Lights and Brains: Injectible LED's Interact with Brain Cells

The quest to put computers in the brain has just come a step closer.  Tiny LED lights have been implanted deep in the brains of rodents.  The LEDs themselves are the size of individual neurons.  They are packaged with other tiny sensors into an ultrathin, flexible device.  The whole device is small enough to be implanted using a needle that positions the device at precise sites deep in the brain. 

Once implanted, the device communicates directly with the brain at the level of cells.  It communicates wirelessly with a module mounted above the rodent’s head, one small enough not to interfere with activity and removable when not in use.  The device itself is completely contained within the brain where it was implanted without any damage to surrounding cells.  Signals sent through the device stimulate genetically modified brain cells, signaling for example for the release of neurotransmitters such as dopamine. 

Photo Credit: MicroLED device next to a human finger.  Image courtesy of University of Illinois-Urbana Champaign and Washington University-St. Louis.

 

"These materials and device structures open up new ways to integrate semiconductor components directly into the brain," said team co-leader John A. Rogers according to a press release from the University of Illinois.  "More generally, the ideas establish a paradigm for delivering sophisticated forms of electronics into the body: ultra-miniaturized devices that are injected into and provide direct interaction with the depths of the tissue."

The device itself is a feat of engineering requiring the effort of an international team based in China, Korea, and at multiple centers across the US.  By miniaturizing the device to the cellular scale and by creating a totally wireless interface, researchers overcame several challenges at once.  For example, larger implantable devices always run the risk of creating scars or lesions in the brain, which may cause serious problems.   "One of the big issues with implanting something into the brain is the potential damage it can cause," team co-leader Michael Bruchas said. "These devices are specifically designed to minimize those problems, and they are much more effective than traditional approaches."

In addition, because this device communicates and receives its power wirelessly, there are no wires or optical fibers passing from the brain to the outside world.  Previous devices were larger and nonflexible. They were implanted only on the surface of brain structures, but this new device is implantable deep within those structures and able to interact with units as small as a single cell.

Along with the LED lights, the device includes temperature and light sensors, microscale heaters, and electrodes that can stimulate and receive brain electrical activity.  Power to the device is provided wirelessly through a radio frequency system. 

It is impossible to predict the future of efforts to connect brains and computers. This work obviously represents a significant advance toward that end.  "These cellular-scale, injectable devices represent frontier technologies with potentially broad implications," Rogers said. Being able to monitor and trigger the brain of living animals at the cellular level is likely to become a profoundly valuable tool for research.  Medical research, too, is also likely to be affected, not just in responding to patients with paralysis but also in research and perhaps even therapy in other diseases involving the brain or other organs, where these devices are also implantable. 

Some, of course, will speculate about even wider implications for this technology.  Will it open the way to control people by controling their brains?  Perhaps.  Will it open the way for our brains to communicate with computers and the internet?  There is little doubt that this step will inspire more work along those lines. 

This article is entitled "Injectable, Cellular-Scale Optoelectronics with Applications for Wireless Optogenetics" and is published in the April 12, 2012 issue of the journal Science, a publication of the American Association for the Advancement of Science. 

Parthenogenesis and "Virgin Birth"? Rhetoric and Research

Despite roadblocks, the field of stem cell research remains profoundly attractive. The idea of being able to regenerate damaged or diseased cells in the human body is appealing to nearly everyone who cares about human health.

But technical problems remain. Much has been learned in the past decade, but the pathway to medical treatments still faces many challenging problems. One worry in particular is that implanted stem cells might develop into cancer. Others challenges including getting the cells to multiply, integrate with other cells, function as they should, and avoid being rejected as an infection.

A new solution may be on the horizon, one that addresses many of these problems—moral and technical—all at once. At least that’s the claim made by a team led by Wolfram Zimmerman and colleagues at Georg-August-Universität Göttingen in Germany. Working with laboratory mice, Zimmerman’s team used mouse eggs to create what are known as parthenotes. Without being fertilized, the mouse eggs were manipulated so that they began to develop as if they were fertilized, up to a point.

PHOTO: Mouse embryonic stem cells. This image is a work of a National Science Foundation employee, taken or made as part of that person's official duties. As a work of the U.S. federal government, the image is in the public domain. This image was copied from wikipedia:en.

Parthenogenesis exists in nature. It has been observed in some plants, fish, and reptiles. Over the past decade, researchers have learned how to induce parthenogenesis in mice, monkeys, and humans. In every case, however, the resulting parthenotes fail to develop normally, which means they could never be implanted to produce a child. But they do develop for a few days, long enough for the precursors of pluripotent stem cells to develop.

What is new in the research reported on February 22, 2013 is unexpected success in the use of these stem cells derived from mouse parthenotes. These cells—parthenogenetic stem cells or PSCs—were developed and eventually implanted into damaged mouse hearts. Quite simply, they worked in ways that seem to overcome most if not all of the technical hurdles.

The research appears in the Journal of Clinical Investigation, which carried a companion article claiming that the new research “may overcome all…formidable barriers” that currently stand in the way of stem cell medicine. The original article makes this claim: “One of our key observations involved the capacity of PSCs to exhibit essentially normal cardiogenesis in vitro and in vivo.” In other words, both in the dish and in the mouse, implanted cells fully integrate into the beating heart.

Both the research article and the companion piece make another claim: PSCs are ethically acceptable. That’s because parthenotes are not embryos. Taking cells from parthenotes avoids all the moral concerns that surround the use of cells derived from embryos. Here is the claim: Research using human PSCs, derived from human parthenotes, involves “no destruction of viable embryos,” according to the research article. The companion piece simply notes that compared to embryonic stem cells, PSCs “do not have the same ethical implications.”

If only it were that simple. But plain the fact is that some who object to the use of human embryos in research are already on record as objecting to the use of human parthenotes.

Their logic is fairly straightforward. If human embryos are off limits and if parthenotes cannot be clearly and definitely distinguished from embryos, then human parthenotes are equally off limits to research.
They are not claiming that parthenotes are little people, nor are they being silly or obstructionist. They are only claiming that we do not have enough scientific clarity and certitude to proceed with moral confidence in the work of creating and destroying parthenotes, regardless of the benefit.

Just to be clear, I personally disagree with this objection. But researchers and regulators should be aware that some, at least, will balk at this new line of research, technically attractive as it may be.

For example, in a statement given to the UK Parliament, the Church of Scotland made this comment:

“We reject the suggestion made by various researchers that hybrid embryos, parthenotes and embryos that have been modified to make then non-viable would be an ethical solution to deriving stem cells from embryos. Whatever the status of such creations, it is would be at least as unethical to use methods that would create an ‘embryo’ so deformed that it could not be viable and which therefore inherently denies its potential to develop.” 

Politically more important is the response that will come from Catholics. Some Catholic scholars have defended the moral legitimacy of research using human parthenotes. There is simply no way, they argue, to equate the parthenote with the embryo. The parthenote is not a product of conception. In more popular rhetoric: If “life begins at conception,” then the parthenote is not “life.” Nor can it develop normally. It meets none standard definitions of an embryo.

Others are not so certain. They translate scientific and theological uncertainty into a moral prohibition. Creating and destroying a parthenotes requires that we know for sure that they are not embryos. Such certainty is lacking, at least for now. In the face of uncertainty, they argue, we must not proceed.

On the Catholic website www.ewtn.com, E. Christian Brugger addresses the question: Is the parthenotes enough like and embryo to be considered an embryo? His answer:

“The question presently is unsettled.” He adds this: “Although the empirical question of the status of a human parthenote is unsettled, the underlying moral principle is straightforward. Unless we have moral certainty that a dividing parthenogenetically activated human oocyte is not an embryo, we have an obligation to avoid research with human parthenotes.”

And at the end he concludes:

“Having said this, the present evidence on whether parthenotes are ever embryos seems to me inconclusive. Given the evidence to date, at least with which I am familiar, I do not think it can be established with moral certitude that parthenotes are never human embryos.”

Personally, I want to see this research go forward, and so I have some suggestions for researchers and reporterss in this field.

First, help religious scholars build the case scientifically, showing in clear terms to the wider public why parthenotes are not functionally like embryos and why a morally robust boundary separates the two. Science itself cannot create that boundary, but it can provide evidence supporting moral and philosophical arguments in favour of such a boundary.

Second, stop using provocative phrases like “virgin birth.” Regrettably, the companion piece in the Journal of Clinical Investigation is published with this title: “Virgin birth: engineered heart muscles from parthenogenetic stem cells.”

Sure, “parthenos” is Greek for virgin, so the etymology supports the use of the term “virgin birth.” But for billions of Christians around this world, this term has a very special religious meaning, one that many associate with the most tender core of their faith.

For scientists to claim they are simulating the “virgin birth” is offensive to anyone who takes the religious meaning of the phrase seriously. It is needlessly provocative, almost the worst thing that could be said if religious support for research is desired.

What’s more, associating parthenogenesis with the “virgin birth” has the bizarre effect of equating the parthenote with the embryo. Christians who hold to the “virgin birth” will claim that in one profoundly non-trivial example (Jesus), what scientists now claim they are creating turned out to be a fully viable embryo. And then they say, “But don’t worry; it’s not a human being”?

The original article, entitled "Parthenogenetic stem cells for tissue engineered heart repair," is published in the February 22, 2013 issue of the Journal of Clinical Investigation, together with the companion piece.

A Living, Breathing Lung-on-a-Chip

Human cells can be grown outside the human body. In a petri dish, they may develop in ways that resemble the cells inside the body. But their function and activity are limited. For example, in a dish, lung cells are just lung cells. They don’t breathe.

Using new technology, however, researchers have put lung cells on a chip. The cells on a chip have suddenly become a lung-on-a-chip, active, moving, and breathing.

In a paper published in the in the November 7 issue of Science Translational Medicine, researchers report on their use of recently-developed organ-on-a-chip technology. They describe how they built and used "a biomimetic microdevice that reconstitutes organ-level lung functions to create a human disease model-on-a-chip."

Caption: Wyss Institute's human breathing lung-on-a-chip. Credit: Wyss Institute, Harvard University. Usage Restrictions: None.

Already the device has led to two discoveries directly applicable to the lung disease, edema, which is a major concern for some cancer patients. First, development of the disease is accelerated by the physical movement of the lungs. This is "something that clinicians and scientists never suspected before," according to Donald Ingber, senior author of the study.

Second, researchers identified one drug, currently under development, that might help prevent the problem. For Ingber, this is the main attraction of organ-on-a-chip technology. "This on-chip model of human pulmonary edema can be used to identify new potential therapeutic agents in vitro," Ingber says.

This could accelerate the speed of drug development and testing while reducing the cost. The main advantage is that an organ-on-a-chip gives researchers the opportunity to test a wide array of potential drug compounds. Tests can be run not just on nonhuman animals or on cultured human cells but on functioning or working small-scale models of human organs.

Beyond its value in pharmaceutical research, it is not clear where this research may lead, but it is one more way in which the boundary we once drew between the living and the nonliving is being erased, along with the line between the natural and the artifical.

The work was funded by the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), Defense Advanced Research Projects Agency (DARPA), and the Wyss Institute for Biologically Inspired Engineering at Harvard University. The paper is entitled "A Human Disease Model of Drug Toxicity–Induced Pulmonary Edema in a Lung-on-a-Chip Microdevice" and appears in the November 7, 2012 issue of Science Translational Medicine.

Better Technology, Better Weapons

Ongoing archeological discoveries from coastal South Africa point consistently to a technological and cultural explosion occurring there more than 70,000 years ago. The latest paper, appearing in the November 7 issue of the journal Nature, fills in more detail about remarkable advances in stone tool technology that only appear in Europe some 50,000 years later.

The new findings, reported by an international team of researchers led by Curtis Marean, help fill in a more comprehensive picture of the culture that flourished on the coast of South Africa for thousands of years. In 2009, Marean's team published a report showing how the controlled use of fire played a key role in the engineering of stone tools. The 2012 paper provides evidence that this technology was used for at least 11,000 years by the inhabitants of the coast.

"Eleven thousand years of continuity is, in reality, an almost unimaginable time span for people to consistently make tools the same way," said Marean. "This is certainly not a flickering pattern."

PHOTO: Caption: These microlith blades show a flat edge with a rounded "cutting" edge. Credit: Simen Oestmo. Used by permission of the ASU Institute of Human Origins for the purposes of illustrating coverage of the accompanying article.

One possibility suggested by this research is that the 70,000 year old technology found in South Africa was brought out of Africa by modern humans. If so, it may help explain why Neandertals disappeared as modern humans entered Europe and Asia. Advances in technology made it possible to create light-weight points for spears or arrows, mostly likely used for small spears launched by spear-throwing devices known as atlatls, which effectively extend the length of the throwing arm.

"When Africans left Africa and entered Neanderthal territory they had projectiles with greater killing reach, and these early moderns probably also had higher levels of pro-social (hyper-cooperative) behavior. These two traits were a knockout punch. Combine them, as modern humans did and still do, and no prey or competitor is safe," said Marean. "This probably laid the foundation for the expansion out of Africa of modern humans and the extinction of many prey as well as our sister species such as Neanderthals."

If there is any truth to this conjecture, it is a sobering truth. This technological advance makes it easier to kill.

The new paper reports on findings at the Pinnacle Point excavation site, a mere some 50 miles from Blombos cave, home to similar findings and to the first "chemical engineering laboratory" for the production of the pigment, ochre. Whoever lived there was technologically and culturally advanced, with all the ambiguities that implies.

The paper, "An Early and Enduring Advanced Technology Originating 71,000 Years Ago in South Africa," appears in the November 7 issue of the journal Nature.

Merging Humans and Robots--More Coffee, Please

With the help of a tiny chip implanted in the brain, human beings who cannot move their own limbs are able to move a robotic arm, in one case taking a drink of coffee on one’s own for the first time in fifteen years.

"The smile on her face was a remarkable thing to see. For all of us involved, we were encouraged that the research is making the kind of progress that we had all hoped," said the trial's lead investigator, Leigh Hochberg, M.D., Ph.D., in a press release issued by the National Institutes of Health, which provided some of the funding. Hochberg is an associate professor of engineering at Brown University and a critical care neurologist at Massachusetts General Hospital (MGH)/Harvard Medical School.

The field of brain-computer interface research is not new, but this is the first peer-reviewed report of people using brain signals to control a robotic arm, making it perform in three-dimensional space much as their natural arms once did. By imagining they were controlling their paralyzed limb, they were able to move the robotic arm. Brain activity is detected as electrical activity by the BrainGate chip, processed by an external computer, and fed into a robot that translates the signals into movement.

More research is underway, and in fact this clinical trial is recruiting more volunteers.

Caption: The BrainGate array, which is implanted on the motor cortex, comprises nearly 100 electrodes on a chip the size of a baby aspirin. Credit: www.braingate2.org Usage Restrictions: With Credit.

With future advances, researchers hope to be able to improve the quality of movement in prosthetic limbs or to restore in part the function of paralyzed limbs, perhaps by creating an electronic by-pass to normal nerves.

"This is another big jump forward to control the movements of a robotic arm in three-dimensional space. We're getting closer to restoring some level of everyday function to people with limb paralysis," said John Donoghue, Ph.D., who leads the development of BrainGate technology and is the director of the Institute for Brain Science at Brown University.

Beyond therapy, it is possible to imagine other uses as we humans and our machines co-evolve and increasingly converge, probably to do more than drink coffee.

This report is published in the May 17, 2012 issue of Nature.

Brain Regeneration: Mouse Brains and Human Futures

Embryonic stem cells are surprisingly capable of regenerating portions of the brains of mice according to a report published in the November 25 issue of the journal Science. What is unexpected about this report is not the extent of the repairs so much as where they occurred in the brain.

The hypothalamus, which is involved basic metabolism and complex behaviors, has usually been regarded as less open to regeneration, whether naturally or by biomedical intervention. Naturally, a limited number of neurons develop during adulthood, but these are not enough to restore this area of the brain after injury or disease. “The neurons that are added during adulthood in both regions are generally smallish and are thought to act a bit like volume controls over specific signaling,” explained Jeffrey Macklis of Harvard Medical School and one of the lead researchers in the study.

“Here we've rewired a high-level system of brain circuitry that does not naturally experience neurogenesis,” Macklis said, “and this restored substantially normal function.”

The report reached this conclusion: “these experiments demonstrate that synaptic integration… [by] donor neurons can impart an organism-level rescue of metabolic defects, thereby providing a proof of concept for cell-mediated repair of a neuronal circuit controlling a complex phenotype.”

While it is important to underscore that this work is performed on mice, the results suggest that something similar might be possible someday in human beings with brain injuries. “The finding that these embryonic cells are so efficient at integrating with the native neuronal circuitry makes us quite excited about the possibility of applying similar techniques to other neurological and psychiatric diseases of particular interest to our laboratory," according to Matthew Anderson in a press release issued by Harvard Medical School.

For now, research continues using mice as models for human disease or spinal cord injury. “The next step for us is to ask parallel questions of other parts of the brain and spinal cord, those involved in ALS and with spinal cord injuries,” according to Macklis. "In these cases, can we rebuild circuitry in the mammalian brain? I suspect that we can."

This study, coming so quickly on the heels of another report showing the functional integration of human embryonic stem cells into the mouse brain, suggests that embryonic stem cell research may indeed open new ways to treat brain disease or injury. Both studies, however, open the possibility that the use of technologies of brain regeneration will not stop with disease. As always, the growing power of medicine to treat disease is also an expansion of the possibility of human enhancement. All this if far in the future. But already, advocates of human enhancement have noticed its significance. See, for example, the re-posting of the original press release on Ray Kurweil's transhumanist blog.

The report, entitled “Transplanted Hypothalamic Neurons Restore Leptin Signaling and Ameliorate Obesity in db/db Mice,” appears in the November 25, 2011 issue of Science.

Stem Cells, Working Brains, and Human Enhancement

Research using human pluripotent stem cells—whether derived from an embryo or induced into a pluripotent state—holds great promise for regenerating parts of the human body by producing new cells to replace diseased or damaged cells. Nowhere is this potential more intriguing than in the human brain.

During the past decade, researchers have learned to turn human pluripotent cells into neurons. They have tested these neurons in cell cultures, where they seem to function like normal neurons. They have implanted these human neurons in mouse brains, where human cells thrive like normal cells. The big question is whether they do the work of brain cells. Long before cells are implanted in human brains, researchers want to know whether the cells will function properly in any working brain, starting with a mouse brain.

Now comes evidence that the implanted cells seem to be fully function, integrated in the basic process of the mouse brain. In the report published in the November 21 issue of PNAS, researchers at the University of Wisconsin report on their use of a new technology, optogenetics, to test the function of the implanted cells. This technology uses light rather than electricity to stimulate implanted neurons. The result, it is claimed, is the best evidence so far that implanted cells are integrated fully into the functioning brain, sending and receiving signals as part of living neural networks.

”We show for the first time that these transplanted cells can both listen and talk to surrounding neurons of the adult brain,” said lead author Jason P. Weick in a press release from the University.

By using optogenetics, this study provides evidence that implanted human neurons derived from pluripotent stem cells can become functionally integrated into systems of a living brain, sending and receiving signals from surrounding or “host” cells and interacting with brain circuitry in a way that is consistent with normal brain rhythms.

According to the paper published in PNAS, the neurons derived from pluripotent cells “can participate in and modulate neural network activity through functional synaptic integration, suggesting they are capable of contributing to neural network information processing…”

What’s more, the researchers discovered that optogenetics may someday have a clinical use far beyond its value as a research tool. The fact that implanted cells can be stimulated using a light signal may someday become part of the way stem cells are used on human patients. According to Su-Chun Zhang, also an author of the report, “You can imagine that if the transplanted cells don't behave as they should, you could use this system to modulate them using light.”

Still more challenges must be met before neurons derived from human pluripotent cells are implanted successfully in the human brain. But this study advances the field in a critically important way and provides strong evidence that implanted cells might one day take on the function of damaged cells in the living human brain.

If human brains can be regenerated even in highly limited ways, the consequences will be profound. The most obvious applications will be to treat patients who have lost some part of brain function due to stroke, brain injury, or disease.

And if that becomes possible, it is not hard to imagine that the same technology will be used to regenerate the brains of those whose only “disease” is aging. Furthermore, it is quite likely that at some point in the future, implanted neurons derived from pluripotent cells will be genetically modified first, perhaps to prevent disease but also perhaps to enhance the performance of the brain into which they become functionally integrated.

It is important to stress that treatment for complex disorders of the brain, such as Alzheimer’s Disease, are still a long way off. But this research is an important step, showing that the basic concept of stem cell treatment may provide one form of treatment. But is that becomes possible, it may also become possible to enhance the cognitive capacity of people without disease.

The milestone reported here is just one more step--of which there must be hundreds or thousands--leading us closer to the day when human brains might be regenerated or renewed. Few will object to the use of such treatments to restore functioning neurons to those with Huntington's disease or early onset Alzheimers. And if early onset Alzheimers, why not late onset? And if late onset dementia, why not age-related cognitive decline? At what point do we cross the line from therapy to enhancement, and does such a line even exist?

So while we stress that these treatments are not available today--and may never be--they will very likely come in time. And when they come, they will open the path for completely new ways to extend the functional lifespan of the human brain.
The report, entitled "Human embryonic stem cell-derived neurons adopt and regulate the activity of an established neural network," appeared in the Nov 21, 2011 issue of PNAS.