One Sensational Hand

A decade ago, Dennis Aabo Sørensen lost his hand in an accident.  Now, thanks to an international team of physicians and technicians, he can feel objects once again, this time through the use of a bionic hand that is directly connected to the nerve cells in his arm. 

Sørensen is the world's first amputee able to use his bionic hand to experience the sensation of feeling.  Because he can feel what he touches, he is able to use his bionic hand with far more agility than other amputees, knowing instantly when he is squeezing something too hard and likely to crush or harm it.

Photo Credit: Sensory feedback enabled prosthesis, close-up.  Credit: LifeHand 2/Patrizia Tocci.  LINK to Video. 

 

“The sensory feedback was incredible,” reports the 36 year-old amputee from Denmark according to a press release from the Ecole Polytechnique Fédérale de Lausanne.  “I could feel things that I hadn’t been able to feel in over nine years.” In a laboratory setting wearing a blindfold and earplugs, Sørensen was able to detect how strongly he was grasping, as well as the shape and consistency of different objects he picked up with his prosthetic. “When I held an object, I could feel if it was soft or hard, round or square.”

 

The bionic hand, of course, is equipped with touch sensors.  But the real key is the bi-directional or two-way connection between the hand's electronics and the brain's neurons.  Tiny, cell-size links between electrodes and nerve endings were implanted into Sørensen's arm.  Then his new hand was attached and the wires connected. 

 

Over time and with a little practice, he could feel different shapes and degrees of hardness.  The sensation was as fast as normal touch.  Signals passed from the bionic fingers to the brain and then from the brain to the hand, controlling its movements.

 

For those in need of bionic hands, this work marks a real milestone.  Ordinarily we take two-way processing for granted.  But the way things feel helps us use our hands with versatility and skill. 

 

What this means in broader terms is a little less clear.  Bionic restoration is a key frontier in today's medicine.  But the technologies of healing or restoration can quickly become the technologies of enhancement.  Perhaps someday, we will look back at Sørensen's hand as a kind of evolutionary advance, bringing not just the restoration of touch but the extension of power. 

 

The paper, entitled "Restoring NaturalSensory Feedback in Real-Time Bidirectional Hand Prostheses," is the work of an international team largely based in Italy and Switzerland.  It appears in the 5 February 2014 issue of Science Translational Medicine. 

Rapamycin: Extended Lifespan, Extended Decline?

Ever since 2009, it has been known that the drug rapamycin extends the lifespan of mice.  The journal Science identified this discovery as one of the top 10 research breakthroughs for that year.  The news was all the more exciting because rapamycin already has FDA approval for other uses.

So researchers want to know just how rapamycin extends the lifespan.  Does it actually slow the entire aging process?  Or does it just slow down certain diseases, such as cancer?  

New research testing the effects of rapamycin on mice suggests that the drug probably does not slow the aging process itself.  It does slow the development of cancer and a few other diseases.  But rapamycin is no fountain of youth.  In fact, if it were used just by itself to extend the lifespan of human beings, it might merely draw out the aging process.  In other words, it might extend the lifespan but not extend the healthspan.

Photo: Public domain through Wikimedia. Thanks to Rama.

The research was conducted by a team led by Dan Ehninger and his colleagues at the German Center for Neurodegenerative Diseases. It is published in the August 2013 issue of The Journal of Clinical Investigation, which is freely available online.  In addition to the research article, the journal is publishing an expert commentary that warns about any drug that brings an increase in lifespan that “is accompanied by more disability and disease and a greater loss of physiological functions, i.e., a reduced quality of life.”  By itself, rapamycin could do just that.

On the bright side, the new study shows even more conclusively that rapamycin extends the lifespan of mice by the equivalent of almost a decade of human life.  It also provides a small benefit for cognitive function.  So despite the mixed results, the journal commentary advocates clinical trials involving human patients, perhaps those with dementia.  According to the journal article, the research supports “the feasibility of clinical trials to study the efficacy of rapamycin in treating diseases of the elderly, especially those that are debilitating and for which no current treatment is known, such as Alzheimer’s disease and other neurodegenerative diseases.”

Advocates of anti-aging research will see this new study as something of a set-back, but it is not likely to slow down basic work in the field.  Opponents of anti-aging research are likely to renew their warnings about the prospect of more years of declining health.  Any effort to enhance our humanity, whether it is by increasing cognitive ability or extending the lifespan, is always accompanied by a down-side, by side effects so costly that true enhancement is impossible.  The warning is serious, but advocates of human enhancement are not likely to be convinced.   

The research article is entitled “Rapamycin Extends Murine Lifespan but Has Limited Effects on Aging.”  The commentary is entitled “Rapamycin, Anti-aging, and Avoiding the Fate of Tithonus.”  Both are available free to the public in the August 2013 issue of The Journal of Clinical Investigation.

Deep Brain Cognitive Enhancement: The Latest News

The search for new methods of cognitive enhancement has just reached new depths.  Researchers in Austria and the UK report exciting new evidence that a form of noninvasive deep brain stimulation enhances the brain’s ability to do arithmetic. 

"With just five days of cognitive training and noninvasive, painless brain stimulation, we were able to bring about long-lasting improvements in cognitive and brain functions," says Roi Cohen Kadosh of the University of Oxford and lead author of the report that appears in the May 16, 2013 issue of Current Biology.  His comments were provided by the journal.

Photo Credit.  Photo by Ad Meskens of an original oil painting by Laurent de La Hyre (French, 1606-1656).  The title of the painting is Allegory of Arithmetic (Allegorie van de rekenkunde) and it dates to about 1650.  The original painting is in the Walters Art Museum, Baltimore, Maryland.  It was photographed on 18 July 2007 by Ad Meskens, who has made it freely available with proper credit.

In this study, the team used a form of noninvasive deep brain stimulation known as “transcranial random noise stimulation” or TRNS.  The TRNS input was combined with more traditional math training and drills.  Twenty-five young adults, males and females, were divided into two groups, one receiving math training with the TRNS and the other receiving math training combined with a “sham” version of TRNS, a kind of placebo. 

Not only did those who received TRNS do well immediately, but the benefits lasted for at least six months.  In addition, brain monitors detected different brain activity for those receiving TRNS.  This suggests that TRNS modifies brain function.

According to Cohen Kadosh, "If we can enhance mathematics, therefore, there is a good chance that we will be able to enhance simpler cognitive functions."

In the paper’s conclusion, the authors state that TRNS “can enhance learning with respect to high-level cognitive functions, namely algorithmic manipulation and factual recall in mental arithmetic. When this learning is based on deep-level cognitive processing, as is the case for calculation arithmetic, such enhancements are extremely long-lived both behaviorally and physiologically.

Then they sum up with these words:

Both the behavioral and physiological changes displayed extreme longevity, spanning a period of 6 months, but only when learning involved deep-level cognitive processing. By its demonstration of such longevity and, for the calculation task, generalization to new, unlearned material, the present study highlights TRNS as a promising tool for enhancing high-level cognition and facilitating learning. These findings have significant scientific and translational implications for cognitive enhancement in both healthy individuals and patients suffering from disorders characterized by arithmetic deficits.

The paper, Snowball et al.: "Long-Term Enhancement of Brain Function and Cognition Using Cognitive Training and Brain Stimulation," appears in the May 16, 2013 issue of Current Biology. 

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. 

Brain Renewal? Enhancing Aging Brains

An aging mind may be a fountain of wisdom, but an aging brain is not very good as a source of new neurons. As we age, quite apart from diseases like Alzheimer’s, we lose our ability to remember and to concentrate. It seems that in order to remain sharp, the brain has to regenerate itself by forming new neurons. While neurogenesis continues throughout life, it declines markedly in old age.

Photo credit: published under GNU Free Documentation License, uploaded 23 Sept 2007 by Ccrai008.

Research published today may suggest a way to change that. Scientists at the German Cancer Center in Heidelberg report on their work with mice. They identified a molecule called Dickkopf-1 or Dkk1 in the brains of old mice. When they blocked the production of Dkk1, old mouse brains began to create new brain cells.

“We released a brake on neuronal birth, thereby resetting performance in spatial memory tasks back to levels observed in younger animals,” said Ana Martin-Villalba in a press release from Cell Press, which published the results.

It turns out that clinical trials are already underway involving antibodies for Dkk1. These trials are not related to neurogenesis but to prevention of osteoporosis. What is learned there, however, may be directly helpful to the possibility that blocking Dkk1 is feasible, safe, and effective in countering the effects of declining neurogenesis, which includes both memory loss and depression.

The report concludes with these comments: “Our study raises the possibility that neutralization of Dkk1 might be beneficial in counteracting depression-like behavior and improving cognitive decline in the aging population….The contribution of newly generated young neurons to memory and affective behavior opens tantalizing opportunities for the prevention of affective impairments and age-related cognitive decline.”

These words are carefully chosen, first to caution against undue optimism but also to steer away from the idea of “human enhancement.” But unless we think of aging as a disease, what is envisioned here is clearly a form of enhancement. Normally aging human beings may, someday in the future, be treated not because they have a disease such as Alzheimer’s but because their memory is not as sharp as it once was or as retentive as they would like.

But labeling this an “enhancement” is not likely to dampen public interest. On the contrary, the enhancment potential of blocking Dkk1 is the very thing that is most likely to drive public support.

And that suggests we need to consider once again just what it is we say we do not like about enhancement.

The article is entitled "Loss of Dickkopf-1 restores neurogenesis in old age and counteracts cognitive decline" and appears in the February 7, 2013 issue of Cell Stem Cell.

Past and Future Selves

Are you done changing? Are your values and personality pretty much set for life? Regardless of our age, most of us seem to think so.

According to new research, people generally recognize that they have changed over the past decade. But in the decade ahead? Overwhelmingly, people think their biggest changes are behind them. It’s as if their present state is the defining moment, when values and personality traits are fully realized and fix forever. The research team, led by Jordi Quoidbach, called this the “End of History Illusion.”

In six studies involving more than 19,000 participants, researchers “found consistent evidence to indicate that people underestimate how much they will change in the future,” according to the study appearing in the 5 January 2013 issue of the journal Science.

Like most illusions, this one comes with a big cost. Thinking they won’t change makes it more likely they will “make decisions that their future selves regret.”

What’s most amazing about this illusion is that it seems to hold true at all ages. In fact, some of the results suggested that more than their grandparents, young people think they are done changing.

Caption: Painting, Girl in a Mirror (1632) by Paulus Moreelse, purchased by the Rijksmuseum Amsterdam with support of the Vereniging Rembrandt. In the public domain.

This much, at least, was clear to the researchers: “At every stage of adult life that we could analyze. Both teenagers and grandparents seem to believe that the pace of personal change has slowed to a crawl and that they have recently become the people they will remain. History, it seems, is always ending today.”

While the researchers are clearly speaking of the history of the individual, their research raises the question of whether there’s a similar illusion when it comes to human history. For example, do we routinely underestimate the amount of technological change that lies ahead or its cultural and social impact? We acknowledge the profound cultural changes in past decades, but do we underestimate what is coming?

We marvel at the transformations of human evolution, but do we fail to imagine the changes that lie ahead? According to the researchers, "people may confuse the difficulty of imagining personal change with the unlikelihood of change itself." If that is true of the human individual, might it also be true of the human species?

The research appears as “The End of History Illusion” in the 4 January 2013 issue of the journal Science, a publication of the American Association for the Advancement of Science.

Enhancement at Work: A New Report

A new report on human enhancement and its growing impact on the workplace has just been released by top-level British science and policy groups. The Royal Society, the Academy of Medical Science, the British Academy, and the Royal Academy of Engineering collaborated on a research project throughout 2012, resulting in the November 2012 report.

Image from the cover of Human Enhancement and the Future of Work.

Among the conclusions: "Advances in a range of areas in science and engineering such as neuroscience, regenerative medicine and bionics are already enhancing, or could in the next decade enhance, the physical and cognitive capacity of individuals in the workplace." The report is entitled Human Enhancement and the Future of Work.

Even the advocates of human enhancement find something uniquely troubling about the prospect of enhancement technologies in the workplace. Will employers coerce their workers? Will use of enhancement technology be a non-negotiable prerequisite for success in an increasingly competitive work environment? Will employees have full access to information about potential side-effects?

The report notes the following: "Cognitive-enhancing drugs present the greatest immediate challenge...They are already available without prescription through internet purchasing, are relatively cheap and are increasinly being used by healthy individuals."

In response to these challenges, the report does not recommend sanctions or bans, but it does press the case urgently for widening the dialogue and reforming policies and regulations.

Resveratrol and Enhancement? Not So Fast

Does resveratrol help healthy people become even healthier? Does it improve metabolic health and possibly even help us live longer?

A new study casts doubts on these hopes. In the October 25 issue of Cell Metabolism, researchers at Washington University School of Medicine publish the results of their study involving 29 healthy middle-aged women. They asked whether resveratrol boosts metabolic health. When they ran the tests and collected the evidence, the answer was simple: No.

The study divided the women into two groups. Fifteen were given 75 milligrams of resveratrol each day, the same as they would get in 8 liters (more than 10 bottles) of red wine. The other fourteen received a sugar-pill placebo.

Researchers measured the women's sensitivity to insulin and the rate of the glucose uptake. The result, according to Samuel Klein, senior investigator, is that "we were unable to detect any effect of resveratrol. In addition, we took small samples of muscle and fat tissue from these women to look for possible effects of resveratrol in the body's cells, and again, we could not find any changes in the signaling pathways involved in metabolism," Klein said in a press release issued by Washington University School of Medicine.

Photo Credit: Robert Boston. No usage restrictions.

This study is small, but what makes it interesting is that it involves healthy human beings. In nonhuman trials, resveratrol seems to enhance the health of healthy animals. And in human trials involving people with metabolic problems, resveratrol seems beneficial.

According to Klein, "Few studies have evaluated the effects of resveratrol in people," Klein explains. "Those studies were conducted in people with diabetes, older adults with impaired glucose tolerance or obese people who had more metabolic problems than the women we studied. So it is possible that resveratrol could have beneficial effects in people who are more metabolically abnormal than the subjects who participated in the study."

That point goes right to the heart of the human enhancement debate. Often, "enhancement" is distinguished from therapy. While therapy improves the health of the sick, enhancement improves the health of the healthy. This study seems to suggest that resveratrol may be therapeutic, but it is not an enhancement.

Right now, however, the picture is not completely clear. Those who drink red wine in moderation are less likely than others to develop heart disease and diabetes? Is it the resveratrol, the wine, or the interactions between them?

According to Klein, "We were unable to detect a metabolic benefit of resveratrol supplementation in our study population, but this does not preclude the possibility that resveratrol could have a synergistic effect when combined with other compounds in red wine."

The article, entitled "Resveratrol Supplementation Does Not Improve Metabolic Function in Nonobese Women with Normal Glucose Tolerance," appears in the October 25 issue of Cell Metabolism.

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.

Extending Healthy Lifespans? A Pill on the Horizon?

Resveratrol, the much-hyped ingredient found in red wine and sold widely as a nutritional supplement, is known to improve the health and extend the lifespan of mice. Can it do the same for humans? Without nasty side effects? And at what dose?

A study published today in Cell Metabolism helps unravel a few more of resveratrol’s mysteries. In particular, researchers have shed new light on how resveratrol works. Key to its effectiveness is a gene known as SIRT1, found in slightly different forms in species as different as yeast and humans. SIRT1 plays many roles, some tied to core metabolic processes. The new study shows that in mice, even a low dose of resveratrol interacts with SIRT1 to improve metabolism.

What makes this study especially interesting is that researchers had to create a special strain of mice in order to test whether SIRT1 is necessary for resveratrol to work. If mice have no SIRT1, they do not develop properly. So two graduate students, Nathan Price and Ana Gomes, developed a novel strain of mice with an unusual copy of the SIRT1 gene, one that could be switched off at adulthood.

By administering a drug (tamoxifen), researchers can “induce” or switch the SIRT1 gene on and off, a strategy that will likely be used in other studies. "This is a drug inducible, whole body deletion of a gene," David Sinclair, the study's senior author, said in a press release from Harvard Medical School. "This is something that's rarely been done so efficiently. Moving forward, this mouse model will be valuable to many different labs for other areas of research."

Photo by R. Cole-Turner

In this case, the switchable SIRT1 mouse provided proof that SIRT1 is key to resveratrol’s effectiveness. Why is that important? Because resveratrol is a complex molecule that interacts with the body in many unknown ways. While it may be beneficial, it may have unwanted side effects. So researchers are trying to design a more simple molecule that provides the benefits of resveratrol without all the risks. One strategy is to boost SIRT1 activity. By proving that SIRT1 is involved, this study provides support for that strategy, which is already being pursued by pharmaceutical firms.

"The results were surprisingly clear," said. "Without the mitochondria-boosting gene SIRT1, resveratrol does not work."

Are we any nearer a magic pill that slows aging or promotes longevity? Perhaps. The headline of the press release from the publisher, Cell Press, claims that this work “restores hope for anti-aging pill.” Remember, of course, that the work reported here is entirely with mice.

Even so, the paper itself concludes with this statement: “This model supports the enticing possibility of designing and developing potent small molecules that provide the health benefits of resveratrol by activating SIRT1 and downstream pathways to treat metabolic and other age-related diseases.”

The treatment of age-related diseases, including diabetes, is a huge target for pharmaceutical firms. But beyond that lies that even bigger market for human enhancement, specifically for enhancing the span of healthy decades.

The study, "SIRT1 Is Required for AMPK Activation and the Beneficial Effects of Resveratrol on Mitochondrial Function," appears in the May 1, 2012 issue of Cell Metabolism.

Stem Cells and Type I Diabetes

Is this just too good to be true? That’s my first reaction when I read the press release with this headline: “Stem cell therapy reverses diabetes.”

The full report was published on January 9 by an open source medical journal, BioMed Central. If the procedure it describes can be replicated, it is promising indeed. Researchers claim to have a device that “educates” the patient’s own stem cells.

The device is called a “Stem Cell Educator.” Apparently when the patient’s blood passes through the device, stem cells naturally occurring in the patient’s blood are “educated” or re-set to a more normal, functional level. The device separates the patients blood, selecting lymphocytes for special treatment by exposing them to stem cells that were originally derived from donor human umbilical cords.

No cells are exchanged or added to the patient’s blood. Instead, the patient’s own cells are reset by exposure to specific factors given off by the donor stem cells that are kept in a living culture inside the device. After two or three hours of “education,” the patient’s lymphocytes seem to perform a lot better.

The result? Researchers claim in their report that “a single treatment produces lasting improvement in metabolic control. In initial results indicate Stem Cell Educator therapy reverses autoimmunity and promotes regeneration of isletβcells.” The need for insulin was reduced and the benefits lasted at least as long as 40 weeks after the treatment.

The study also makes this claim:

Successful immune modulation by CB-SCs and the resulting clinical improvement in patient status may have important implications for other autoimmune and inflammation-related diseases without the safety and ethical concerns associated with conventional stem cell-based approaches.

Whether these findings are replicated is a key question at this point. The claims are pretty extraordinary, but the general strategy of "re-educating" rather than replacing cells seems to be showing a lot of promise. For an example, see my earlier post, "Is Aging a Disease of Stem Cells?"

The study was led Yong Zhao of the University of Illinois at Chicago, who directed an international team and prepared the report, entitled “Reversal of type 1 diabetes via islet beta cell regeneration following immune modulation by cord blood-derived multipotent stem cells.” The full text is published by the online journal BioMed Central and is freely available to the public.

Hope for Aging Brains

When electrical wires lose their insulation, they have to be replaced. When the nerves and brain cells in our bodies lose theirs, they regenerate it naturally.

Up to a point, that is. As the decades pass, our bodies lose the ability to regenerate themselves. The results are obvious: wrinkled skin, weak muscles, and forgetful brains.

All the more tragic for those among us with diseases that attack the very processes of regeneration. Multiple sclerosis (MS), for example, keeps the body from restoring the insulating layers that protect nerve fibers. The insulation—“myelin”—breaks down naturally. In most human brains, “remyelination” is a constant process, rebuilding the myelin that protects the brain cells and allows them to do their work. For people with MS, remyelination is under attack.

Working with mice, researchers seem to have found a way to reinstate the remyelination process. In a report in the January 6 issue of Cell Stem Cell, researchers at Harvard and Cambridge Universities show that the capacity for remyelination can be restored in aging mice.

The cells that are responsible for remyelination are still present in the aging mouse. It’s just that they have been switched off. By exposing these cells to switching signals present in a much younger mouse, researchers were able to reverse the effects of aging on the cells that do the work of remyelination.

How did they do this? They literally joined the old and the young mouse together surgically. This allows their blood to circulate together. In the young blood, apparently, were various chemical signals that reset the switches in the cells of the brains of the aging mice. The result: spontaneous remyelination.

According to Robin Franklin, one of the researchers, the study shows that “age-associated decline in remyelination is reversible. We found that remyelination in old adult mice can be made to work as efficiently as it does in young adult mice.” Franklin, who is Director of the MS Society's Cambridge Centre for Myelin Repair at the University of Cambridge, made her comments in a press release issued by her university.

What’s perhaps most interesting about this report is that it is a kind of stem cell research that doesn’t implant stem cells. It works on the principle that stem cells already exist in the patient’s body but that they’ve been silenced by age or disease. They need to be switched back on or rejuvenated. According to Franklin, “remyelination therapies do not need to be based on stem cell transplantation since the stem cells already present in the brain and spinal cord can be made to regenerate myelin - regardless of the patient's age."

As interesting as this is, it is important to stress that this is a “proof of concept” study. The techniques here are simply not applicable to human beings. They are encouraging because they suggest that perhaps some day, researchers will discover just what it is in the young body that keeps it young. What are the specific factors that keep the body’s own stem cells switched on? And if it circulates in the blood as this study shows, perhaps these factors could simply be injected.

Of course, if researchers discover how to do this, it’s not just people with diseases like MS who will be interested. One of the interesting social features about this work is that it is funded in part by the UK MS Society and the American MS Society. In other words, the funding is motivated by the search for a cure for a very specific disease. But the mice is the study were aging, not ill. That suggests to me, at least, that the larger portion of the “beneficiaries” of this work will be aging humans, not those with MS. If so, then this study is one more step in the quest of human enhancement, suggesting that it may be possible to reverse aging in the one part of the body where it is most feared—the human brain.

The journal report ends with this comment: “Moreover, this work demonstrates that the CNS maintains its responsiveness to age-regulated circulatory factors, such that age-dependent deficiencies in repair of these tissues can, in part, be reversed by circulating factors.”

The paper, “Rejuvenation of regeneration in the aging central nervous system,”' is published in the January 6 issue of Cell Stem Cell.

Is Aging a Disease of Stem Cells?

Is aging a disease? And if it is a disease, what “causes” it? Is it simply natural for bodies to age over time, or is something wrong with them, something that could be “fixed”?

In a report in the January 3 issue of Nature Communications, researchers at the University of Pittsburgh School of Medicine report on work with mice that are bred especially to age quickly. The mice have a version of progeria, a disease in humans that causes children to age well before their time.

The research team looked at differences in stem cells or progenitor cells, which healthy bodies naturally keep in reserve as a source for new cells to replace worn-out cells. Not surprisingly, they found that the progeria mice had fewer progenitor cells than their healthy counterparts. What’s more, the few progenitor cells in the progeria mice failed to function normally. For example, they didn’t produce replacement cells as needed.

If that’s the problem, can it be “fixed”? The researchers, led by senior investigators Johnny Huard and Laura Niedernhofer, injected the rapidly-aging progeria mice with progenitor cells from the muscles of healthy mice. The result was pretty amazing.

"We wanted to see if we could rescue these rapidly aging animals, so we injected stem/progenitor cells from young, healthy mice into the abdomens of 17-day-old progeria mice," Dr. Huard said in a press release issued by the University of Pittsburgh. "Typically the progeria mice die at around 21 to 28 days of age, but the treated animals lived far longer—some even lived beyond 66 days. They also were in better general health."

How did this work? Did the injected cells start producing replacement cells? Possibly, but the main effect of the injected cells seems to have been to change the host cells in the body of the progeria mice. In other words, the injected healthy progenitor cells changed the progeria mouse’s own cells into more healthy, more normal cells.

"This leads us to think that healthy cells secrete factors to create an environment that help correct the dysfunction present in the native stem cell population and aged tissue," Dr. Niedernhofer said. "In a culture dish experiment, we put young stem cells close to, but not touching, progeria stem cells, and the unhealthy cells functionally improved." Fascinating!

What about mice that are aging normally? Would the injection of progenitor cells from younger mice, for example, also “rescue” non-progeria but aging mice?

Whether anything like this could be done safely in human beings is a big question that will require a lot more research. It may turn out that injecting progenitor cells into a human patient with premature aging might help stall the aging but might also create other problems, such as cancer. In time, it may be possible to get the benefits while managing the risks.

The Pitt research, although dealing with mice with progeria, opens profound questions about humanity, aging, enhancement, and the possibility of extending the human lifespan.

The biggest question of all is whether something like this would slow the aging process in normal or healthy human beings. In other words, is this yet another possible pathway to human enhancement? Could this be used to “treat aging as a disease”?

Is aging a disease? Dr. Niedernhofer’s comment is revealing: "Our experiments showed that mice that have progeria, a disorder of premature aging, were healthier and lived longer after an injection of stem cells from young, healthy animals," Dr. Niedernhofer said. "That tells us that stem cell dysfunction is a cause of the changes we see with aging." A dysfunction? A disease? A difference?

On the question of religion and the morality of extending the human lifespan, probably the best book on the market is Religion and the Implications of Radical Life Extension, edited by Calvin Mercer and Derek Maher. I have an essay in the book reflecting on the question from the standpoint of Christianity.

My take? Extending the human lifespan is not immoral or obviously wrong, but Christians hope for a transformation, not an extension. More of the same is too little.

The report appeared in the January 3 issue of Nature Communications. It is entitled Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model and is available free to the public.

Enhancing the Brain: A New Approach?

A molecule that protects you against viruses may also be slowing down your brain. That’s the startling finding just reported by researchers at the Baylor College of Medicine.

In the December 9 issue of Cell, a research team led by Mauro Costa-Mattioli report on how a key component of the immune system may also play a central role in the brain’s ability to form memories.

The molecule in question is the enzyme “protein kinase RNA-activated” or PKR for short. PKR is well-known to biomedical researchers. It is found in nearly all vertebrates and helps fight viral infections.

What was unknown is how PKR plays a pivotal role in regulating how the brain forms memories. Using mice, Costa-Mattioli’s team found that PKR actually slows down the brain’s ability to form memories. By blocking the production of PKR in mice, Costa-Mattioli’s team was able to produce mice with enhanced memory.

“The molecule PKR (the double-stranded RNA-activated protein kinase) was originally described as a sensor of viral infections, but its function in the brain was totally unknown," said Costa-Mattioli in a press release issued by Baylor Medical College.

The researchers used two methods to block PKR. They produced mice that were genetically modified so they couldn’t produce PKR. But they also used a drug that inhibits the production of PKR. In both cases, memory capacity was enhanced.

How does PKR act in the brain? Apparently by interacting with another key molecule, interferon-γ or IFN-γ, which is also best known for its role in the immune system. Researchers believe that in the brain, PKR and IFN-γ interact, keeping each other in balance. Suppressing PKR seems to increase the role of IFN-γ and the activity of the brain, particularly the neurons that are creating long-term memories.

“These data are totally unexpected, and show that two molecules classically known to play a role in viral infection and the immune response regulate the kind of brain activity that leads to the formation of long-term memory in the adult brain,” said Costa-Mattioli.

What is perhaps most startling about the report is that a drug that inhibits PKR enhances memory in mice. “It is indeed quite amazing that we can also enhance both memory and brain activity with a drug that specifically targets PKR,” according to Costa-Mattioli.

If a drug enhances memory capacity in mice, could it work in humans? That’s a big jump, one that will take much more research before anything is even tested in human beings. But researchers suggest that this is possible and worth exploring. Costa-Mattioli said, "More investigation is undoubtedly necessary to translate these findings to effective therapies but we would be delighted if our scientific studies were to contribute in some way to this ultimate goal."

“Our identity and uniqueness is made up of our memories," Costa-Mattioli said. "This molecule could hold the key to how we can keep our memories longer, but also how we create new ones.”

Will this provide a new strategy in dealing with diseases that rob us of our old memories and of our capacity to create new ones? Given the stakes, research will explore these possibilities.

If the research is applicable to human beings (and why not?) and if it provides a new path to preventing or delaying dementia, it will also open new ways to think about the enhancement of human cognition. The mice in the study were not suffering from any memory loss, but the speed at which they were able to learn a new task was enhanced nearly four-fold.

Given the wide-spread interest in cognitive enhancement, especially on university campuses and among transhumanists, we should expect to hear more about how inhibiting PKR just may make you smarter.

The article, "Suppression of PKR Promotes Network Excitability and Enhanced Cognition by Interferon-γ-Mediated Disinhibition,” appears in the December 9 issue of Cell.

Cognitive Enhancement: Campus Update

Use of drugs to boost academic performance is nothing new, but The Washington Post has just published a news story suggesting that use of these drugs is increasing on college campuses.

The story, written by Post reporter Jenna Johnson, refers to a study at the University of Maryland that suggests that students who take cognitive enhancers study less, party more, and have slightly lower grade point averages than their classmates. That suggests that their main purpose for using the drugs is stay competitive without letting studies get in the way of college.

There is little doubt, however, that the drugs are also being used by highly focused, academically competitive students in demanding programs. Their purpose: to add an edge to their hard work in order to stay in the top one or two percent of the competitive pile. As the Post reports, one name for these drugs is “Ivy League crack.”

The drugs in question are familiar enough—mostly Ritalin and Adderall. Students without prescriptions can easily buy these drugs from other students.

Should use of these drugs be treated as crimes? Or should those who wish to excel academically be allowed to use whatever means helps them achieve that end? For more on that debate, see the now-classic 2008 article in the journal Nature, in which prominent bioethicists such as Stanford’s Henry Greely argue for greater tolerance and openness.

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.

Resveratrol and Human Enhancement

The debate over human enhancement may just have entered a new phase. Resveratrol, the natural compound found in red wine, has now been shown to improve the metabolism of human beings. While the word "enhancement" does not appear in the published report, the research will almost certainly be read by many as evidence that the use of resveratrol enhances human health and may even increase the human lifespan.

In the more prosaic language of the report, the news is simply this: Resveratrol, the natural compound found in red wine, has now been shown to improve the metabolism of human beings.

In the 2 November 2011 issue of the journal Cell Metabolism, researchers in the Netherlands and Switzerland report that a 30-day course of resveratrol brought about significant improvement in the basic metabolic functions of obese men.

Research using animals has shown that resveratrol can have a number of benefits related to how the body uses energy. In some species, resveratrol has been shown to increase average longevity. In other experiments involving lab animals, a reduction of 30-50% in calorie intake below what the animals normally eat has been shown to benefit the metabolism and extend the lifespan. Others studies show that resveratrol seems to mimic the effects of calorie restriction.

Now come hints that resveratrol may have some of these same effects on human beings. In the Cell Metabolism article, researchers report that the men who received the 150mg/day dose of resveratrol showed a number of changes that mimic what happens with calorie reduction. 150mg is about 100 times the amount of resveratrol found in an ordinary glass of red wine.

One of the researchers, Patrick Schrauwen, commented on the study in a press release issued by Maastricht University in the Netherlands: “We saw a lot of small effects, but consistently pointing in a good direction of improved metabolic health.” The study was concluded after 30 days, and so long-term benefits or side-effects are not known.

In particular, no one knows whether resveratrol has the capacity to extend the human lifespan. But the positive results published on 2 November will surely intensify the debate over the effects and the ethics of resveratrol.

In this study, resveratrol was administered to men who were obese but otherwise healthy. One way some bioethicists distinguish between morally legitimate “therapy” and morally questionable biomedical “enhancement” is by insisting that medicine must stick to treating those with disease. It is unethical, these bioethicists argue, to “enhance” people by using medicine to benefit those who are not sick. Their views are challenged by others who believe that technology should be used for human enhancement.

While this study may have observed that moral limit of treating only those with a “disease,” there is little reason to believe that the metabolic benefits of resveratrol are limited to those who are obese. On the contrary, there is every reason to think that this study will be used by advocates of human enhancement. In particular they will see this as the best evidence yet that resveratrol can be used to extend the human lifespan.

My prediction is that this study will encourage more widespread use of resveratrol. Most who use it will be seeking some form of enhancement if not an increase in longevity.

The article, “Calorie restriction-like effects of 30 days of resveratrol (resVidaTM) supplementation on energy metabolism and metabolic profile in obese humans,” appears in the 2 Nov 2011 issue of Cell Metabolism, where it is available free to the public.

A New Approach to Enhancement?

Some people object to human germline modification because they do not like the idea of one generation messing with the DNA of future generations. Even worse, they say, is modifying the genes for the sake of…gasp!...enhancement!

But now comes a tantalizing study in tomorrow’s issue of Nature hinting at the possibility that what we do to live longer may change the lifespan of our grandchildren. It’s only a hint—the research reported here involves the faithful nematode, Caenorhabditis elegans. By exposing one generation of these tiny worms to just three proteins, researchers in Anne Brunet’s lab at Stanford produced worms that live up to 30% longer. The surprising thing is that the enhanced lifespan was passed to the next 2-3 generations. The really surprising thing is that the lifespan of the C. elegans great-grandchildren was enhanced even though no DNA sequences were modified. In other words: germline enhancement without genetic modification.

How is that possible? Epigenetics. The three proteins changed the way the DNA is structured or packed without changing the DNA code itself. Such epigenetic changes can change the way genes are expressed. The effect can be dramatic—in this case, a 30% longer lifespan. What’s more, the epigenetic change can be passed to future generations. Most often, epigenetic changes are reset during reproduction. But in some cases, epigenetic modifications are passed to the next 2-3 generations. When that happens, the structure and the expression of DNA are changed even though the DNA sequence remains unchanged. Over time, however, the effect washes out so that the great-great-grandchildren are back to the starting point.

Will this epigenetics-to-lifespan relationship be found in human beings? Who knows. Again, it must be repeated: this research involves flatworms. Humans are just a bit more complicated. Already, however, Brunet’s lab is looking for something similar in mice and in African killfish.

Whether anything similar will be found in human beings, this research already suggests a truly interesting thought experiment. Suppose this leads someday to a human-application technology. Would it be opposed by those who object to human germline modification? Sure, future human beings would be changed without their consent. But no genes are changed, and the changes are not permanent.

Perhaps the more sobering thought is this. Maybe this research will lead to a startling discovery. Never mind some new technology. Might it turn out that what health-minded human beings normally do—eat their green vegetables, get their exercise—has the effect of enhancing their offspring by modifying the expression of their genes by means of generating inheritable epigenetic changes? Could be. If just three proteins make C. elegans progeny live 30% longer, just imagine how your dinner might change your grandchildren (assuming, of course, that you’re in your reproductive years or younger).

The article, “Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans,” appears in the October 20 issue of Nature.