Brain Implants are Coming: Can They Repair Stroke Damage?

Recent research on rats at Tel Aviv University is offering hope that we may soon have access to brain implants which could help to bypass damaged areas of brain, and allow relatively normal functioning after stroke and other types of brain damage.

Matti Mintz of Tel Aviv University in Israel and his colleagues have created a synthetic cerebellum which can receive sensory inputs from the brainstem - a region that acts as a conduit for neuronal information from the rest of the body. Their device can interpret these inputs, and send a signal to a different region of the brainstem that prompts motor neurons to execute the appropriate movement.

"It's proof of concept that we can record information from the brain, analyse it in a way similar to the biological network, and return it to the brain," says Mintz, who presented the work this month at the Strategies for Engineered Negligible Senescence meeting in Cambridge, UK.

...The team analysed brainstem signals feeding into a real cerebellum and the output it generated in response. They then used this information to generate a synthetic version on a chip that sits outside the skull and is wired into the brain using electrodes.

To test the chip, they anaesthetised a rat and disabled its cerebellum before hooking up their synthetic version. They then tried to teach the anaesthetised animal a conditioned motor reflex - a blink - by combining an auditory tone with a puff of air on the eye, until the animal blinked on hearing the tone alone. They first tried this without the chip connected, and found the rat was unable to learn the motor reflex. But once the artificial cerebellum was connected, the rat behaved as a normal animal would, learning to connect the sound with the need to blink.

...The next step is to model larger areas of the cerebellum that can learn a sequence of movements and test the chip in a conscious animal - a much greater challenge. "This is very demanding because of the decrease of [neural] signal quality due to artefacts caused by movement," says Robert Prueckl of Guger Technologies in Graz, Austria, who is working with Mintz. He thinks this can be achieved, though, by developing improved software to tune out noise and better techniques for implanting the electrodes. Ultimately, the goal is to build chips that can replicate complex areas of the brain _NewScientist

Yes, the implant used by the researchers was only able to substitute for a small part of the cerebellum -- which is only one part of the brain. Still, it is a start. The challenge is to enlarge and consolidate this understanding of the motor system. Then we can move beyond these early victories to the far more complex and difficult challenges of substituting for more complex signaling that occurs in the cortical and subcortical tissues.

And yet it would be best not to underestimate this achievement. The cerebellum helps to control and coordinate body movement, which is a very important function of being human. Those who have lost the ability to initiate, control, coordinate, and terminate basic movements, understand how important the motor system is to quality of life.

Cyborg brain part replacement is not the end goal, of course. We really want to re-grow any damaged brain parts or nerve connections which have been lost. But cyborg replacements will be an important bridge between where we are now and where we would like to go.

Brain Cell Regeneration Using Reprogrammed Astroglia

The brain consists of two major cell types: neurons, which transmit information, and glial cells, which support and protect neurons. Interestingly, evidence suggests that some glial cells, including astroglia, can be directly converted into neurons by specific proteins, a transformation that may aid in the functional repair of damaged brain tissue. However, in order for the repaired brain areas to function properly, it is important that astroglia be directed into appropriate neuronal subclasses. In this study, we show that non-neurogenic astroglia from the cerebral cortex can be reprogrammed in vitro using just a single transcription factor to yield fully functional excitatory or inhibitory neurons. We achieved this result through forced expression of the same transcription factors that instruct the genesis of these distinct neuronal subtypes during embryonic forebrain development. Moreover we demonstrate that reactive astroglia isolated from the adult cortex after local injury can be reprogrammed into synapse-forming excitatory or inhibitory neurons following a similar strategy. Our findings provide evidence that endogenous glial cells may prove a promising strategy for replacing neurons that have degenerated due to trauma or disease. _PLOS

Scientists from the Helmholtz Center and Ludwig-Maximilians University in Munich, have used a virus to reprogram brain helper cells -- astroglia -- into actual neurons. They were able to convert astroglia from early post-natal and adult mouse brains into either excitatory or inhibitory neurons, depending upon the transcription factors which were introduced.

The study adds to growing evidence that certain cell types can be transformed directly into other cell types without first being converted into stem cells. Researchers have previously transformed skin cells into neurons, and one type of pancreatic cell into another. Marius Wernig, a coauthor of the skin cell study and a stem cell biologist at Stanford University, says there's a growing awareness that it may not be necessary to erase a cell's existing identity before giving it a new one.

...this latest study "means that these astroglial cells could be converted in the brain" without the need for a transplant. Berninger says that one of the next challenges is to determine whether these reprogrammed neurons can survive and function in a living brain.

Fortunately, the brain seems to have a ready source of astroglia. When the brain is injured, these cells proliferate, similar to the way the skin repairs itself after a wound. The researchers found they could also derive neurons from injury-induced astroglia taken from the brains of adult mice. _TechnologyReview

More:

we first aimed at a more potent neuronal reprogramming by inducing higher and more persistent expression of neurogenic fate determinants in astroglial cells. This allowed us not only to obtain fully functional neurons that also establish synapses from astroglial cells in vitro but also to demonstrate that distinct neurogenic transcription factors, such as on the one hand Neurog2 and on the other Dlx2 alone or in combination with Mash1, can indeed instruct the selective generation of different neuronal subtypes, such as glutamatergic and GABAergic neurons, respectively. Moreover, we found that the reprogramming efficiency of postnatal cortical astroglia towards GABAergic neurons by Dlx2 could be enhanced by first expanding the astroglial cells under neurosphere conditions prior to forced expression of Dlx2. Given that following brain injury reactive astroglia from the adult cerebral cortex de-differentiate, resume proliferation, and can give rise to self-renewing neurospheres in vitro [16], we finally show that neuronal reprogramming and subtype specification are not restricted to postnatal stages but can also be achieved from adult cortical astroglia responding to injury. _PLOS

The findings are a striking reminder that nature offers us many more possibilities than we can presently conceive of. But perhaps we will grow in our conceptual capacity, over time.

The possibility of regenerating brain tissue in situ -- without the need for inserting new cells from elsewhere -- offers new hope for brain trauma, infection, infarct, atrophy, and senility. But it also offers a distinctly new possibility which most observors are not quite ready to think about -- much less discuss.

I am referring to the possibility of growing entirely new neural networks in situ, from astroglia. The possibility that humans can induce their own brains to create entirely new brain centers and pathways, using more advanced forms of such techniques, should not be overlooked.

There is currently a race between biological methods of repairing and enhancing human organs, and technological methods of compensating for organ damage or loss -- the cyborg approach. A cyborg may utilise nano-technological enhancement, and thus manifest no outward sign of distinction from standard normal humans. The same would be true for most biological enhancements or remediation.

This lack of overt differences between ordinary persons and enhanced persons is quite important to most military uses of enhanced individuals, and to virtually all covert uses by government and other organisations.

But these tools of transformation are not likely to remain limited to deep pocketed groups and individuals. Garage biohackers are not as uncommon as you might think, and are performing a similar service for bio-hacking as the garage techno-hackers performed for microcomputers in the early days. And it is also extremely likely that persons involved in expensive and large scale research into bio-transformation technologies will set off on their own as they discover the ability to profit from their technical knowledge and skills.

Cross-posted at Al Fin

Glimpses Into the Near Future

The master control program for development and repair of the human organism is being de-encrypted. Using tools from genetic programming, stem cell research, and nanotechnology, it will be possible to assist the body in maintaining health and youth. Here is a brief progress report for a few interesting tools and technologies:

Creating embryonic stem cell (ESC) lines is controversial. Destroying embryos to create a single ESC line strikes some as wasteful of human life. But what if you could take an embryo and create millions of distinct ESC lines from it?

This Nature abstract discusses the protein Nanog, which may allow the creation of any number of "hybrid" ESC lines-- reprogramming adult stem cells to pluripotency. Eventually it should even be possible to reprogram adult stem cells without having to use an ESC. Here is a bit more detail in this Bio.com newsrelease:

The Edinburgh scientists fused mouse embryonic stem cells with brain stem cells, a type of adult stem cell. They found that the addition of Nanog resulted in a massive increase in the numbers of hybrid cells, all of which behaved like embryonic stem cells. Most importantly the hybrid cells showed the capacity to make many different cell types, such as heart and gut. "This means that the genetic programme of the brain cells has been erased and replaced by the unspecialised programme of an early embryo cell" says Dr Jose Silva, first author of this study.

Dr Silva adds "The effect of Nanog is remarkable. All of the hybrid cells become fully converted to embryonic stem cells. If we can figure out how Nanog does this, it may become possible to switch cell types without fusion or cloning." However, the Edinburgh team must also identify at least one other key gene. "Nanog has great power" says Professor Smith, "but it does not work in isolation, only in partnership with other genes present in embryonic stem cells".

As an organism ages, it loses the ability to replace lost cells. At some point, cells lose the ability to replicate, but even before that point they show signs of incompetence in gene expression. This Nature abstract discusses research that reveals this increased variation in gene expression of aging myocytes:

One possible mechanism by which increased DNA damage could lead to cellular degeneration and death is by stochastic deregulation of gene expression. Here we directly test for increased transcriptional noise in aged tissue by dissociating single cardiomyocytes from fresh heart samples of both young and old mice, followed by global mRNA amplification and quantification of mRNA levels in a panel of housekeeping and heart-specific genes. Although gene expression levels already varied among cardiomyocytes from young heart, this heterogeneity was significantly elevated at old age. We had demonstrated previously an increased load of genome rearrangements and other mutations in the heart of aged mice3, 4.

This means that in order to perform DNA repair on senescent cells, it will be necessary to have templates of relatively young cells of that type. At some point it would be necessary to replace the old cells with new cells--much like replacing the rotten planking of an old wooden boat with new planking. It is still the same boat, but the new planking gives it a new life. Stem cells--tissue specific programmed ASC's from preserved ESC's--would provide the replacement cells.

That is why drugs such as the recent Korean discovery CGK-733 will not work as life extenders. They only extend the replication lifetime of cells--they do not keep the ageing cells young. The senescent incompetence of gene expression is still present, along with increasing risks of cancerous transformation.

Next, what good is a body made of young vibrant cells, if the mind is asleep or deranged? This Eurekalert newsrelease discusses the discovery of Neuropeptide-S, a new brain protein that promises to help wake the walking sleepers.

Neuropeptide S (NPS), so named by Rainer K. Reinscheid, Ph.D., assistant professor, Program in Pharmaceutical Sciences, University of California, Irvine, is produced by a small cluster of cells in the brainstem, yet its specialized receptors are found in several areas of the brain, including those that are associated with the regulation of arousal, sleep and wakefulness, anxiety, appetite, learning and memory. Dr. Reinscheid and his colleagues reported finding the new neuropeptide just last year and described animal studies showing how binding of NPS to its receptors on the surfaces of neurons promotes strong arousal, suppresses all phases of sleep and lessens anxiety in stressful or unfamiliar situations.

Now, at ICN 2006, Dr. Reinscheid's group reports how NPS also can reduce the biochemical and behavioral symptoms of schizophrenia in an established animal model for this mental illness that affects some 2 million Americans. Animals pretreated with NPS before receiving a drug that normally induces psychotic-like behaviors did not develop the signature behavioral symptoms and neurochemical features of schizophrenia, reported Naoe Okamura, M.D., Ph.D., who is a co-worker of Dr. Reinscheid at the University of California, Irvine.

"Although preliminary, our animal studies indicate the NPS receptor should be explored as a target for the development of novel antipsychotic drugs. Whether molecules activating the NPS system will prove to be better drugs than others used to treat the symptoms of schizophrenia remains to be seen. We still have a very long way to go before proving it can alleviate symptoms in humans as we've seen it do in rodents," said Dr. Reinscheid.

A peptide that wakes people up, and makes them less anxious and perhaps less psychotic too? Quite the improvement over amphetamine. Perhaps exactly what is needed in the coming age of tumultuous transition to a next level world.

Some nanotechnologists and singularitarians believe that tiny nanobots will be able to store and carry the early genome to all cells, and busily repair any errors that may occur in replication--even in ageing cells. Such nanobots could conceivably detect early cancerous transformation, and act to trigger apoptosis in cells with such changes.

Research in biotechnology is now at such a profound level, that breakthroughs in one are can quickly lead to breakthroughs in several other areas. It is obvious that ageing is related to malignancy as well as autoimmune and other inflammatory diseases. In addition, improvements in the tools of biotechnology research almost immediately suggest newer and more profound areas of research and discovery. It is becoming easier to believe Ray Kurzweil's analysis of exponential knowledge growth.

Now, two more postings on aging: the first deals with mitigating the effects of aging in those already old. The second posting will deal with new theories of cryopreservation that may finally provide a workable way forward to safely place people into "stasis" for later "re-animation".

A compound that stimulates the secretion of growth hormone can help older adults improve their physical function and lower their body fat percentage, according to study results that will be presented Wednesday, June 21, at the International Congress of Neuroendocrinology in Pittsburgh. The results will be presented by Dr. George Merriam, professor of medicine at the University of Washington and a physician with the VA Puget Sound Health Care System. Merriam helped coordinate endocrine aspects of this multi-site study, along with Dr. Heidi White of Duke University and researchers at Pfizer, Inc. Nearly 400 adults from 65 to 84 years old were enrolled in the study, and were divided into groups receiving a placebo or one of four different levels of an oral growth hormone secretagogue (GHS), which stimulates the secretion of human growth hormone. Researchers measured the participants' fat and lean body (muscle) mass, as well as their performance in physical tests like stair climbing and a heel-to-toe walk. The participants also received blood tests for levels of growth hormone and a compound called IGF-1, a hormone which responds to growth hormone and mediates some of its effects. Participants receiving the GHS treatment saw a significant increase in lean body mass – about 1.5 kilograms, or 3.3 pounds. The GHS treatment led to improved physical function over the six- to 12-month study period. Participants also had higher levels of growth hormone and IGF-1 in their bloodstreams. Patients receiving the GHS treatment had minor side effects, including increased fatigue, insomnia, and fasting glucose levels. Growth hormone is vital in childhood growth, and production of the hormone peaks during puberty. However, it continues to affect physical function throughout our lives, and it regulates metabolism and body composition. As adults move into middle age, growth hormone production begins to taper off. Many of the effects of aging – increased abdominal fat, reduced muscle mass, and decreased physical function – look very similar to the symptoms of growth hormone deficiency in younger people. As those aging effects set in, many older adults find it difficult to care for themselves, and they lose quality of life and often turn to long-term care. Source.

Last, new ideas on cryopreservation:

In medicine, cryopreservation involves preserving organs and tissues for transplantation or other uses. Only certain kinds of cells and tissues, including sperm and embryos, currently can be frozen and successfully rewarmed. A major problem hindering wider use of cyropreservation is formation of ice crystals, which damage cell structures. Cyropreservation may be most familiar, however, as the controversial idea that humans, stricken with incurable diseases, might be frozen and then revived years or decades later when cures are available. Bogdan's experiments involved a form of water termed "glassy water," or low-density amorphous ice (LDA), which is produced by slowly supercooling diluted aqueous droplets. LDA melts into highly viscous water (HVW). Bogdan reports that HVW is not a new form of water, as some scientists believed. ...."It may seem fantastic, but the fact that in aqueous solution, [the] water component can be slowly supercooled to the glassy state and warmed back without the crystallization implies that, in principle, if the suitable cyroprotectant is created, cells in plants and living matter could withstand a large supercooling and survive," Bogdan explained. In present cryopreservation, the cells being preserved are often damaged due to freezing of water either on cooling or subsequent warming to room temperature. "Damage of the cells occurs due to the extra-cellular and intra-cellular ice formation which leads to dehydration and separation into the ice and concentrated unfrozen solution. If we could, by slow cooling/warming, supercool and then warm the cells without the crystallization of water then the cells would be undamaged." Source: American Chemical Society More at source.

In the future, several approaches to aging will be available. Those who choose to age "normally" will have the option of "optimising their years" without adding to them appreciably. HGH promoters, pumps, and depo injections will be useful for them. Others will want to add a few decades of high functioning years to their lives. For those, drugs that aid in DNA repair, protein crosslink repair, calorie restriction mimetics, and anti-oxidant/anti-inflammatory supplements will probably do the trick. For those who want more radical extension to their lives, SENS-like approaches to rejuvenation engineering may eventually pay off. Stem cell repair and organ re-growth will definitely be available in the next few decades. More cyborg replacement parts will also be available in the next half century. The grand strategy is genetic engineering of a longer living body that rejuvenates itself constantly, and heals rapidly when injured.

Should safe and reliable cryogenics become available before the more radical lifespan extension strategies, it is conceivable that some might opt to be placed in "suspended animation" until the technologies for longer life are perfected. That might be particularly true for those dying prematurely of terminal illnesses.

Research into these technologies is being funded, sometimes under other descriptions. It is very likely that the goal of doubling the human lifespan will be achieved before the end of the century. Perhaps before the midpoint of the century.