Tag Archives: Massachusetts Institute of Technology

A 3D printed eye cornea and a 3D printed copy of your brain (also: a Brad Pitt connection)

Sometimes it’s hard to keep up with 3D tissue printing news. I have two news bits, one concerning eyes and another concerning brains.

3D printed human corneas

A May 29, 2018 news item on ScienceDaily trumpets the news,

The first human corneas have been 3D printed by scientists at Newcastle University, UK.

It means the technique could be used in the future to ensure an unlimited supply of corneas.

As the outermost layer of the human eye, the cornea has an important role in focusing vision.

Yet there is a significant shortage of corneas available to transplant, with 10 million people worldwide requiring surgery to prevent corneal blindness as a result of diseases such as trachoma, an infectious eye disorder.

In addition, almost 5 million people suffer total blindness due to corneal scarring caused by burns, lacerations, abrasion or disease.

The proof-of-concept research, published today [May 29, 2018] in Experimental Eye Research, reports how stem cells (human corneal stromal cells) from a healthy donor cornea were mixed together with alginate and collagen to create a solution that could be printed, a ‘bio-ink’.

Here are the proud researchers with their cornea,

Caption: Dr. Steve Swioklo and Professor Che Connon with a dyed cornea. Credit: Newcastle University, UK

A May 30,2018 Newcastle University press release (also on EurekAlert but published on May 29, 2018), which originated the news item, adds more details,

Using a simple low-cost 3D bio-printer, the bio-ink was successfully extruded in concentric circles to form the shape of a human cornea. It took less than 10 minutes to print.

The stem cells were then shown to culture – or grow.

Che Connon, Professor of Tissue Engineering at Newcastle University, who led the work, said: “Many teams across the world have been chasing the ideal bio-ink to make this process feasible.

“Our unique gel – a combination of alginate and collagen – keeps the stem cells alive whilst producing a material which is stiff enough to hold its shape but soft enough to be squeezed out the nozzle of a 3D printer.

“This builds upon our previous work in which we kept cells alive for weeks at room temperature within a similar hydrogel. Now we have a ready to use bio-ink containing stem cells allowing users to start printing tissues without having to worry about growing the cells separately.”

The scientists, including first author and PhD student Ms Abigail Isaacson from the Institute of Genetic Medicine, Newcastle University, also demonstrated that they could build a cornea to match a patient’s unique specifications.

The dimensions of the printed tissue were originally taken from an actual cornea. By scanning a patient’s eye, they could use the data to rapidly print a cornea which matched the size and shape.

Professor Connon added: “Our 3D printed corneas will now have to undergo further testing and it will be several years before we could be in the position where we are using them for transplants.

“However, what we have shown is that it is feasible to print corneas using coordinates taken from a patient eye and that this approach has potential to combat the world-wide shortage.”

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

3D bioprinting of a corneal stroma equivalent by Abigail Isaacson, Stephen Swioklo, Che J. Connon. Experimental Eye Research Volume 173, August 2018, Pages 188–193 and 2018 May 14 pii: S0014-4835(18)30212-4. doi: 10.1016/j.exer.2018.05.010. [Epub ahead of print]

This paper is behind a paywall.

A 3D printed copy of your brain

I love the title for this May 30, 2018 Wyss Institute for Biologically Inspired Engineering news release: Creating piece of mind by Lindsay Brownell (also on EurekAlert),

What if you could hold a physical model of your own brain in your hands, accurate down to its every unique fold? That’s just a normal part of life for Steven Keating, Ph.D., who had a baseball-sized tumor removed from his brain at age 26 while he was a graduate student in the MIT Media Lab’s Mediated Matter group. Curious to see what his brain actually looked like before the tumor was removed, and with the goal of better understanding his diagnosis and treatment options, Keating collected his medical data and began 3D printing his MRI [magnetic resonance imaging] and CT [computed tomography] scans, but was frustrated that existing methods were prohibitively time-intensive, cumbersome, and failed to accurately reveal important features of interest. Keating reached out to some of his group’s collaborators, including members of the Wyss Institute at Harvard University, who were exploring a new method for 3D printing biological samples.

“It never occurred to us to use this approach for human anatomy until Steve came to us and said, ‘Guys, here’s my data, what can we do?” says Ahmed Hosny, who was a Research Fellow with at the Wyss Institute at the time and is now a machine learning engineer at the Dana-Farber Cancer Institute. The result of that impromptu collaboration – which grew to involve James Weaver, Ph.D., Senior Research Scientist at the Wyss Institute; Neri Oxman, [emphasis mine] Ph.D., Director of the MIT Media Lab’s Mediated Matter group and Associate Professor of Media Arts and Sciences; and a team of researchers and physicians at several other academic and medical centers in the US and Germany – is a new technique that allows images from MRI, CT, and other medical scans to be easily and quickly converted into physical models with unprecedented detail. The research is reported in 3D Printing and Additive Manufacturing.

“I nearly jumped out of my chair when I saw what this technology is able to do,” says Beth Ripley, M.D. Ph.D., an Assistant Professor of Radiology at the University of Washington and clinical radiologist at the Seattle VA, and co-author of the paper. “It creates exquisitely detailed 3D-printed medical models with a fraction of the manual labor currently required, making 3D printing more accessible to the medical field as a tool for research and diagnosis.”

Imaging technologies like MRI and CT scans produce high-resolution images as a series of “slices” that reveal the details of structures inside the human body, making them an invaluable resource for evaluating and diagnosing medical conditions. Most 3D printers build physical models in a layer-by-layer process, so feeding them layers of medical images to create a solid structure is an obvious synergy between the two technologies.

However, there is a problem: MRI and CT scans produce images with so much detail that the object(s) of interest need to be isolated from surrounding tissue and converted into surface meshes in order to be printed. This is achieved via either a very time-intensive process called “segmentation” where a radiologist manually traces the desired object on every single image slice (sometimes hundreds of images for a single sample), or an automatic “thresholding” process in which a computer program quickly converts areas that contain grayscale pixels into either solid black or solid white pixels, based on a shade of gray that is chosen to be the threshold between black and white. However, medical imaging data sets often contain objects that are irregularly shaped and lack clear, well-defined borders; as a result, auto-thresholding (or even manual segmentation) often over- or under-exaggerates the size of a feature of interest and washes out critical detail.

The new method described by the paper’s authors gives medical professionals the best of both worlds, offering a fast and highly accurate method for converting complex images into a format that can be easily 3D printed. The key lies in printing with dithered bitmaps, a digital file format in which each pixel of a grayscale image is converted into a series of black and white pixels, and the density of the black pixels is what defines the different shades of gray rather than the pixels themselves varying in color.

Similar to the way images in black-and-white newsprint use varying sizes of black ink dots to convey shading, the more black pixels that are present in a given area, the darker it appears. By simplifying all pixels from various shades of gray into a mixture of black or white pixels, dithered bitmaps allow a 3D printer to print complex medical images using two different materials that preserve all the subtle variations of the original data with much greater accuracy and speed.

The team of researchers used bitmap-based 3D printing to create models of Keating’s brain and tumor that faithfully preserved all of the gradations of detail present in the raw MRI data down to a resolution that is on par with what the human eye can distinguish from about 9-10 inches away. Using this same approach, they were also able to print a variable stiffness model of a human heart valve using different materials for the valve tissue versus the mineral plaques that had formed within the valve, resulting in a model that exhibited mechanical property gradients and provided new insights into the actual effects of the plaques on valve function.

“Our approach not only allows for high levels of detail to be preserved and printed into medical models, but it also saves a tremendous amount of time and money,” says Weaver, who is the corresponding author of the paper. “Manually segmenting a CT scan of a healthy human foot, with all its internal bone structure, bone marrow, tendons, muscles, soft tissue, and skin, for example, can take more than 30 hours, even by a trained professional – we were able to do it in less than an hour.”

The researchers hope that their method will help make 3D printing a more viable tool for routine exams and diagnoses, patient education, and understanding the human body. “Right now, it’s just too expensive for hospitals to employ a team of specialists to go in and hand-segment image data sets for 3D printing, except in extremely high-risk or high-profile cases. We’re hoping to change that,” says Hosny.

In order for that to happen, some entrenched elements of the medical field need to change as well. Most patients’ data are compressed to save space on hospital servers, so it’s often difficult to get the raw MRI or CT scan files needed for high-resolution 3D printing. Additionally, the team’s research was facilitated through a joint collaboration with leading 3D printer manufacturer Stratasys, which allowed access to their 3D printer’s intrinsic bitmap printing capabilities. New software packages also still need to be developed to better leverage these capabilities and make them more accessible to medical professionals.

Despite these hurdles, the researchers are confident that their achievements present a significant value to the medical community. “I imagine that sometime within the next 5 years, the day could come when any patient that goes into a doctor’s office for a routine or non-routine CT or MRI scan will be able to get a 3D-printed model of their patient-specific data within a few days,” says Weaver.

Keating, who has become a passionate advocate of efforts to enable patients to access their own medical data, still 3D prints his MRI scans to see how his skull is healing post-surgery and check on his brain to make sure his tumor isn’t coming back. “The ability to understand what’s happening inside of you, to actually hold it in your hands and see the effects of treatment, is incredibly empowering,” he says.

“Curiosity is one of the biggest drivers of innovation and change for the greater good, especially when it involves exploring questions across disciplines and institutions. The Wyss Institute is proud to be a space where this kind of cross-field innovation can flourish,” says Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School (HMS) and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS).

Here’s an image illustrating the work,

Caption: This 3D-printed model of Steven Keating’s skull and brain clearly shows his brain tumor and other fine details thanks to the new data processing method pioneered by the study’s authors. Credit: Wyss Institute at Harvard University

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

From Improved Diagnostics to Presurgical Planning: High-Resolution Functionally Graded Multimaterial 3D Printing of Biomedical Tomographic Data Sets by Ahmed Hosny , Steven J. Keating, Joshua D. Dilley, Beth Ripley, Tatiana Kelil, Steve Pieper, Dominik Kolb, Christoph Bader, Anne-Marie Pobloth, Molly Griffin, Reza Nezafat, Georg Duda, Ennio A. Chiocca, James R.. Stone, James S. Michaelson, Mason N. Dean, Neri Oxman, and James C. Weaver. 3D Printing and Additive Manufacturing http://doi.org/10.1089/3dp.2017.0140 Online Ahead of Print:May 29, 2018

This paper appears to be open access.

A tangential Brad Pitt connection

It’s a bit of Hollywood gossip. There was some speculation in April 2018 that Brad Pitt was dating Dr. Neri Oxman highlighted in the Wyss Institute news release. Here’s a sample of an April 13, 2018 posting on Laineygossip (Note: A link has been removed),

It took him a long time to date, but he is now,” the insider tells PEOPLE. “He likes women who challenge him in every way, especially in the intellect department. Brad has seen how happy and different Amal has made his friend (George Clooney). It has given him something to think about.”

While a Pitt source has maintained he and Oxman are “just friends,” they’ve met up a few times since the fall and the insider notes Pitt has been flying frequently to the East Coast. He dropped by one of Oxman’s classes last fall and was spotted at MIT again a few weeks ago.

Pitt and Oxman got to know each other through an architecture project at MIT, where she works as a professor of media arts and sciences at the school’s Media Lab. Pitt has always been interested in architecture and founded the Make It Right Foundation, which builds affordable and environmentally friendly homes in New Orleans for people in need.

“One of the things Brad has said all along is that he wants to do more architecture and design work,” another source says. “He loves this, has found the furniture design and New Orleans developing work fulfilling, and knows he has a talent for it.”

It’s only been a week since Page Six first broke the news that Brad and Dr Oxman have been spending time together.

I’m fascinated by Oxman’s (and her colleagues’) furniture. Rose Brook writes about one particular Oxman piece in her March 27, 2014 posting for TCT magazine (Note: Links have been removed),

MIT Professor and 3D printing forerunner Neri Oxman has unveiled her striking acoustic chaise longue, which was made using Stratasys 3D printing technology.

Oxman collaborated with Professor W Craig Carter and Composer and fellow MIT Professor Tod Machover to explore material properties and their spatial arrangement to form the acoustic piece.

Christened Gemini, the two-part chaise was produced using a Stratasys Objet500 Connex3 multi-colour, multi-material 3D printer as well as traditional furniture-making techniques and it will be on display at the Vocal Vibrations exhibition at Le Laboratoire in Paris from March 28th 2014.

An Architect, Designer and Professor of Media, Arts and Science at MIT, Oxman’s creation aims to convey the relationship of twins in the womb through material properties and their arrangement. It was made using both subtractive and additive manufacturing and is part of Oxman’s ongoing exploration of what Stratasys’ ground-breaking multi-colour, multi-material 3D printer can do.

Brook goes on to explain how the chaise was made and the inspiration that led to it. Finally, it’s interesting to note that Oxman was working with Stratasys in 2014 and that this 2018 brain project is being developed in a joint collaboration with Statasys.

That’s it for 3D printing today.

Santiago Ramón y Cajal and the butterflies of the soul

The Cajal exhibit of drawings was here in Vancouver (Canada) this last fall (2017) and I still carry the memory of that glorious experience (see my Sept. 11, 2017 posting for more about the show and associated events). It seems Cajal’s drawings had a similar response in New York city, from a January 18, 2018 article by Roberta Smith for the New York Times,

It’s not often that you look at an exhibition with the help of the very apparatus that is its subject. But so it is with “The Beautiful Brain: The Drawings of Santiago Ramón y Cajal” at the Grey Art Gallery at New York University, one of the most unusual, ravishing exhibitions of the season.

The show finished its run on March 31, 2018 and is now on its way to the Massachusetts Institute of Technology (MIT) in Boston, Massachusetts for its opening on May 3, 2018. It looks like they have an exciting lineup of events to go along with the exhibit (from MIT’s The Beautiful Brain: The Drawings of Santiago Ramón y Cajal exhibit and event page),

SUMMER PROGRAMS

ONGOING

Spotlight Tours
Explorations led by local and Spanish scientists, artists, and entrepreneurs who will share their unique perspectives on particular aspects of the exhibition. (2:00 pm on select Tuesdays and Saturdays)

Tue, May 8 – Mark Harnett, Fred and Carole Middleton Career Development Professor at MIT and McGovern Institute Investigator Sat, May 26 – Marion Boulicault, MIT Graduate Student and Neuroethics Fellow in the Center for Sensorimotor Neural Engineering Tue, June 5 – Kelsey Allen, Graduate researcher, MIT Center for Brains, Minds, and Machines Sat, Jun 23 – Francisco Martin-Martinez, Research Scientist in MIT’s Laboratory for Atomistic & Molecular Mechanics and President of the Spanish Foundation for Science and Technology Jul 21 – Alex Gomez-Marin, Principal Investigator of the Behavior of Organisms Laboratory in the Instituto de Neurociencias, Spain Tue, Jul 31– Julie Pryor, Director of Communications at the McGovern Institute for Brain Research at MIT Tue, Aug 28 – Satrajit Ghosh, Principal Research Scientist at the McGovern Institute for Brain Research at MIT, Assistant Professor in the Department of Otolaryngology at Harvard Medical School, and faculty member in the Speech and Hearing Biosciences and Technology program in the Harvard Division of Medical Sciences

Idea Hub
Drop in and explore expansion microscopy in our maker-space.

Visualizing Science Workshop
Experiential learning with micro-scale biological images. (pre-registration required)

Gallery Demonstrations
Researchers share the latest on neural anatomy, signal transmission, and modern imaging techniques.

EVENTS

Teen Science Café: Mindful Matters
MIT researchers studying the brain share their mind-blowing findings.

Neuron Paint Night
Create a painting of cerebral cortex neurons and learn about the EyeWire citizen science game.

Cerebral Cinema Series
Hear from researchers and then compare real science to depictions on the big screen.

Brainy Trivia
Test your brain power in a night of science trivia and short, snappy research talks.

Come back to see our exciting lineup for the fall!

If you don’t have a chance to see the show or if you’d like a preview, I encourage you to read Smith’s article as it has embedded several Cajal drawings and rendered them exceptionally well.

For those who like a little contemporary (and related) science with their art, there’s a March 30, 2018 Harvard Medical Schoo (HMS)l news release by Kevin Jang (also on EurekAlert), Note: All links save one have been removed,

Drawing of the cells of the chick cerebellum by Santiago Ramón y Cajal, from “Estructura de los centros nerviosos de las aves,” Madrid, circa 1905

 

Modern neuroscience, for all its complexity, can trace its roots directly to a series of pen-and-paper sketches rendered by Nobel laureate Santiago Ramón y Cajal in the late 19th and early 20th centuries.

His observations and drawings exposed the previously hidden composition of the brain, revealing neuronal cell bodies and delicate projections that connect individual neurons together into intricate networks.

As he explored the nervous systems of various organisms under his microscope, a natural question arose: What makes a human brain different from the brain of any other species?

At least part of the answer, Ramón y Cajal hypothesized, lay in a specific class of neuron—one found in a dazzling variety of shapes and patterns of connectivity, and present in higher proportions in the human brain than in the brains of other species. He dubbed them the “butterflies of the soul.”

Known as interneurons, these cells play critical roles in transmitting information between sensory and motor neurons, and, when defective, have been linked to diseases such as schizophrenia, autism and intellectual disability.

Despite more than a century of study, however, it remains unclear why interneurons are so diverse and what specific functions the different subtypes carry out.

Now, in a study published in the March 22 [2018] issue of Nature, researchers from Harvard Medical School, New York Genome Center, New York University and the Broad Institute of MIT and Harvard have detailed for the first time how interneurons emerge and diversify in the brain.

Using single-cell analysis—a technology that allows scientists to track cellular behavior one cell at a time—the team traced the lineage of interneurons from their earliest precursor states to their mature forms in mice. The researchers identified key genetic programs that determine the fate of developing interneurons, as well as when these programs are switched on or off.

The findings serve as a guide for efforts to shed light on interneuron function and may help inform new treatment strategies for disorders involving their dysfunction, the authors said.

“We knew more than 100 years ago that this huge diversity of morphologically interesting cells existed in the brain, but their specific individual roles in brain function are still largely unclear,” said co-senior author Gordon Fishell, HMS professor of neurobiology and a faculty member at the Stanley Center for Psychiatric Research at the Broad.

“Our study provides a road map for understanding how and when distinct interneuron subtypes develop, giving us unprecedented insight into the biology of these cells,” he said. “We can now investigate interneuron properties as they emerge, unlock how these important cells function and perhaps even intervene when they fail to develop correctly in neuropsychiatric disease.”

A hippocampal interneuron. Image: Biosciences Imaging Gp, Soton, Wellcome Trust via Creative CommonsA hippocampal interneuron. Image: Biosciences Imaging Gp, Soton, Wellcome Trust via Creative Commons

Origins and Fates

In collaboration with co-senior author Rahul Satija, core faculty member of the New York Genome Center, Fishell and colleagues analyzed brain regions in developing mice known to contain precursor cells that give rise to interneurons.

Using Drop-seq, a single-cell sequencing technique created by researchers at HMS and the Broad, the team profiled gene expression in thousands of individual cells at multiple time points.

This approach overcomes a major limitation in past research, which could analyze only the average activity of mixtures of many different cells.

In the current study, the team found that the precursor state of all interneurons had similar gene expression patterns despite originating in three separate brain regions and giving rise to 14 or more interneuron subtypes alone—a number still under debate as researchers learn more about these cells.

“Mature interneuron subtypes exhibit incredible diversity. Their morphology and patterns of connectivity and activity are so different from each other, but our results show that the first steps in their maturation are remarkably similar,” said Satija, who is also an assistant professor of biology at New York University.

“They share a common developmental trajectory at the earliest stages, but the seeds of what will cause them to diverge later—a handful of genes—are present from the beginning,” Satija said.

As they profiled cells at later stages in development, the team observed the initial emergence of four interneuron “cardinal” classes, which give rise to distinct fates. Cells were committed to these fates even in the early embryo. By developing a novel computational strategy to link precursors with adult subtypes, the researchers identified individual genes that were switched on and off when cells began to diversify.

For example, they found that the gene Mef2c—mutations of which are linked to Alzheimer’s disease, schizophrenia and neurodevelopmental disorders in humans—is an early embryonic marker for a specific interneuron subtype known as Pvalb neurons. When they deleted Mef2c in animal models, Pvalb neurons failed to develop.

These early genes likely orchestrate the execution of subsequent genetic subroutines, such as ones that guide interneuron subtypes as they migrate to different locations in the brain and ones that help form unique connection patterns with other neural cell types, the authors said.

The identification of these genes and their temporal activity now provide researchers with specific targets to investigate the precise functions of interneurons, as well as how neurons diversify in general, according to the authors.

“One of the goals of this project was to address an incredibly fascinating developmental biology question, which is how individual progenitor cells decide between different neuronal fates,” Satija said. “In addition to these early markers of interneuron divergence, we found numerous additional genes that increase in expression, many dramatically, at later time points.”

The association of some of these genes with neuropsychiatric diseases promises to provide a better understanding of these disorders and the development of therapeutic strategies to treat them, a particularly important notion given the paucity of new treatments, the authors said.

Over the past 50 years, there have been no fundamentally new classes of neuropsychiatric drugs, only newer versions of old drugs, the researchers pointed out.

“Our repertoire is no better than it was in the 1970s,” Fishell said.

“Neuropsychiatric diseases likely reflect the dysfunction of very specific cell types. Our study puts forward a clear picture of what cells to look at as we work to shed light on the mechanisms that underlie these disorders,” Fishell said. “What we will find remains to be seen, but we have new, strong hypotheses that we can now test.”

As a resource for the research community, the study data and software are open-source and freely accessible online.

A gallery of the drawings of Santiago Ramón y Cajal is currently on display in New York City, and will open at the MIT Museum in Boston in May 2018.

Christian Mayer, Christoph Hafemeister and Rachel Bandler served as co-lead authors on the study.

This work was supported by the National Institutes of Health (R01 NS074972, R01 NS081297, MH071679-12, DP2-HG-009623, F30MH114462, T32GM007308, F31NS103398), the European Molecular Biology Organization, the National Science Foundation and the Simons Foundation.

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

Developmental diversification of cortical inhibitory interneurons by Christian Mayer, Christoph Hafemeister, Rachel C. Bandler, Robert Machold, Renata Batista Brito, Xavier Jaglin, Kathryn Allaway, Andrew Butler, Gord Fishell, & Rahul Satija. Nature volume 555, pages 457–462 (22 March 2018) doi:10.1038/nature25999 Published: 05 March 2018

This paper is behind a paywall.

New path to viable memristor/neuristor?

I first stumbled onto memristors and the possibility of brain-like computing sometime in 2008 (around the time that R. Stanley Williams and his team at HP Labs first published the results of their research linking Dr. Leon Chua’s memristor theory to their attempts to shrink computer chips). In the almost 10 years since, scientists have worked hard to utilize memristors in the field of neuromorphic (brain-like) engineering/computing.

A January 22, 2018 news item on phys.org describes the latest work,

When it comes to processing power, the human brain just can’t be beat.

Packed within the squishy, football-sized organ are somewhere around 100 billion neurons. At any given moment, a single neuron can relay instructions to thousands of other neurons via synapses—the spaces between neurons, across which neurotransmitters are exchanged. There are more than 100 trillion synapses that mediate neuron signaling in the brain, strengthening some connections while pruning others, in a process that enables the brain to recognize patterns, remember facts, and carry out other learning tasks, at lightning speeds.

Researchers in the emerging field of “neuromorphic computing” have attempted to design computer chips that work like the human brain. Instead of carrying out computations based on binary, on/off signaling, like digital chips do today, the elements of a “brain on a chip” would work in an analog fashion, exchanging a gradient of signals, or “weights,” much like neurons that activate in various ways depending on the type and number of ions that flow across a synapse.

In this way, small neuromorphic chips could, like the brain, efficiently process millions of streams of parallel computations that are currently only possible with large banks of supercomputers. But one significant hangup on the way to such portable artificial intelligence has been the neural synapse, which has been particularly tricky to reproduce in hardware.

Now engineers at MIT [Massachusetts Institute of Technology] have designed an artificial synapse in such a way that they can precisely control the strength of an electric current flowing across it, similar to the way ions flow between neurons. The team has built a small chip with artificial synapses, made from silicon germanium. In simulations, the researchers found that the chip and its synapses could be used to recognize samples of handwriting, with 95 percent accuracy.

A January 22, 2018 MIT news release by Jennifer Chua (also on EurekAlert), which originated the news item, provides more detail about the research,

The design, published today [January 22, 2018] in the journal Nature Materials, is a major step toward building portable, low-power neuromorphic chips for use in pattern recognition and other learning tasks.

The research was led by Jeehwan Kim, the Class of 1947 Career Development Assistant Professor in the departments of Mechanical Engineering and Materials Science and Engineering, and a principal investigator in MIT’s Research Laboratory of Electronics and Microsystems Technology Laboratories. His co-authors are Shinhyun Choi (first author), Scott Tan (co-first author), Zefan Li, Yunjo Kim, Chanyeol Choi, and Hanwool Yeon of MIT, along with Pai-Yu Chen and Shimeng Yu of Arizona State University.

Too many paths

Most neuromorphic chip designs attempt to emulate the synaptic connection between neurons using two conductive layers separated by a “switching medium,” or synapse-like space. When a voltage is applied, ions should move in the switching medium to create conductive filaments, similarly to how the “weight” of a synapse changes.

But it’s been difficult to control the flow of ions in existing designs. Kim says that’s because most switching mediums, made of amorphous materials, have unlimited possible paths through which ions can travel — a bit like Pachinko, a mechanical arcade game that funnels small steel balls down through a series of pins and levers, which act to either divert or direct the balls out of the machine.

Like Pachinko, existing switching mediums contain multiple paths that make it difficult to predict where ions will make it through. Kim says that can create unwanted nonuniformity in a synapse’s performance.

“Once you apply some voltage to represent some data with your artificial neuron, you have to erase and be able to write it again in the exact same way,” Kim says. “But in an amorphous solid, when you write again, the ions go in different directions because there are lots of defects. This stream is changing, and it’s hard to control. That’s the biggest problem — nonuniformity of the artificial synapse.”

A perfect mismatch

Instead of using amorphous materials as an artificial synapse, Kim and his colleagues looked to single-crystalline silicon, a defect-free conducting material made from atoms arranged in a continuously ordered alignment. The team sought to create a precise, one-dimensional line defect, or dislocation, through the silicon, through which ions could predictably flow.

To do so, the researchers started with a wafer of silicon, resembling, at microscopic resolution, a chicken-wire pattern. They then grew a similar pattern of silicon germanium — a material also used commonly in transistors — on top of the silicon wafer. Silicon germanium’s lattice is slightly larger than that of silicon, and Kim found that together, the two perfectly mismatched materials can form a funnel-like dislocation, creating a single path through which ions can flow.

The researchers fabricated a neuromorphic chip consisting of artificial synapses made from silicon germanium, each synapse measuring about 25 nanometers across. They applied voltage to each synapse and found that all synapses exhibited more or less the same current, or flow of ions, with about a 4 percent variation between synapses — a much more uniform performance compared with synapses made from amorphous material.

They also tested a single synapse over multiple trials, applying the same voltage over 700 cycles, and found the synapse exhibited the same current, with just 1 percent variation from cycle to cycle.

“This is the most uniform device we could achieve, which is the key to demonstrating artificial neural networks,” Kim says.

Writing, recognized

As a final test, Kim’s team explored how its device would perform if it were to carry out actual learning tasks — specifically, recognizing samples of handwriting, which researchers consider to be a first practical test for neuromorphic chips. Such chips would consist of “input/hidden/output neurons,” each connected to other “neurons” via filament-based artificial synapses.

Scientists believe such stacks of neural nets can be made to “learn.” For instance, when fed an input that is a handwritten ‘1,’ with an output that labels it as ‘1,’ certain output neurons will be activated by input neurons and weights from an artificial synapse. When more examples of handwritten ‘1s’ are fed into the same chip, the same output neurons may be activated when they sense similar features between different samples of the same letter, thus “learning” in a fashion similar to what the brain does.

Kim and his colleagues ran a computer simulation of an artificial neural network consisting of three sheets of neural layers connected via two layers of artificial synapses, the properties of which they based on measurements from their actual neuromorphic chip. They fed into their simulation tens of thousands of samples from a handwritten recognition dataset commonly used by neuromorphic designers, and found that their neural network hardware recognized handwritten samples 95 percent of the time, compared to the 97 percent accuracy of existing software algorithms.

The team is in the process of fabricating a working neuromorphic chip that can carry out handwriting-recognition tasks, not in simulation but in reality. Looking beyond handwriting, Kim says the team’s artificial synapse design will enable much smaller, portable neural network devices that can perform complex computations that currently are only possible with large supercomputers.

“Ultimately we want a chip as big as a fingernail to replace one big supercomputer,” Kim says. “This opens a stepping stone to produce real artificial hardware.”

This research was supported in part by the National Science Foundation.

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

SiGe epitaxial memory for neuromorphic computing with reproducible high performance based on engineered dislocations by Shinhyun Choi, Scott H. Tan, Zefan Li, Yunjo Kim, Chanyeol Choi, Pai-Yu Chen, Hanwool Yeon, Shimeng Yu, & Jeehwan Kim. Nature Materials (2018) doi:10.1038/s41563-017-0001-5 Published online: 22 January 2018

This paper is behind a paywall.

For the curious I have included a number of links to recent ‘memristor’ postings here,

January 22, 2018: Memristors at Masdar

January 3, 2018: Mott memristor

August 24, 2017: Neuristors and brainlike computing

June 28, 2017: Dr. Wei Lu and bio-inspired ‘memristor’ chips

May 2, 2017: Predicting how a memristor functions

December 30, 2016: Changing synaptic connectivity with a memristor

December 5, 2016: The memristor as computing device

November 1, 2016: The memristor as the ‘missing link’ in bioelectronic medicine?

You can find more by using ‘memristor’ as the search term in the blog search function or on the search engine of your choice.

Graphite ‘gold’ rush?

Someone in Germany (I think) is very excited about graphite, more specifically, there’s excitement around graphite flakes located in the province of Québec, Canada. Although, the person who wrote this news release might have wanted to run a search for ‘graphite’ and ‘gold rush’. The last graphite gold rush seems to have taken place in 2013.

Here’s the March 1, 2018 news release on PR Newswire (Cision), Note: Some links have been removed),

PALM BEACH, Florida, March 1, 2018 /PRNewswire/ —

MarketNewsUpdates.com News Commentary

Much like the gold rush in North America in the 1800s, people are going out in droves searching for a different kind of precious metal, graphite. The thing your third grade pencils were made of is now one of the hottest commodities on the market. This graphite is not being mined by your run-of-the-mill old-timey soot covered prospectors anymore. Big mining companies are all looking for this important resource integral to the production of lithium ion batteries due to the rise in popularity of electric cars. These players include Graphite Energy Corp. (OTC: GRXXF) (CSE: GRE), Teck Resources Limited (NYSE: TECK), Nemaska Lithium (TSX: NMX), Lithium Americas Corp. (TSX: LAC), and Cruz Cobalt Corp. (TSX-V: CUZ) (OTC: BKTPF).

These companies looking to manufacturer their graphite-based products, have seen steady positive growth over the past year. Their development of cutting-edge new products seems to be paying off. But in order to continue innovating, these companies need the graphite to do it. One junior miner looking to capitalize on the growing demand for this commodity is Graphite Energy Corp.

Graphite Energy is a mining company, that is focused on developing graphite resources. Graphite Energy’s state-of-the-art mining technology is friendly to the environment and has indicate graphite carbon (Cg) in the range of 2.20% to 22.30% with average 10.50% Cg from their Lac Aux Bouleaux Graphite Property in Southern Quebec [Canada].

Not Just Any Graphite Will Do

Graphite is one of the most in demand technology metals that is required for a green and sustainable world. Demand is only set to increase as the need for lithium ion batteries grows, fueled by the popularity of electric vehicles. However, not all graphite is created equal. The price of natural graphite has more than doubled since 2013 as companies look to maintain environmental standards which the use of synthetic graphite cannot provide due to its pollutant manufacturing process. Synthetic graphite is also very expensive to produce, deriving from petroleum and costing up to ten times as much as natural graphite. Therefore manufacturers are interested in increasing the proportion of natural graphite in their products in order to lower their costs.

High-grade large flake graphite is the solution to the environmental issues these companies are facing. But there is only so much supply to go around. Recent news by Graphite Energy Corp. on February 26th [2018] showed promising exploratory results. The announcement of the commencement of drilling is a positive step forward to meeting this increased demand.

Everything from batteries to solar panels need to be made with this natural high-grade flake graphite because what is the point of powering your home with the sun or charging your car if the products themselves do more harm than good to the environment when produced. However, supply consistency remains an issue since mines have different raw material impurities which vary from mine to mine. Certain types of battery technology already require graphite to be almost 100% pure. It is very possible that the purity requirements will increase in the future.

Natural graphite is also the basis of graphene, the uses of which seem limited only by scientists’ imaginations, given the host of new applications announced daily. In a recent study by ResearchSEA, a team from the Ocean University of China and Yunnan Normal University developed a highly efficient dye-sensitized solar cell using a graphene layer. This thin layer of graphene will allow solar panels to generate electricity when it rains.

Graphite Energy Is Keeping It Green

Whether it’s the graphite for the solar panels that will power the homes of tomorrow, or the lithium ion batteries that will fuel the latest cars, these advancements need to made in an environmentally conscious way. Mining companies like Graphite Energy Corp. specialize in the production of environmentally friendly graphite. The company will be producing its supply of natural graphite with the lowest environmental footprint possible.

From Saltwater To Clean Water Using Graphite

The world’s freshwater supply is at risk of running out. In order to mitigate this global disaster, worldwide spending on desalination technology was an estimated $16.6 billion in 2016. Due to the recent intense droughts in California, the state has accelerated the construction of desalination plants. However, the operating costs and the impact on the environment due to energy requirements for the process, is hindering any real progress in the space, until now.

Jeffrey Grossman, a professor at MIT’s [Massachusetts Institute of Technology, United States] Department of Materials Science and Engineering (DMSE), has been looking into whether graphite/graphene might reduce the cost of desalination.

“A billion people around the world lack regular access to clean water, and that’s expected to more than double in the next 25 years,” Grossman says. “Desalinated water costs five to 10 times more than regular municipal water, yet we’re not investing nearly enough money into research. If we don’t have clean energy we’re in serious trouble, but if we don’t have water we die.”

Grossman’s lab has demonstrated strong results showing that new filters made from graphene could greatly improve the energy efficiency of desalination plants while potentially reducing other costs as well.

Graphite/Graphene producers like Graphite Energy Corp. (OTC: GRXXF) (CSE: GRE) are moving quickly to provide the materials necessary to develop this new generation of desalination plants.

Potential Comparables

Cruz Cobalt Corp. (TSX-V: CUZ) (OTC: BKTPF) Cruz Cobalt Corp. is cobalt mining company involved in the identification, acquisition and exploration of mineral properties. The company’s geographical segments include the United States and Canada. They are focused on acquiring and developing high-grade Cobalt projects in politically stable, environmentally responsible and ethical mining jurisdictions, essential for the rapidly growing rechargeable battery and renewable energy.

Nemaska Lithium (TSE: NMX.TO)

Nemaska Lithium is lithium mining company. The company is a supplier of lithium hydroxide and lithium carbonate to the emerging lithium battery market that is largely driven by electric vehicles. Nemaska mining operations are located in the mining friendly jurisdiction of Quebec, Canada. Nemaska Lithium has received a notice of allowance of a main patent application on its proprietary process to produce lithium hydroxide and lithium carbonate.

Lithium Americas Corp. (TSX: LAC.TO)

Lithium Americas is developing one of North America’s largest lithium deposits in northern Nevada. It operates nearly two lithium projects namely Cauchari-Olaroz project which is located in Argentina, and the Lithium Nevada project located in Nevada. The company manufactures specialty organoclay products, derived from clays, for sale to the oil and gas and other sectors.

Teck Resources Limited (NYSE: TECK)

Teck Resources Limited is a Canadian metals and mining company.Teck’s principal products include coal, copper, zinc, with secondary products including lead, silver, gold, molybdenum, germanium, indium and cadmium. Teck’s diverse resources focuses on providing products that are essential to building a better quality of life for people around the globe.

Graphite Mining Today For A Better Tomorrow

Graphite mining will forever be intertwined with the latest advancements in science and technology. Graphite deserves attention for its various use cases in automotive, energy, aerospace and robotics industries. In order for these and other industries to become sustainable and environmentally friendly, a reliance on graphite is necessary. Therefore, this rapidly growing sector has the potential to fuel investor interest in the mining space throughout 2018. The near limitless uses of graphite has the potential to impact every facet of our lives. Companies like Graphite Energy Corp. (OTC: GRXXF); (CSE: GRE) is at the forefront in this technological revolution.

For more information on Graphite Energy Corp. (OTC: GRXXF) (CSE: GRE), please visit streetsignals.com for a free research report.

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Hopefully my insertions of ‘Canada’ and the ‘United States’ help to clarify matters. North America and the United States are not synonyms although they are sometimes used synonymously.

There is another copy of this news release on Wall Street Online (Deutschland), both in English and German.By the way, that was my first clue that there might be some German interest. The second clue was the Graphite Energy Corp. homepage. Unusually for a company with ‘headquarters’ in the Canadian province of British Columbia, there’s an option to read the text in German.

Graphite Energy Corp. seems to be a relatively new player in the ‘rush’ to mine graphite flakes for use in graphene-based applications. One of my first posts about mining for graphite flakes was a July 26, 2011 posting concerning Northern Graphite and their mining operation (Bissett Creek) in Ontario. I don’t write about them often but they are still active if their news releases are to be believed. The latest was issued February 28, 2018 and offers “financial metrics for the Preliminary Economic Assessment (the “PEA”) on the Company’s 100% owned Bissett Creek graphite project.”

The other graphite mining company mentioned here is Lomiko Metals. The latest posting here about Lomiko is a December 23, 2015 piece regarding an analysis and stock price recommendation by a company known as SeeThruEquity. Like Graphite Energy Corp., Lomiko’s mines are located in Québec and their business headquarters in British Columbia. Lomiko has a March 16, 2018 news release announcing its reinstatement for trading on the TSX (Toronto Stock Exchange),

(Vancouver, B.C.) Lomiko Metals Inc. (“Lomiko”) (“Lomiko”) (TSX-V: LMR, OTC: LMRMF, FSE: DH8C) announces it has been successful in its reinstatement application with the TSX Venture Exchange and trading will begin at the opening on Tuesday, March 20, 2018.

Getting back to the flakes, here’s more about Graphite Energy Corp.’s mine (from the About Lac Aux Bouleaux webpage),

Lac Aux Bouleaux

The Lac Aux Bouleaux Property is comprised of 14 mineral claims in one contiguous block totaling 738.12 hectares land on NTS 31J05, near the town of Mont-Laurier in southern Québec. Lac Aux Bouleaux “LAB” is a world class graphite property that borders the only producing graphite in North America [Note: There are three countries in North America, Canada, the United States, and Mexico. Québec is in Canada.]. On the property we have a full production facility already built which includes an open pit mine, processing facility, tailings pond, power and easy access to roads.

High Purity Levels

An important asset of LAB is its metallurgy. The property contains a high proportion of large and jumbo flakes from which a high purity concentrate was proven to be produced across all flakes by a simple flotation process. The concentrate can then be further purified using the province’s green and affordable hydro-electricity to be used in lithium-ion batteries.

The geological work performed in order to verify the existing data consisted of visiting approachable graphite outcrops, historical exploration and development work on the property. Large flake graphite showings located on the property were confirmed with flake size in the range of 0.5 to 2 millimeters, typically present in shear zones at the contact of gneisses and marbles where the graphite content usually ranges from 2% to 20%. The results of the property are outstanding showing to have jumbo flake natural graphite.

An onsite mill structure, a tailing dam facility, and a historical open mining pit is already present and constructed on the property. The property is ready to be put into production based on the existing infrastructure already built. The company would hope to be able to ship by rail its mined graphite directly to Teslas Gigafactory being built in Nevada [United States] which will produce 35GWh of batteries annually by 2020.

Adjacent Properties

The property is located in a very active graphite exploration and production area, adjacent to the south of TIMCAL’s Lac des Iles graphite mine in Quebec which is a world class deposit producing 25,000 tonnes of graphite annually. There are several graphite showings and past producing mines in its vicinity, including a historic deposit located on the property.

The open pit mine in operation since 1989 with an onsite plant ranked 5th in the world production of graphite. The mine is operated by TIMCAL Graphite & Carbon which is a subsidiary of Imerys S.A., a French multinational company. The mine has an average grade of 7.5% Cg (graphite carbon) and has been producing 50 different graphite products for various graphite end users around the globe.

Canadians! We have great flakes!

Tracking artificial intelligence

Researchers at Stanford University have developed an index for measuring (tracking) the progress made by artificial intelligence (AI) according to a January 9, 2018 news item on phys.org (Note: Links have been removed),

Since the term “artificial intelligence” (AI) was first used in print in 1956, the one-time science fiction fantasy has progressed to the very real prospect of driverless cars, smartphones that recognize complex spoken commands and computers that see.

In an effort to track the progress of this emerging field, a Stanford-led group of leading AI thinkers called the AI100 has launched an index that will provide a comprehensive baseline on the state of artificial intelligence and measure technological progress in the same way the gross domestic product and the S&P 500 index track the U.S. economy and the broader stock market.

For anyone curious about the AI100 initiative, I have a description of it in my Sept. 27, 2016 post highlighting the group’s first report or you can keep on reading.

Getting back to the matter at hand, a December 21, 2017 Stanford University press release by Andrew Myers, which originated the news item, provides more detail about the AI index,

“The AI100 effort realized that in order to supplement its regular review of AI, a more continuous set of collected metrics would be incredibly useful,” said Russ Altman, a professor of bioengineering and the faculty director of AI100. “We were very happy to seed the AI Index, which will inform the AI100 as we move forward.”

The AI100 was set in motion three years ago when Eric Horvitz, a Stanford alumnus and former president of the Association for the Advancement of Artificial Intelligence, worked with his wife, Mary Horvitz, to define and endow the long-term study. Its first report, released in the fall of 2016, sought to anticipate the likely effects of AI in an urban environment in the year 2030.

Among the key findings in the new index are a dramatic increase in AI startups and investment as well as significant improvements in the technology’s ability to mimic human performance.

Baseline metrics

The AI Index tracks and measures at least 18 independent vectors in academia, industry, open-source software and public interest, plus technical assessments of progress toward what the authors call “human-level performance” in areas such as speech recognition, question-answering and computer vision – algorithms that can identify objects and activities in 2D images. Specific metrics in the index include evaluations of academic papers published, course enrollment, AI-related startups, job openings, search-term frequency and media mentions, among others.

“In many ways, we are flying blind in our discussions about artificial intelligence and lack the data we need to credibly evaluate activity,” said Yoav Shoham, professor emeritus of computer science.

“The goal of the AI Index is to provide a fact-based measuring stick against which we can chart progress and fuel a deeper conversation about the future of the field,” Shoham said.

Shoham conceived of the index and assembled a steering committee including Ray Perrault from SRI International, Erik Brynjolfsson of the Massachusetts Institute of Technology and Jack Clark from OpenAI. The committee subsequently hired Calvin LeGassick as project manager.

“The AI Index will succeed only if it becomes a community effort,” Shoham said.

Although the authors say the AI Index is the first index to track either scientific or technological progress, there are many other non-financial indexes that provide valuable insight into equally hard-to-quantify fields. Examples include the Social Progress Index, the Middle East peace index and the Bangladesh empowerment index, which measure factors as wide-ranging as nutrition, sanitation, workload, leisure time, public sentiment and even public speaking opportunities.

Intriguing findings

Among the findings of this inaugural index is that the number of active AI startups has increased 14-fold since 2000. Venture capital investment has increased six times in the same period. In academia, publishing in AI has increased a similarly impressive nine times in the last 20 years while course enrollment has soared. Enrollment in the introductory AI-related machine learning course at Stanford, for instance, has grown 45-fold in the last 30 years.

In technical metrics, image and speech recognition are both approaching, if not surpassing, human-level performance. The authors noted that AI systems have excelled in such real-world applications as object detection, the ability to understand and answer questions and classification of photographic images of skin cancer cells

Shoham noted that the report is still very U.S.-centric and will need a greater international presence as well as a greater diversity of voices. He said he also sees opportunities to fold in government and corporate investment in addition to the venture capital funds that are currently included.

In terms of human-level performance, the AI Index suggests that in some ways AI has already arrived. This is true in game-playing applications including chess, the Jeopardy! game show and, most recently, the game of Go. Nonetheless, the authors note that computers continue to lag considerably in the ability to generalize specific information into deeper meaning.

“AI has made truly amazing strides in the past decade,” Shoham said, “but computers still can’t exhibit the common sense or the general intelligence of even a 5-year-old.”

The AI Index was made possible by funding from AI100, Google, Microsoft and Toutiao. Data supporting the various metrics were provided by Elsevier, TrendKite, Indeed.com, Monster.com, the Google Trends Team, the Google Brain Team, Sand Hill Econometrics, VentureSource, Crunchbase, Electronic Frontier Foundation, EuroMatrix, Geoff Sutcliffe, Kevin Leyton-Brown and Holger Hoose.

You can find the AI Index here. They’re featuring their 2017 report but you can also find data (on the menu bar on the upper right side of your screen), along with a few provisos. I was curious as to whether any AI had been used to analyze the data and/or write the report. A very cursory look at the 2017 report did not answer that question. I’m fascinated by the failure to address what I think is an obvious question. It suggests that even very, very bright people can become blind and I suspect that’s why the group seems quite eager to get others involved, from the 2017 AI Index Report,

As the report’s limitations illustrate, the AI Index will always paint a partial picture. For this reason, we include subjective commentary from a cross-section of AI experts. This Expert Forum helps animate the story behind the data in the report and adds interpretation the report lacks.

Finally, where the experts’ dialogue ends, your opportunity to Get Involved begins [emphasis mine]. We will need the feedback and participation of a larger community to address the issues identified in this report, uncover issues we have omitted, and build a productive process for tracking activity and progress in Artificial Intelligence. (p. 8)

Unfortunately, it’s not clear how one becomes involved. Is there a forum or do you get in touch with one of the team leaders?

I wish them good luck with their project and imagine that these minor hiccups will be dealt with in near term.

The devil’s (i.e., luciferase) in the bioluminescent plant

The American Chemical Society (ACS) and the Massachusetts Institute of Technology (MIT) have both issued news releases about the latest in bioluminescence.The researchers tested their work on watercress, a vegetable that was viewed in almost sacred terms in my family; it was not easily available in Vancouver (Canada) when I was child.

My father would hunt down fresh watercress by checking out the Chinese grocery stores. He could spot the fresh stuff from across the street while driving at 30 miles or more per hour. Spotting it entailed an immediate hunt for parking (my father hated to pay so we might have go around the block a few times or more) and a dash out of the car to ensure that he got his watercress before anyone else spotted it. These days it’s much more easily available and, thankfully, my father has passed on so he won’t have to think about glowing watercress.

Getting back to bioluninescent vegetable research, the American Chemical Society’s Dec. 13, 2017 news release on EurekAlert (and as a Dec. 13, 2017 news item on ScienceDaily) makes the announcement,

The 2009 film “Avatar” created a lush imaginary world, illuminated by magical, glowing plants. Now researchers are starting to bring this spellbinding vision to life to help reduce our dependence on artificial lighting. They report in ACS’ journal Nano Letters a way to infuse plants with the luminescence of fireflies.

Nature has produced many bioluminescent organisms, however, plants are not among them. Most attempts so far to create glowing greenery — decorative tobacco plants in particular — have relied on introducing the genes of luminescent bacteria or fireflies through genetic engineering. But getting all the right components to the right locations within the plants has been a challenge. To gain better control over where light-generating ingredients end up, Michael S. Strano and colleagues recently created nanoparticles that travel to specific destinations within plants. Building on this work, the researchers wanted to take the next step and develop a “nanobionic,” glowing plant.

The team infused watercress and other plants with three different nanoparticles in a pressurized bath. The nanoparticles were loaded with light-emitting luciferin; luciferase, which modifies luciferin and makes it glow; and coenzyme A, which boosts luciferase activity. Using size and surface charge to control where the sets of nanoparticles could go within the plant tissues, the researchers could optimize how much light was emitted. Their watercress was half as bright as a commercial 1 microwatt LED and 100,000 times brighter than genetically engineered tobacco plants. Also, the plant could be turned off by adding a compound that blocks luciferase from activating luciferin’s glow.

Here’s a video from MIT detailing their research,

A December 13, 2017 MIT news release (also on EurekAlert) casts more light on the topic (I couldn’t resist the word play),

Imagine that instead of switching on a lamp when it gets dark, you could read by the light of a glowing plant on your desk.

MIT engineers have taken a critical first step toward making that vision a reality. By embedding specialized nanoparticles into the leaves of a watercress plant, they induced the plants to give off dim light for nearly four hours. They believe that, with further optimization, such plants will one day be bright enough to illuminate a workspace.

“The vision is to make a plant that will function as a desk lamp — a lamp that you don’t have to plug in. The light is ultimately powered by the energy metabolism of the plant itself,” says Michael Strano, the Carbon P. Dubbs Professor of Chemical Engineering at MIT and the senior author of the study

This technology could also be used to provide low-intensity indoor lighting, or to transform trees into self-powered streetlights, the researchers say.

MIT postdoc Seon-Yeong Kwak is the lead author of the study, which appears in the journal Nano Letters.

Nanobionic plants

Plant nanobionics, a new research area pioneered by Strano’s lab, aims to give plants novel features by embedding them with different types of nanoparticles. The group’s goal is to engineer plants to take over many of the functions now performed by electrical devices. The researchers have previously designed plants that can detect explosives and communicate that information to a smartphone, as well as plants that can monitor drought conditions.

Lighting, which accounts for about 20 percent of worldwide energy consumption, seemed like a logical next target. “Plants can self-repair, they have their own energy, and they are already adapted to the outdoor environment,” Strano says. “We think this is an idea whose time has come. It’s a perfect problem for plant nanobionics.”

To create their glowing plants, the MIT team turned to luciferase, the enzyme that gives fireflies their glow. Luciferase acts on a molecule called luciferin, causing it to emit light. Another molecule called co-enzyme A helps the process along by removing a reaction byproduct that can inhibit luciferase activity.

The MIT team packaged each of these three components into a different type of nanoparticle carrier. The nanoparticles, which are all made of materials that the U.S. Food and Drug Administration classifies as “generally regarded as safe,” help each component get to the right part of the plant. They also prevent the components from reaching concentrations that could be toxic to the plants.

The researchers used silica nanoparticles about 10 nanometers in diameter to carry luciferase, and they used slightly larger particles of the polymers PLGA and chitosan to carry luciferin and coenzyme A, respectively. To get the particles into plant leaves, the researchers first suspended the particles in a solution. Plants were immersed in the solution and then exposed to high pressure, allowing the particles to enter the leaves through tiny pores called stomata.

Particles releasing luciferin and coenzyme A were designed to accumulate in the extracellular space of the mesophyll, an inner layer of the leaf, while the smaller particles carrying luciferase enter the cells that make up the mesophyll. The PLGA particles gradually release luciferin, which then enters the plant cells, where luciferase performs the chemical reaction that makes luciferin glow.

The researchers’ early efforts at the start of the project yielded plants that could glow for about 45 minutes, which they have since improved to 3.5 hours. The light generated by one 10-centimeter watercress seedling is currently about one-thousandth of the amount needed to read by, but the researchers believe they can boost the light emitted, as well as the duration of light, by further optimizing the concentration and release rates of the components.

Plant transformation

Previous efforts to create light-emitting plants have relied on genetically engineering plants to express the gene for luciferase, but this is a laborious process that yields extremely dim light. Those studies were performed on tobacco plants and Arabidopsis thaliana, which are commonly used for plant genetic studies. However, the method developed by Strano’s lab could be used on any type of plant. So far, they have demonstrated it with arugula, kale, and spinach, in addition to watercress.

For future versions of this technology, the researchers hope to develop a way to paint or spray the nanoparticles onto plant leaves, which could make it possible to transform trees and other large plants into light sources.

“Our target is to perform one treatment when the plant is a seedling or a mature plant, and have it last for the lifetime of the plant,” Strano says. “Our work very seriously opens up the doorway to streetlamps that are nothing but treated trees, and to indirect lighting around homes.”

The researchers have also demonstrated that they can turn the light off by adding nanoparticles carrying a luciferase inhibitor. This could enable them to eventually create plants that shut off their light emission in response to environmental conditions such as sunlight, the researchers say.

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

A Nanobionic Light-Emitting Plant by Seon-Yeong Kwak, Juan Pablo Giraldo, Min Hao Wong, Volodymyr B. Koman, Tedrick Thomas Salim Lew, Jon Ell, Mark C. Weidman, Rosalie M. Sinclair, Markita P. Landry, William A. Tisdale, and Michael S. Strano. Nano Lett., 2017, 17 (12), pp 7951–7961 DOI: 10.1021/acs.nanolett.7b04369 Publication Date (Web): November 17, 2017

Copyright © 2017 American Chemical Society

This paper is behind a paywall.

A 3D printed ‘living’ tattoo

MIT engineers have devised a 3-D printing technique that uses a new kind of ink made from genetically programmed living cells. Courtesy of the researchers [and MIT]

If that image isn’t enough, there’s also a video abstract (I don’t think I’ve seen one of these before) for the paper,

For those who’d still like to read the text, here’s more from a December 5, 2017 MIT (Massachusetts Institute of Technology) news release (also on EurekAlert),

MIT engineers have devised a 3-D printing technique that uses a new kind of ink made from genetically programmed living cells.

The cells are engineered to light up in response to a variety of stimuli. When mixed with a slurry of hydrogel and nutrients, the cells can be printed, layer by layer, to form three-dimensional, interactive structures and devices.

The team has then demonstrated its technique by printing a “living tattoo” — a thin, transparent patch patterned with live bacteria cells in the shape of a tree. Each branch of the tree is lined with cells sensitive to a different chemical or molecular compound. When the patch is adhered to skin that has been exposed to the same compounds, corresponding regions of the tree light up in response.

The researchers, led by Xuanhe Zhao, the Noyce Career Development Professor in MIT’s Department of Mechanical Engineering, and Timothy Lu, associate professor of biological engineering and of electrical engineering and computer science, say that their technique can be used to fabricate “active” materials for wearable sensors and interactive displays. Such materials can be patterned with live cells engineered to sense environmental chemicals and pollutants as well as changes in pH and temperature.

What’s more, the team developed a model to predict the interactions between cells within a given 3-D-printed structure, under a variety of conditions. The team says researchers can use the model as a guide in designing responsive living materials.

Zhao, Lu, and their colleagues have published their results today [December 5, 2017] in the journal Advanced Materials. The paper’s co-authors are graduate students Xinyue Liu, Hyunwoo Yuk, Shaoting Lin, German Alberto Parada, Tzu-Chieh Tang, Eléonore Tham, and postdoc Cesar de la Fuente-Nunez.

A hardy alternative

In recent years, scientists have explored a variety of responsive materials as the basis for 3D-printed inks. For instance, scientists have used inks made from temperature-sensitive polymers to print heat-responsive shape-shifting objects. Others have printed photoactivated structures from polymers that shrink and stretch in response to light.

Zhao’s team, working with bioengineers in Lu’s lab, realized that live cells might also serve as responsive materials for 3D-printed inks, particularly as they can be genetically engineered to respond to a variety of stimuli. The researchers are not the first to consider 3-D printing genetically engineered cells; others have attempted to do so using live mammalian cells, but with little success.

“It turns out those cells were dying during the printing process, because mammalian cells are basically lipid bilayer balloons,” Yuk says. “They are too weak, and they easily rupture.”

Instead, the team identified a hardier cell type in bacteria. Bacterial cells have tough cell walls that are able to survive relatively harsh conditions, such as the forces applied to ink as it is pushed through a printer’s nozzle. Furthermore, bacteria, unlike mammalian cells, are compatible with most hydrogels — gel-like materials that are made from a mix of mostly water and a bit of polymer. The group found that hydrogels can provide an aqueous environment that can support living bacteria.

The researchers carried out a screening test to identify the type of hydrogel that would best host bacterial cells. After an extensive search, a hydrogel with pluronic acid was found to be the most compatible material. The hydrogel also exhibited an ideal consistency for 3-D printing.

“This hydrogel has ideal flow characteristics for printing through a nozzle,” Zhao says. “It’s like squeezing out toothpaste. You need [the ink] to flow out of a nozzle like toothpaste, and it can maintain its shape after it’s printed.”

From tattoos to living computers

Lu provided the team with bacterial cells engineered to light up in response to a variety of chemical stimuli. The researchers then came up with a recipe for their 3-D ink, using a combination of bacteria, hydrogel, and nutrients to sustain the cells and maintain their functionality.

“We found this new ink formula works very well and can print at a high resolution of about 30 micrometers per feature,” Zhao says. “That means each line we print contains only a few cells. We can also print relatively large-scale structures, measuring several centimeters.”

They printed the ink using a custom 3-D printer that they built using standard elements combined with fixtures they machined themselves. To demonstrate the technique, the team printed a pattern of hydrogel with cells in the shape of a tree on an elastomer layer. After printing, they solidified, or cured, the patch by exposing it to ultraviolet radiation. They then adhere the transparent elastomer layer with the living patterns on it, to skin.

To test the patch, the researchers smeared several chemical compounds onto the back of a test subject’s hand, then pressed the hydrogel patch over the exposed skin. Over several hours, branches of the patch’s tree lit up when bacteria sensed their corresponding chemical stimuli.

The researchers also engineered bacteria to communicate with each other; for instance they programmed some cells to light up only when they receive a certain signal from another cell. To test this type of communication in a 3-D structure, they printed a thin sheet of hydrogel filaments with “input,” or signal-producing bacteria and chemicals, overlaid with another layer of filaments of an “output,” or signal-receiving bacteria. They found the output filaments lit up only when they overlapped and received input signals from corresponding bacteria .

Yuk says in the future, researchers may use the team’s technique to print “living computers” — structures with multiple types of cells that communicate with each other, passing signals back and forth, much like transistors on a microchip.

“This is very future work, but we expect to be able to print living computational platforms that could be wearable,” Yuk says.

For more near-term applications, the researchers are aiming to fabricate customized sensors, in the form of flexible patches and stickers that could be engineered to detect a variety of chemical and molecular compounds. They also envision their technique may be used to manufacture drug capsules and surgical implants, containing cells engineered produce compounds such as glucose, to be released therapeutically over time.

“We can use bacterial cells like workers in a 3-D factory,” Liu says. “They can be engineered to produce drugs within a 3-D scaffold, and applications should not be confined to epidermal devices. As long as the fabrication method and approach are viable, applications such as implants and ingestibles should be possible.”

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

3D Printing of Living Responsive Materials and Devices by Xinyue Liu, Hyunwoo Yuk, Shaoting Lin, German Alberto Parada, Tzu-Chieh Tang, Eléonore Tham, Cesar de la Fuente-Nunez, Timothy K. Lu, and Xuanhe Zhao. Advanced Materials DOI: 10.1002/adma.201704821 Version of Record online: 5 DEC 2017

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

This paper is behind a paywall.

A transatlantic report highlighting the risks and opportunities associated with synthetic biology and bioengineering

I love e-Life, the open access journal where its editors noted that a submitted synthetic biology and bioengineering report was replete with US and UK experts (along with a European or two) but no expert input from other parts of the world. In response the authors added ‘transatlantic’ to the title. It was a good decision since it was too late to add any new experts if the authors planned to have their paper published in the foreseeable future.

I’ve commented many times here when panels of experts include only Canadian, US, UK, and, sometimes, European or Commonwealth (Australia/New Zealand) experts that we need to broaden our perspectives and now I can add: or at least acknowledge (e.g. transatlantic) that the perspectives taken are reflective of a rather narrow range of countries.

Now getting to the report, here’s more from a November 21, 2017 University of Cambridge press release,

Human genome editing, 3D-printed replacement organs and artificial photosynthesis – the field of bioengineering offers great promise for tackling the major challenges that face our society. But as a new article out today highlights, these developments provide both opportunities and risks in the short and long term.

Rapid developments in the field of synthetic biology and its associated tools and methods, including more widely available gene editing techniques, have substantially increased our capabilities for bioengineering – the application of principles and techniques from engineering to biological systems, often with the goal of addressing ‘real-world’ problems.

In a feature article published in the open access journal eLife, an international team of experts led by Dr Bonnie Wintle and Dr Christian R. Boehm from the Centre for the Study of Existential Risk at the University of Cambridge, capture perspectives of industry, innovators, scholars, and the security community in the UK and US on what they view as the major emerging issues in the field.

Dr Wintle says: “The growth of the bio-based economy offers the promise of addressing global environmental and societal challenges, but as our paper shows, it can also present new kinds of challenges and risks. The sector needs to proceed with caution to ensure we can reap the benefits safely and securely.”

The report is intended as a summary and launching point for policy makers across a range of sectors to further explore those issues that may be relevant to them.

Among the issues highlighted by the report as being most relevant over the next five years are:

Artificial photosynthesis and carbon capture for producing biofuels

If technical hurdles can be overcome, such developments might contribute to the future adoption of carbon capture systems, and provide sustainable sources of commodity chemicals and fuel.

Enhanced photosynthesis for agricultural productivity

Synthetic biology may hold the key to increasing yields on currently farmed land – and hence helping address food security – by enhancing photosynthesis and reducing pre-harvest losses, as well as reducing post-harvest and post-consumer waste.

Synthetic gene drives

Gene drives promote the inheritance of preferred genetic traits throughout a species, for example to prevent malaria-transmitting mosquitoes from breeding. However, this technology raises questions about whether it may alter ecosystems [emphasis mine], potentially even creating niches where a new disease-carrying species or new disease organism may take hold.

Human genome editing

Genome engineering technologies such as CRISPR/Cas9 offer the possibility to improve human lifespans and health. However, their implementation poses major ethical dilemmas. It is feasible that individuals or states with the financial and technological means may elect to provide strategic advantages to future generations.

Defence agency research in biological engineering

The areas of synthetic biology in which some defence agencies invest raise the risk of ‘dual-use’. For example, one programme intends to use insects to disseminate engineered plant viruses that confer traits to the target plants they feed on, with the aim of protecting crops from potential plant pathogens – but such technologies could plausibly also be used by others to harm targets.

In the next five to ten years, the authors identified areas of interest including:

Regenerative medicine: 3D printing body parts and tissue engineering

While this technology will undoubtedly ease suffering caused by traumatic injuries and a myriad of illnesses, reversing the decay associated with age is still fraught with ethical, social and economic concerns. Healthcare systems would rapidly become overburdened by the cost of replenishing body parts of citizens as they age and could lead new socioeconomic classes, as only those who can pay for such care themselves can extend their healthy years.

Microbiome-based therapies

The human microbiome is implicated in a large number of human disorders, from Parkinson’s to colon cancer, as well as metabolic conditions such as obesity and type 2 diabetes. Synthetic biology approaches could greatly accelerate the development of more effective microbiota-based therapeutics. However, there is a risk that DNA from genetically engineered microbes may spread to other microbiota in the human microbiome or into the wider environment.

Intersection of information security and bio-automation

Advancements in automation technology combined with faster and more reliable engineering techniques have resulted in the emergence of robotic ‘cloud labs’ where digital information is transformed into DNA then expressed in some target organisms. This opens the possibility of new kinds of information security threats, which could include tampering with digital DNA sequences leading to the production of harmful organisms, and sabotaging vaccine and drug production through attacks on critical DNA sequence databases or equipment.

Over the longer term, issues identified include:

New makers disrupt pharmaceutical markets

Community bio-labs and entrepreneurial startups are customizing and sharing methods and tools for biological experiments and engineering. Combined with open business models and open source technologies, this could herald opportunities for manufacturing therapies tailored to regional diseases that multinational pharmaceutical companies might not find profitable. But this raises concerns around the potential disruption of existing manufacturing markets and raw material supply chains as well as fears about inadequate regulation, less rigorous product quality control and misuse.

Platform technologies to address emerging disease pandemics

Emerging infectious diseases—such as recent Ebola and Zika virus disease outbreaks—and potential biological weapons attacks require scalable, flexible diagnosis and treatment. New technologies could enable the rapid identification and development of vaccine candidates, and plant-based antibody production systems.

Shifting ownership models in biotechnology

The rise of off-patent, generic tools and the lowering of technical barriers for engineering biology has the potential to help those in low-resource settings, benefit from developing a sustainable bioeconomy based on local needs and priorities, particularly where new advances are made open for others to build on.

Dr Jenny Molloy comments: “One theme that emerged repeatedly was that of inequality of access to the technology and its benefits. The rise of open source, off-patent tools could enable widespread sharing of knowledge within the biological engineering field and increase access to benefits for those in developing countries.”

Professor Johnathan Napier from Rothamsted Research adds: “The challenges embodied in the Sustainable Development Goals will require all manner of ideas and innovations to deliver significant outcomes. In agriculture, we are on the cusp of new paradigms for how and what we grow, and where. Demonstrating the fairness and usefulness of such approaches is crucial to ensure public acceptance and also to delivering impact in a meaningful way.”

Dr Christian R. Boehm concludes: “As these technologies emerge and develop, we must ensure public trust and acceptance. People may be willing to accept some of the benefits, such as the shift in ownership away from big business and towards more open science, and the ability to address problems that disproportionately affect the developing world, such as food security and disease. But proceeding without the appropriate safety precautions and societal consensus—whatever the public health benefits—could damage the field for many years to come.”

The research was made possible by the Centre for the Study of Existential Risk, the Synthetic Biology Strategic Research Initiative (both at the University of Cambridge), and the Future of Humanity Institute (University of Oxford). It was based on a workshop co-funded by the Templeton World Charity Foundation and the European Research Council under the European Union’s Horizon 2020 research and innovation programme.

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

A transatlantic perspective on 20 emerging issues in biological engineering by Bonnie C Wintle, Christian R Boehm, Catherine Rhodes, Jennifer C Molloy, Piers Millett, Laura Adam, Rainer Breitling, Rob Carlson, Rocco Casagrande, Malcolm Dando, Robert Doubleday, Eric Drexler, Brett Edwards, Tom Ellis, Nicholas G Evans, Richard Hammond, Jim Haseloff, Linda Kahl, Todd Kuiken, Benjamin R Lichman, Colette A Matthewman, Johnathan A Napier, Seán S ÓhÉigeartaigh, Nicola J Patron, Edward Perello, Philip Shapira, Joyce Tait, Eriko Takano, William J Sutherland. eLife; 14 Nov 2017; DOI: 10.7554/eLife.30247

This paper is open access and the editors have included their notes to the authors and the authors’ response.

You may have noticed that I highlighted a portion of the text concerning synthetic gene drives. Coincidentally I ran across a November 16, 2017 article by Ed Yong for The Atlantic where the topic is discussed within the context of a project in New Zealand, ‘Predator Free 2050’ (Note: A link has been removed),

Until the 13th century, the only land mammals in New Zealand were bats. In this furless world, local birds evolved a docile temperament. Many of them, like the iconic kiwi and the giant kakapo parrot, lost their powers of flight. Gentle and grounded, they were easy prey for the rats, dogs, cats, stoats, weasels, and possums that were later introduced by humans. Between them, these predators devour more than 26 million chicks and eggs every year. They have already driven a quarter of the nation’s unique birds to extinction.

Many species now persist only in offshore islands where rats and their ilk have been successfully eradicated, or in small mainland sites like Zealandia where they are encircled by predator-proof fences. The songs in those sanctuaries are echoes of the New Zealand that was.

But perhaps, they also represent the New Zealand that could be.

In recent years, many of the country’s conservationists and residents have rallied behind Predator-Free 2050, an extraordinarily ambitious plan to save the country’s birds by eradicating its invasive predators. Native birds of prey will be unharmed, but Predator-Free 2050’s research strategy, which is released today, spells doom for rats, possums, and stoats (a large weasel). They are to die, every last one of them. No country, anywhere in the world, has managed such a task in an area that big. The largest island ever cleared of rats, Australia’s Macquarie Island, is just 50 square miles in size. New Zealand is 2,000 times bigger. But, the country has committed to fulfilling its ecological moonshot within three decades.

In 2014, Kevin Esvelt, a biologist at MIT, drew a Venn diagram that troubles him to this day. In it, he and his colleagues laid out several possible uses for gene drives—a nascent technology for spreading designer genes through groups of wild animals. Typically, a given gene has a 50-50 chance of being passed to the next generation. But gene drives turn that coin toss into a guarantee, allowing traits to zoom through populations in just a few generations. There are a few natural examples, but with CRISPR, scientists can deliberately engineer such drives.

Suppose you have a population of rats, roughly half of which are brown, and the other half white. Now, imagine there is a gene that affects each rat’s color. It comes in two forms, one leading to brown fur, and the other leading to white fur. A male with two brown copies mates with a female with two white copies, and all their offspring inherit one of each. Those offspring breed themselves, and the brown and white genes continue cascading through the generations in a 50-50 split. This is the usual story of inheritance. But you can subvert it with CRISPR, by programming the brown gene to cut its counterpart and replace it with another copy of itself. Now, the rats’ children are all brown-furred, as are their grandchildren, and soon the whole population is brown.

Forget fur. The same technique could spread an antimalarial gene through a mosquito population, or drought-resistance through crop plants. The applications are vast, but so are the risks. In theory, gene drives spread so quickly and relentlessly that they could rewrite an entire wild population, and once released, they would be hard to contain. If the concept of modifying the genes of organisms is already distasteful to some, gene drives magnify that distaste across national, continental, and perhaps even global scales.

These excerpts don’t do justice to this thought-provoking article. If you have time, I recommend reading it in its entirety  as it provides some insight into gene drives and, with some imagination on the reader’s part, the potential for the other technologies discussed in the report.

One last comment, I notice that Eric Drexler is cited as on the report’s authors. He’s familiar to me as K. Eric Drexler, the author of the book that popularized nanotechnology in the US and other countries, Engines of Creation (1986) .

Editing the genome with CRISPR ((clustered regularly interspaced short palindromic repeats)-carrying nanoparticles

MIT (Massachusetts Institute of Technology) researchers have developed a new nonviral means of delivering CRISPR ((clustered regularly interspaced short palindromic repeats)-CAS9 gene therapy according to a November 13, 2017 news item on Nanowerk,

In a new study, MIT researchers have developed nanoparticles that can deliver the CRISPR genome-editing system and specifically modify genes in mice. The team used nanoparticles to carry the CRISPR components, eliminating the need to use viruses for delivery.

Using the new delivery technique, the researchers were able to cut out certain genes in about 80 percent of liver cells, the best success rate ever achieved with CRISPR in adult animals.

In a new study, MIT researchers have developed nanoparticles that can deliver the CRISPR genome-editing system and specifically modify genes, eliminating the need to use viruses for delivery. Image: MIT News

A November 13, 2017 MIT news release (also on EurekAlert), which originated the news item, provides more details about the research and a good description of and comparison between using a viral system and using a nanoparticle-based system to deliver CRISPR-CAS9,

“What’s really exciting here is that we’ve shown you can make a nanoparticle that can be used to permanently and specifically edit the DNA in the liver of an adult animal,” says Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES).

One of the genes targeted in this study, known as Pcsk9, regulates cholesterol levels. Mutations in the human version of the gene are associated with a rare disorder called dominant familial hypercholesterolemia, and the FDA recently approved two antibody drugs that inhibit Pcsk9. However these antibodies need to be taken regularly, and for the rest of the patient’s life, to provide therapy. The new nanoparticles permanently edit the gene following a single treatment, and the technique also offers promise for treating other liver disorders, according to the MIT team.

Anderson is the senior author of the study, which appears in the Nov. 13 [2017] issue of Nature Biotechnology. The paper’s lead author is Koch Institute research scientist Hao Yin. Other authors include David H. Koch Institute Professor Robert Langer of MIT, professors Victor Koteliansky and Timofei Zatsepin of the Skolkovo Institute of Science and Technology [Russia], and Professor Wen Xue of the University of Massachusetts Medical School.

Targeting disease

Many scientists are trying to develop safe and efficient ways to deliver the components needed for CRISPR, which consists of a DNA-cutting enzyme called Cas9 and a short RNA that guides the enzyme to a specific area of the genome, directing Cas9 where to make its cut.

In most cases, researchers rely on viruses to carry the gene for Cas9, as well as the RNA guide strand. In 2014, Anderson, Yin, and their colleagues developed a nonviral delivery system in the first-ever demonstration of curing a disease (the liver disorder tyrosinemia) with CRISPR in an adult animal. However, this type of delivery requires a high-pressure injection, a method that can also cause some damage to the liver.

Later, the researchers showed they could deliver the components without the high-pressure injection by packaging messenger RNA (mRNA) encoding Cas9 into a nanoparticle instead of a virus. Using this approach, in which the guide RNA was still delivered by a virus, the researchers were able to edit the target gene in about 6 percent of hepatocytes, which is enough to treat tyrosinemia.

While that delivery technique holds promise, in some situations it would be better to have a completely nonviral delivery system, Anderson says. One consideration is that once a particular virus is used, the patient will develop antibodies to it, so it couldn’t be used again. Also, some patients have pre-existing antibodies to the viruses being tested as CRISPR delivery vehicles.

In the new Nature Biotechnology paper, the researchers came up with a system that delivers both Cas9 and the RNA guide using nanoparticles, with no need for viruses. To deliver the guide RNAs, they first had to chemically modify the RNA to protect it from enzymes in the body that would normally break it down before it could reach its destination.

The researchers analyzed the structure of the complex formed by Cas9 and the RNA guide, or sgRNA, to figure out which sections of the guide RNA strand could be chemically modified without interfering with the binding of the two molecules. Based on this analysis, they created and tested many possible combinations of modifications.

“We used the structure of the Cas9 and sgRNA complex as a guide and did tests to figure out we can modify as much as 70 percent of the guide RNA,” Yin says. “We could heavily modify it and not affect the binding of sgRNA and Cas9, and this enhanced modification really enhances activity.”

Reprogramming the liver

The researchers packaged these modified RNA guides (which they call enhanced sgRNA) into lipid nanoparticles, which they had previously used to deliver other types of RNA to the liver, and injected them into mice along with nanoparticles containing mRNA that encodes Cas9.

They experimented with knocking out a few different genes expressed by hepatocytes, but focused most of their attention on the cholesterol-regulating Pcsk9 gene. The researchers were able to eliminate this gene in more than 80 percent of liver cells, and the Pcsk9 protein was undetectable in these mice. They also found a 35 percent drop in the total cholesterol levels of the treated mice.

The researchers are now working on identifying other liver diseases that might benefit from this approach, and advancing these approaches toward use in patients.

“I think having a fully synthetic nanoparticle that can specifically turn genes off could be a powerful tool not just for Pcsk9 but for other diseases as well,” Anderson says. “The liver is a really important organ and also is a source of disease for many people. If you can reprogram the DNA of your liver while you’re still using it, we think there are many diseases that could be addressed.”

“We are very excited to see this new application of nanotechnology open new avenues for gene editing,” Langer adds.

The research was funded by the National Institutes of Health (NIH), the Russian Scientific Fund, the Skoltech Center, and the Koch Institute Support (core) Grant from the National Cancer Institute.

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

Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing by Hao Yin, Chun-Qing Song, Sneha Suresh, Qiongqiong Wu, Stephen Walsh, Luke Hyunsik Rhym, Esther Mintzer, Mehmet Fatih Bolukbasi, Lihua Julie Zhu, Kevin Kauffman, Haiwei Mou, Alicia Oberholzer, Junmei Ding, Suet-Yan Kwan, Roman L Bogorad, Timofei Zatsepin, Victor Koteliansky, Scot A Wolfe, Wen Xue, Robert Langer, & Daniel G Anderson. Nature Biotechnology doi:10.1038/nbt.4005 Published online: 13 November 2017

This paper is behind a paywall.

Why don’t you CRISPR yourself?

It must have been quite the conference. Josiah Zayner plunged a needle into himself and claimed to have changed his DNA (deoxyribonucleic acid) while giving his talk. (*Segue: There is some Canadian content if you keep reading.*) From an Oct. 10, 2017 article by Adele Peters for Fast Company (Note: A link has been removed),

“What we’ve got here is some DNA, and this is a syringe,” Josiah Zayner tells a room full of synthetic biologists and other researchers. He fills the needle and plunges it into his skin. “This will modify my muscle genes and give me bigger muscles.”

Zayner, a biohacker–basically meaning he experiments with biology in a DIY lab rather than a traditional one–was giving a talk called “A Step-by-Step Guide to Genetically Modifying Yourself With CRISPR” at the SynBioBeta conference in San Francisco, where other presentations featured academics in suits and the young CEOs of typical biotech startups. Unlike the others, he started his workshop by handing out shots of scotch and a booklet explaining the basics of DIY [do-it-yourwelf] genome engineering.

If you want to genetically modify yourself, it turns out, it’s not necessarily complicated. As he offered samples in small baggies to the crowd, Zayner explained that it took him about five minutes to make the DNA that he brought to the presentation. The vial held Cas9, an enzyme that snips DNA at a particular location targeted by guide RNA, in the gene-editing system known as CRISPR. In this case, it was designed to knock out the myostatin gene, which produces a hormone that limits muscle growth and lets muscles atrophy. In a study in China, dogs with the edited gene had double the muscle mass of normal dogs. If anyone in the audience wanted to try it, they could take a vial home and inject it later. Even rubbing it on skin, Zayner said, would have some effect on cells, albeit limited.

Peters goes on to note that Zayner has a PhD in molecular biology and biophysics and worked for NASA (US National Aeronautics and Space Administration). Zayner’s Wikipedia entry fills in a few more details (Note: Links have been removed),

Zayner graduated from the University of Chicago with a Ph.D. in biophysics in 2013. He then spent two years as a researcher at NASA’s Ames Research Center,[2] where he worked on Martian colony habitat design. While at the agency, Zayner also analyzed speech patterns in online chat, Twitter, and books, and found that language on Twitter and online chat is closer to how people talk than to how they write.[3] Zayner found NASA’s scientific work less innovative than he expected, and upon leaving in January 2016, he launched a crowdfunding campaign to provide CRISPR kits to let the general public experiment with editing bacterial DNA. He also continued his grad school business, The ODIN, which sells kits to let the general public experiment at home. As of May 2016, The ODIN had four employees and operates out of Zayner’s garage.[2]

He refers to himself as a biohacker and believes in the importance in letting the general public participate in scientific experimentation, rather than leaving it segregated to labs.[2][4][1] Zayner found the biohacking community exclusive and hierarchical, particularly in the types of people who decide what is “safe”. He hopes that his projects can let even more people experiment in their homes. Other scientists responded that biohacking is inherently privileged, as it requires leisure time and money, and that deviance from the safety rules of concern would lead to even harsher regulations for all.[5] Zayner’s public CRISPR kit campaign coincided with wider scrutiny over genetic modification. Zayner maintained that these fears were based on misunderstandings of the product, as genetic experiments on yeast and bacteria cannot produce a viral epidemic.[6][7] In April 2015, Zayner ran a hoax on Craigslist to raise awareness about the future potential of forgery in forensics genetics testing.[8]

In February 2016, Zayner performed a full body microbiome transplant on himself, including a fecal transplant, to experiment with microbiome engineering and see if he could cure himself from gastrointestinal and other health issues. The microbiome from the donors feces successfully transplanted in Zayner’s gut according to DNA sequencing done on samples.[2] This experiment was documented by filmmakers Kate McLean and Mario Furloni and turned into the short documentary film Gut Hack.[9]

In December 2016, Zayner created a fluorescent beer by engineering yeast to contain the green fluorescent protein from jellyfish. Zayner’s company, The ODIN, released kits to allow people to create their own engineered fluorescent yeast and this was met with some controversy as the FDA declared the green fluorescent protein can be seen as a color additive.[10] Zayner, views the kit as a way that individual can use genetic engineering to create things in their everyday life.[11]

I found the video for Zayner’s now completed crowdfunding campaign,

I also found The ODIN website (mentioned in the Wikipedia essay) where they claim to be selling various gene editing and gene engineering kits including the CRISPR editing kits mentioned in Peters’ article,

In 2016, he [Zayner] sold $200,000 worth of products, including a kit for yeast that can be used to brew glowing bioluminescent beer, a kit to discover antibiotics at home, and a full home lab that’s roughly the cost of a MacBook Pro. In 2017, he expects to double sales. Many kits are simple, and most buyers probably aren’t using the supplies to attempt to engineer themselves (many kits go to classrooms). But Zayner also hopes that as people using the kits gain genetic literacy, they experiment in wilder ways.

Zayner sells a full home biohacking lab that’s roughly the cost of a MacBook Pro. [Photo: The ODIN]

He questions whether traditional research methods, like randomized controlled trials, are the only way to make discoveries, pointing out that in newer personalized medicine (such as immunotherapy for cancer, which is personalized for each patient), a sample size of one person makes sense. At his workshop, he argued that people should have the choice to self-experiment if they want to; we also change our DNA when we drink alcohol or smoke cigarettes or breathe in dirty city air. Other society-sanctioned activities are more dangerous. “We sacrifice maybe a million people a year to the car gods,” he said. “If you ask someone, ‘Would you get rid of cars?’–no.” …

US researchers both conventional and DIY types such as Zayner are not the only ones who are editing genes. The Chinese study mentioned in Peters’ article was written up in an Oct. 19, 2015 article by Antonio Regalado for the MIT [Massachusetts Institute of Technology] Technology Review (Note: Links have been removed),

Scientists in China say they are the first to use gene editing to produce customized dogs. They created a beagle with double the amount of muscle mass by deleting a gene called myostatin.

The dogs have “more muscles and are expected to have stronger running ability, which is good for hunting, police (military) applications,” Liangxue Lai, a researcher with the Key Laboratory of Regenerative Biology at the Guangzhou Institutes of Biomedicine and Health, said in an e-mail.

Lai and 28 colleagues reported their results last week in the Journal of Molecular Cell Biology, saying they intend to create dogs with other DNA mutations, including ones that mimic human diseases such as Parkinson’s and muscular dystrophy. “The goal of the research is to explore an approach to the generation of new disease dog models for biomedical research,” says Lai. “Dogs are very close to humans in terms of metabolic, physiological, and anatomical characteristics.”

Lai said his group had no plans breed to breed the extra-muscular beagles as pets. Other teams, however, could move quickly to commercialize gene-altered dogs, potentially editing their DNA to change their size, enhance their intelligence, or correct genetic illnesses. A different Chinese Institute, BGI, said in September it had begun selling miniature pigs, created via gene editing, for $1,600 each as novelty pets.

People have been influencing the genetics of dogs for millennia. By at least 36,000 years ago, early humans had already started to tame wolves and shape the companions we have today. Charles Darwin frequently cited dog breeding in The Origin of Species to demonstrate how evolution gradually occurs by a process of selection. With CRISPR, however, evolution is no longer gradual or subject to chance. It is immediate and under human control.

It is precisely that power that is stirring wide debate and concern over CRISPR. Yet at least some researchers think that gene-edited dogs could put a furry, friendly face on the technology. In an interview this month, George Church, a professor at Harvard University who leads a large effort to employ CRISPR editing, said he thinks it will be possible to augment dogs by using DNA edits to make them live longer or simply make them smarter.

Church said he also believed the alteration of dogs and other large animals could open a path to eventual gene editing of people. “Germline editing of pigs or dogs offers a line into it,” he said. “People might say, ‘Hey, it works.’ ”

In the meantime, Zayner’s ideas are certainly thought provoking. I’m not endorsing either his products or his ideas but it should be noted that early science pioneers such as Humphrey Davy and others experimented on themselves. For anyone unfamiliar with Davy, (from the Humphrey Davy Wikipedia entry; Note: Links have been removed),

Sir Humphry Davy, 1st Baronet PRS MRIA FGS (17 December 1778 – 29 May 1829) was a Cornish chemist and inventor,[1] who is best remembered today for isolating a series of substances for the first time: potassium and sodium in 1807 and calcium, strontium, barium, magnesium and boron the following year, as well as discovering the elemental nature of chlorine and iodine. He also studied the forces involved in these separations, inventing the new field of electrochemistry. Berzelius called Davy’s 1806 Bakerian Lecture On Some Chemical Agencies of Electricity[2] “one of the best memoirs which has ever enriched the theory of chemistry.”[3] He was a Baronet, President of the Royal Society (PRS), Member of the Royal Irish Academy (MRIA), and Fellow of the Geological Society (FGS). He also invented the Davy lamp and a very early form of incandescent light bulb.

Canadian content*

A Nov. 11, 2017 posting on the Canadian Broadcasting Corporation’s (CBC) Quirks and Quarks blog notes that self-experimentation has a long history and goes on to describe Zayner’s and others biohacking exploits before describing the legality of biohacking in Canada,

With biohackers entering into the space traditionally held by scientists and clinicians, it begs questions. Professor Timothy Caulfield, a Canada research chair in health, law and policy at the University of Alberta, says when he hears of somebody giving themselves biohacked gene therapy, he wonders: “Is this legal? Is this safe? And if it’s not safe, is there anything that we can do about regulating it? And to be honest with you that’s a tough question and I think it’s an open question.”

In Canada, Caulfield says, Health Canada focuses on products. “You have to have something that you are going to regulate or you have to have something that’s making health claims. So if there is a product that is saying I can cure X, Y, or Z, Health Canada can say, ‘Well let’s make sure the science really backs up that claim.’ The problem with these do-it-yourself approaches is there isn’t really a product. You know these people are experimenting on themselves with something that may or may not be designed for health purposes.”

According to Caufield, if you could buy a gene therapy kit that was being marketed to you to biohack yourself, that would be different. “Health Canada could jump in. But right here that’s not the case,” he says.

There are places in the world that do regulate biohacking, says Caulfield. “Germany, for example, they have specific laws for it. And here in Canada we do have a regulatory framework that says that you cannot do gene therapy that will alter the germ line. In other words, you can’t do gene therapy or any kind of genetic editing that will create a change that you will pass on to your offspring. So that would be illegal, but that’s not what’s happening here. And I don’t think there’s a regulatory framework that adequately captures it.”

Infectious disease and policy experts aren’t that concerned yet about the possibility of a biohacker unleashing a genetically modified super germ into the population.

“I think in the future that could be a problem,”says Caulfield, “but this isn’t something that would be easy to do in your garage. I think it’s complicated science. But having said that, the science is moving quickly. We need to think about how we are going to control the potential harms.”

You can find out more about the ‘wild’ people (mostly men) of early science in Richard Holmes’ 2008 book, The Age of Wonder: How the Romantic Generation Discovered the Beauty and Terror of Science.

Finally, should you be interested in connecting with synthetic biology enthusiasts, entrepreneurs, and others, SynBioBeta is more than a conference; it’s also an activity hub.

ETA January 25, 2018 (five minutes later): There are some CRISPR/CAS9 events taking place in Toronto, Canada on January 24 and 25, 2018. One is a workshop with Portuguese artist, Marta de Menezes, and the other is a panel discussion. See my January 10, 2018 posting for more details.

*’Segue: There is some Canadian content if you keep reading.’ and ‘Canadian content’ added January 25, 2018 six minutes after first publication.

ETA February 20, 2018: Sarah Zhang’s Feb. 20, 2018 article for The Atlantic revisits Josiah Zayner’s decision to inject himself with CRISPR,

When Josiah Zayner watched a biotech CEO drop his pants at a biohacking conference and inject himself with an untested herpes treatment, he realized things had gone off the rails.

Zayner is no stranger to stunts in biohacking—loosely defined as experiments, often on the self, that take place outside of traditional lab spaces. You might say he invented their latest incarnation: He’s sterilized his body to “transplant” his entire microbiome in front of a reporter. He’s squabbled with the FDA about selling a kit to make glow-in-the-dark beer. He’s extensively documented attempts to genetically engineer the color of his skin. And most notoriously, he injected his arm with DNA encoding for CRISPR that could theoretically enhance his muscles—in between taking swigs of Scotch at a live-streamed event during an October conference. (Experts say—and even Zayner himself in the live-stream conceded—it’s unlikely to work.)

So when Zayner saw Ascendance Biomedical’s CEO injecting himself on a live-stream earlier this month, you might say there was an uneasy flicker of recognition.

“Honestly, I kind of blame myself,” Zayner told me recently. He’s been in a soul-searching mood; he recently had a kid and the backlash to the CRISPR stunt in October [2017] had been getting to him. “There’s no doubt in my mind that somebody is going to end up hurt eventually,” he said.

Yup, it’s one of the reasons for rules; people take things too far. The trick is figuring out how to achieve balance between risk taking and recklessness.