a statement produced by the Summit’s organizing committee at the end of the three-day meeting. The situation with regard to his professional status in China is ambiguous. Cyanowski ends his piece with the information that the third summit will take place in London (likely in the UK) in 2021. I encourage you to read Cyanowski’s Nov. 30, 2018 article in its entirety; it’s not long.

Added on Dec. 3, 2018: The story continues. Ed Yong has written a summary of the issues to date in a Dec. 3, 2018 article for The Atlantic (even if you know the story ift’s eyeopening to see all the parts put together.

J. Benjamin Hurlbut, Associate Professor of Life Sciences at Arizona State University (ASU) and Jason Scott Robert, Director of the Lincoln Center for Applied Ethics at Arizona State University have written a provocative (and true) Dec. 3, 2018 essay titled, CRISPR babies raise an uncomfortable reality – abiding by scientific standards doesn’t guarantee ethical research, for The Conversation. h/t phys.org

*[and from elsewhere] added January 17, 2019.

Added on January 23, 2019: He has been fired by his university (Southern University of Science and Technology in Shenzhen) as announced on January 21, 2019.  David Cyranoski provides a details accounting in his January 22, 2019 article for Nature.

Canadian research into nanomaterial workplace exposure in the air and on surfaces

An August 30, 2018 news item on Nanowerk announces the report,

The monitoring of air contamination by engineered nanomaterials (ENM) is a complex process with many uncertainties and limitations owing to the presence of particles of nanometric size that are not ENMs, the lack of validated instruments for breathing zone measurements and the many indicators to be considered.

In addition, some organizations, France’s Institut national de recherche et de sécurité (INRS) and Québec’s Institut de recherche Robert-Sauvé en santé et en sécurité du travail (IRSST) among them, stress the need to also sample surfaces for ENM deposits.

In other words, to get a better picture of the risks of worker exposure, we need to fine-tune the existing methods of sampling and characterizing ENMs and develop new one. Accordingly, the main goal of this project was to develop innovative methodological approaches for detailed qualitative as well as quantitative characterization of workplace exposure to ENMs.

A PDF of the 88-page report is available in English or in French.

An August 30, 2018 (?) abstract of the IRSST report titled An Assessment of Methods of Sampling and Characterizing Engineered Nanomaterials in the Air and on Surfaces in the Workplace (2nd edition) by Maximilien Debia, Gilles L’Espérance, Cyril Catto, Philippe Plamondon, André Dufresne, Claude Ostiguy, which originated the news item, outlines what you can expect from the report,

This research project has two complementary parts: a laboratory investigation and a fieldwork component. The laboratory investigation involved generating titanium dioxide (TiO2) nanoparticles under controlled laboratory conditions and studying different sampling and analysis devices. The fieldwork comprised a series of nine interventions adapted to different workplaces and designed to test a variety of sampling devices and analytical procedures and to measure ENM exposure levels among Québec workers.

The methods for characterizing aerosols and surface deposits that were investigated include: i) measurement by direct-reading instruments (DRI), such as condensation particle counters (CPC), optical particle counters (OPC), laser photometers, aerodynamic diameter spectrometers and electric mobility spectrometer; ii) transmission electron microscopy (TEM) or scanning transmission electron microscopy (STEM) with a variety of sampling devices, including the Mini Particle Sampler® (MPS); iii) measurement of elemental carbon (EC); iv) inductively coupled plasma mass spectrometry (ICP-MS) and (v) Raman spectroscopy.

The workplace investigations covered a variety of industries (e.g., electronics, manufacturing, printing, construction, energy, research and development) and included producers as well as users or integrators of ENMs. In the workplaces investigated, we found nanometals or metal oxides (TiO2, SiO2, zinc oxides, lithium iron phosphate, titanate, copper oxides), nanoclays, nanocellulose and carbonaceous materials, including carbon nanofibers (CNF) and carbon nanotubes (CNT)—single-walled (SWCNT) as well as multiwalled (MWCNT).

The project helped to advance our knowledge of workplace assessments of ENMs by documenting specific tasks and industrial processes (e.g., printing and varnishing) as well as certain as yet little investigated ENMs (nanocellulose, for example).

Based on our investigations, we propose a strategy for more accurate assessment of ENM exposure using methods that require a minimum of preanalytical handling. The recommended strategy is a systematic two-step assessment of workplaces that produce and use ENMs. The first step involves testing with different DRIs (such as a CPC and a laser photometer) as well as sample collection and subsequent microscopic analysis (MPS + TEM/STEM) to clearly identify the work tasks that generate ENMs. The second step, once work exposure is confirmed, is specific quantification of the ENMs detected. The following findings are particularly helpful for detailed characterization of ENM exposure:

  1. The first conclusive tests of a technique using ICP-MS to quantify the metal oxide content of samples collected in the workplace
  2. The possibility of combining different sampling methods recommended by the National Institute for Occupational Safety and Health (NIOSH) to measure elemental carbon as an indicator of NTC/NFC, as well as demonstration of the limitation of this method stemming from observed interference with the black carbon particles required to synthesis carbon materials (for example, Raman spectroscopy showed that less than 6% of the particles deposited on the electron microscopy grid at one site were SWCNTs)
  3. The clear advantages of using an MPS (instead of the standard 37-mm cassettes used as sampling media for electron microscopy), which allows quantification of materials
  4. The major impact of sampling time: a long sampling time overloads electron microscopy grids and can lead to overestimation of average particle agglomerate size and underestimation of particle concentrations
  5. The feasibility and utility of surface sampling, either with sampling pumps or passively by diffusion onto the electron microscopy grids, to assess ENM dispersion in the workplace

These original findings suggest promising avenues for assessing ENM exposure, while also showing their limitations. Improvements to our sampling and analysis methods give us a better understanding of ENM exposure and help in adapting and implementing control measures that can minimize occupational exposure.

You can download the full report in either or both English and French from the ‘Nanomaterials – A Guide to Good Practices Facilitating Risk Management in the Workplace, 2nd Edition‘ webpage.