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Thread: Forsyth scientists make major discovery to advance regenerative medicine

  1. #1

    Forsyth scientists make major discovery to advance regenerative medicine

    This research seems to back up the science behind the implantable Andara™ OFS™ (Oscillating Field Stimulator) by Cyberkinetics. I have read plenty of research publications where peripheral nerve regeneration has been significantly sped up with very specific types of electrical stimulation.

    Good news!


    http://www.eurekalert.org/pub_releas...-fsm022007.php
    Public release date: 28-Feb-2007

    Contact: Jennifer Kelly
    jkelly@forsyth.org
    617-892-8602
    Forsyth Institute

    Forsyth scientists make major discovery to advance regenerative medicine

    First clues into the genetic source of natural electrical signals governing regeneration of nerve and muscle

    Scientists at Forsyth may have moved one step closer to regenerating human spinal cord tissue by artificially inducing a frog tadpole to re-grow its tail at a stage in its development when it is normally impossible. Using a variety of methods including a kind of gene therapy, the scientists altered the electrical properties of cells thus inducing regeneration. This discovery may provide clues about how bioelectricity can be used to help humans regenerate.

    This study, for the first time, gave scientists a direct glimpse of the source of natural electric fields that are crucial for regeneration, as well as revealing how these are produced. In addition, the findings provide the first detailed mechanistic synthesis of bioelectrical, molecular-genetic, and cell-biological events underlying the regeneration of a complex vertebrate structure that includes skin, muscle, vasculature and critically spinal cord. Although the Xenopus (frog) tadpole sometimes has the ability to re-grow its tail, there are specific times during its development that regeneration does not take place (much as human children lose the ability to regenerate finger-tips after 7 years of age). During the Forsyth study, the activity of a yeast proton pump (which produces H+ ion flow and thus sets up regions of higher and lower pH) triggered the regeneration of the frog's tail during the normally quiescent time.

    This research will be published in the April issue of Development and will appear online on February 28, 2007.

    According to the publication's first author, Dany Adams, Ph.D., Assistant Research Investigator at the Forsyth Institute, applied electric fields have long been known to enhance regeneration in amphibia, and in fact have led to clinical trials in human patients. "However, the molecular sources of relevant currents and the mechanisms underlying their control have remained poorly understood," said Adams. "To truly make strides in regenerative medicine, we need to understand the innate components that underlie bioelectrical events during normal development and regeneration. Our ability to stop regeneration by blocking a particular H+ pump and to induce regeneration when it is normally absent, means we have found at least one critical component."

    The research team, led by Michael Levin, Ph.D., Director of the Forsyth Center for Regenerative and Developmental Biology has been using the Xenopus tadpole to study regeneration because it provides an opportunity to see how much can be done with non-embryonic (somatic) cells during regeneration, and it is a perfect model system in which to understand how movement of electric charges leads to the ability to re-grow a fully functioning tail. Furthermore, said Dr. Levin, tail regeneration in Xenopus is more likely to be similar to tissue renewal in human beings than some other regenerative model systems. The Forsyth scientists previously studied the role that apoptosis, a process of programmed cell death in multi-cellular organisms, plays in regeneration.

    Michael Levin, PhD. is an Associate Member of the Staff in The Forsyth Institute Department of Cytokine Biology and the Director of the Forsyth Center for Regenerative and Developmental Biology. Through experimental approaches and mathematical modeling, Dr. Levin and his team examine the processes governing large-scale pattern formation and biological information storage during animal embryogenesis. The lab investigates mechanisms of signaling between cells and tissues that allows a living system to reliably generate and maintain a complex morphology. The Levin team studies these processes in the context of embryonic development and regeneration, with a particular focus on the biophysics of cell behavior.

    ###
    The Forsyth Institute is the world's leading independent organization dedicated to scientific research and education in oral, craniofacial and related biomedical sciences.
    Last edited by cljanney; 02-28-2007 at 12:51 PM.

  2. #2
    Quote Originally Posted by cljanney
    This research seems to back up the science behind the implantable Andara™ OFS™ (Oscillating Field Stimulator) by Cyberkinetics. I have read plenty of research publications where peripheral nerve regeneration has been significantly sped up with very specific types of electrical stimulation.

    Good news!


    http://www.eurekalert.org/pub_releas...-fsm022007.php
    For a long time, there was much controversy and skepticism concerning how electrical fields can alter neuronal growth. Let me briefly describe the mechanisms (or what are believed to be the mechanisms).

    Neurons (and all mammalian cells) have negative voltage across their membranes, typically about -60 mV. This voltage arises from the gradients of sodium (Na) and potassium (K) ions between the inside and outside of the cells. The presence of Na and K channels govern the expression of the ionic gradient as a membrane potential. Normally, K is higher inside the cells and there is a concentration gradient for K to leave the cells. Na has the opposite gradient. Without going into much detail, let me just say that the Na gradient across membranes would generate a +30 mV if Na channels were open while the K gradient would generate a -90 mV if K channels were open. Normally, the resting conductances of Na and K channels in the membrane are such that the membrane potential is about -60 mV.

    If you put an electrode with a "negativity" close to the membrane, it depolarizises the membrane, e.g. reduce the membrane potential -60 mV to -40 mV. Since the inside of the cell is negative, making the outside of the cell negative will tend to reduce the membrane potential.

    When membranes depolarize, they open voltage-sensitive Na and K channels, as well as calcium channel. The voltage-sensitive Na channel is of course what produces action potentials and is responsible for the excitatory activity of neurons. As explained above, when one opens the Na channel, it depolarizes the membrane even more until the membrane potential approaches +30 mV.

    But, at the same time, the depolarization will open the K channel which brings the membrane potential back up to -90 mV. This is what repolarizes the membrane and turns off the Na channel. By the way, the voltage-sensitive K channel is what 4-aminopyridine (Fampridine) blocks. That is why Fampridine increases the excitability of neurons and axons.

    The growth effects of electrical stimulation may result from opening of voltage sensitive calcium (Ca) channels or, in the case of stimulation of nervous tissues such as the brain and spinal cord, or release of neurotransmitters. So, let's take the first.

    Scientists have known for a long time that neurons tend to grow towards anodes (negative electrical poles). If you put a glass pipette with a negative voltage on the inside of the glass pipette and place this in a culture dish with neurons, the presence of a the anode will attract axons to grow into the pipette. Positive (cathodic) poles tend to repulse axons.

    There is local entry of calcium into the neuron or its various processes that have is exposed to negative voltage. The calcium entering the cell in turn may activate phosphatases and kinases. It is not clear what the mechanism is. Recently Moo ming Pu at Berkeley also reported that oscillating stimulation of cells increases cAMP insides cells, providing another rationale.

    Finally, as the article below pointed out, electrical fields have long been known to stimulate limb regeneration. For over a century, scientists have been studying these phenomena but have not yet obtained a good understanding of the mechanisms. It would be very nice if we were to make some advances here.

    Wise.

  3. #3
    Dr Young,
    Thank you for helping me understand.

    I wonder, this must be the theory behind the selling power of "healing" or "therapeutic" magnets. I must admit post injury and surgery, after having 6 different nerve transfers/grafts, I slept with magnet wraps around my neck & shoulder for six months. My neurosurgeon at the Mayo Clinic stated that I had abnormally very fast regenerating nerves. I didn't know whether to chalk it up to the magnets, accupunture & Qigong I was receiving 5x/week for 6 weeks post surgery, or my super human good luck I've always had.

    Christopher

    Magnetism
    From Wikipedia

    ...magnetism can be considered to be basically an electric force that is a direct consequence of relativity.

    Here's more on it...

    http://www.nature.com/news/2007/0702.../070226-8.html

    Published online: 28 February 2007

    Electric switch could turn on limb regeneration

    Tadpoles use a proton pump to direct tissue regrowth.

    Heidi Ledford

    Tadpoles: chop off their tails and they grow back.


    Tadpoles can achieve something that humans may only dream of: pull off a tadpole's thick tail or a tiny developing leg, and it'll grow right back — spinal cord, muscles, blood vessels and all. Now researchers have discovered the key regulator of the electrical signal that convinces Xenopus pollywogs to regenerate amputated tails. The results, reported this week in Development, give some researchers hope for new approaches to stimulating tissue regeneration in humans.

    Researchers have known for decades that an electrical current is created at the site of regenerating limbs. Furthermore, applying an external current speeds up the regeneration process, and drugs that block the current prevent regeneration. The electrical signals help to tell cells what type to grow into, how fast to grow, and where to position themselves in the new limb.

    To investigate, Michael Levin and his colleagues at the Forsyth Center for Regenerative and Developmental Biology in Boston, Massachusetts, sorted through libraries of drug compounds to find ones that prevent tail regeneration but do not interfere with wound healing. One such drug, they found, blocks a molecular pump that transports protons across cell membranes; this kind of proton flow creates a current.

    Levin speculates that the current generated by this proton pump produces a long-range electric field that helps to direct what happens to nerve cells pouring into the site. "We can use this hydrogen pumping as a top-level master control to initiate the regeneration response," says Levin. "We didn't have to specifically say, 'put a little muscle over here, a little muscle over there'."

    The proton pump could also be used to turn on limb regeneration in older tadpoles that would normally have lost this ability. When Levin and his colleagues activated the proton pump during this older phase, tadpoles were more than four times more likely to regrow a perfectly formed tail than their normal counterparts.

    Chop and change

    The notion of regenerating complex organs from adult cells hasn't always been popular, says David Stocum, director of the Indiana University Center for Regenerative Biology and Medicine in Indianapolis. "People used to pooh-pooh the idea," says Stocum, "but now there's renewed interest in it." That interest has been primarily focused on the regenerative power of stem cells. But there is also some interest in direct regeneration from adult cells at the wound site.

    At first glance, dramatic limb and tail regenerations seem to be restricted to 'simpler' creatures, such as the humble planaria flatworm — chop it up into a hundred pieces and you'll soon have a hundred little worms on your hands — and salamanders, which can grow back limbs, tails, jaws, intestines and some parts of their eyes and hearts.

    But there are impressive examples of tissue regeneration in mammals as well. Male deer can grow the bone, skin, nerves and blood vessels of their antlers at a millimetre a day. Humans can regenerate livers, and many children under the age of seven have regrown amputated fingertips. And then there are the odd medical journal case studies of patients who have lost, say, a kidney, only to find years later that they've sprouted a new one.

    Simple switch

    Changes in electrical current have been measured in regenerating fingertips, just as in a tadpole's regenerating tail. But converting humans into fully functioning regenerators will probably take more than directing bioelectrical signals. The formation of scar tissue, for example, could inhibit regeneration in some cases, says David Gardiner, a biologist at the University of California, Irvine.

    But the complex networks needed to construct a complicated organ or appendage are already genetically encoded in all of our cells — we needed them to develop those organs in the first place. "The question is: how do you turn them back on?" Levin says. "When you know the language that these cells use to tell each other what to do, you're a short step away from getting them to do that after an injury."

    The simplicity of the regeneration start signal is promising, says Stocum: it is just possible that a properly tuned electric signal is all humans need to jumpstart tissue regeneration.

  4. #4
    According to the publication's first author, Dany Adams, Ph.D., Assistant Research Investigator at the Forsyth Institute, applied electric fields have long been known to enhance regeneration in amphibia, and in fact have led to clinical trials in human patients. "However, the molecular sources of relevant currents and the mechanisms underlying their control have remained poorly understood," said Adams. "To truly make strides in regenerative medicine, we need to understand the innate components that underlie bioelectrical events during normal development and regeneration.

    Ugg, they can definitely make a name for themselves if they do discover the underlying mechanisms but investing time and money in that area isn't helping the people who could benefit if they focused on ways to apply this to human tissue in need of regeneration instead.

    I'm glad Dr. Borgens chose the applied science path.

  5. #5
    Quote Originally Posted by antiquity
    Ugg, they can definitely make a name for themselves if they do discover the underlying mechanisms but investing time and money in that area isn't helping the people who could benefit if they focused on ways to apply this to human tissue in need of regeneration instead.

    I'm glad Dr. Borgens chose the applied science path.

    My thoughts exactly!!!

    Cavemen didn't need to know the underlying mechanisms of fire to be able to use it productively... and either do I.

    Amazing!

  6. #6
    Senior Member Max's Avatar
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    Electrical tweaking helps tadpole grow new tail

    Electrical tweaking helps tadpole grow new tail

    • 14:00 28 February 2007
    • NewScientist.com news service
    • Roxanne Khamsi
    http://www.newscientist.com/article/...new-tail-.html

  7. #7

    Electric switch could turn on limb regeneration

    Electric switch could turn on limb regeneration

    Tadpoles use a proton pump to direct tissue regrowth.

    Heidi Ledford

    Tadpoles can achieve something that humans may only dream of: pull off a tadpole's thick tail or a tiny developing leg, and it'll grow right back — spinal cord, muscles, blood vessels and all. Now researchers have discovered the key regulator of the electrical signal that convinces Xenopus pollywogs to regenerate amputated tails. The results, reported this week in Development, give some researchers hope for new approaches to stimulating tissue regeneration in humans1.

    Researchers have known for decades that an electrical current is created at the site of regenerating limbs. Furthermore, applying an external current speeds up the regeneration process, and drugs that block the current prevent regeneration. The electrical signals help to tell cells what type to grow into, how fast to grow, and where to position themselves in the new limb.

    To investigate, Michael Levin and his colleagues at the Forsyth Center for Regenerative and Developmental Biology in Boston, Massachusetts, sorted through libraries of drug compounds to find ones that prevent tail regeneration but do not interfere with wound healing. One such drug, they found, blocks a molecular pump that transports protons across cell membranes; this kind of proton flow creates a current.

    Levin speculates that the current generated by this proton pump produces a long-range electric field that helps to direct what happens to nerve cells pouring into the site. "We can use this hydrogen pumping as a top-level master control to initiate the regeneration response," says Levin. "We didn't have to specifically say, 'put a little muscle over here, a little muscle over there'."

    The proton pump could also be used to turn on limb regeneration in older tadpoles that would normally have lost this ability. When Levin and his colleagues activated the proton pump during this older phase, tadpoles were more than four times more likely to regrow a perfectly formed tail than their normal counterparts.

    Chop and change

    The notion of regenerating complex organs from adult cells hasn't always been popular, says David Stocum, director of the Indiana University Center for Regenerative Biology and Medicine in Indianapolis. "People used to pooh-pooh the idea," says Stocum, "but now there's renewed interest in it." That interest has been primarily focused on the regenerative power of stem cells. But there is also some interest in direct regeneration from adult cells at the wound site.

    more:

    http://www.nature.com/news/2007/0702.../070226-8.html

  8. #8
    Quote Originally Posted by cljanney
    Dr Young,
    Thank you for helping me understand.

    I wonder, this must be the theory behind the selling power of "healing" or "therapeutic" magnets. I must admit post injury and surgery, after having 6 different nerve transfers/grafts, I slept with magnet wraps around my neck & shoulder for six months. My neurosurgeon at the Mayo Clinic stated that I had abnormally very fast regenerating nerves. I didn't know whether to chalk it up to the magnets, accupunture & Qigong I was receiving 5x/week for 6 weeks post surgery, or my super human good luck I've always had.

    Christopher

    Magnetism
    From Wikipedia




    Here's more on it...

    http://www.nature.com/news/2007/0702.../070226-8.html
    Christopher,

    I am skeptical of the claims that magnetic fields increase regeneration rates of central or peripheral nerves for several reasons:
    1. The magnetic fields are too weak. The magnets that are used are far too weak to create electrical field changes sufficient to change membrane potentials. By the way, if they did, you should be able to feel something.
    2. Despite decades of claims that magnetic fields stimulate regeneration, I have yet to see any credible paper showing robust results that has been replicated by many laboratories.


    Some 25 years ago, when I was first starting out in the field, I did some work on pulsed electromagnetic fields. To tell you the trth, I was intrigued by the possibilities and spent two years working on it. The results were unfortunately difficult to replicate and not enough was known about the mechanisms to improve the therapy of the experimental paradigms to make the results more reliable. Despite having had some initial promising data, I could not replicate the work, and finally gave up.

    The recent reports that oscillating electromagnetic fields can produce cAMP increases in cells and the findings at Purdue that oscillating electrical currents can improve recovery have rekindle my interest in electromagnetic fields. For example, I have been thinking that we may be able to genetically modify an organism (such as a transgenic mouse) to express luminescence with increasing cAMP. This way, we can actually optimize the electromagnetic fields to produce the most sustained increases in cAMP without having to kill the animal to measure cAMP.

    As I have long told my students... ideas are cheap, work is hard. I wish there was enough time to do everything and to do it well.

    Wise.

  9. #9
    Junior Member
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    Not clinical, but critical

    Quote Originally Posted by antiquity
    Ugg, they can definitely make a name for themselves if they do discover the underlying mechanisms but investing time and money in that area isn't helping the people who could benefit if they focused on ways to apply this to human tissue in need of regeneration instead.

    I'm glad Dr. Borgens chose the applied science path.
    I am also glad Dr. Borgens is doing the work he does. However, as with many therapies that try to "fool" the body into doing something, the body often has no way to regulate the process, and no way to make it stop. For example, when chemotherapy is used to stop cancer cells from dividing, the body can not prevent the drug from stopping other cells from dividing, hence the terrible side effects, including nausea and hair loss. Our goal (mine and the other authors of the work) is to learn how to 'talk the body into doing it by itself' since the body already knows how to regulate its own processes.

    And, it is not just that spinal cords with implanted batteries can not unhook the battery once it's job is done, the embryonic cells that have been implanted into Parkinson's patient's brains could not be stopped from going too far, and the result was too much muscle inhibition - not necessarily a great advantage over too little. So, it's not man made versus biological; a very important part of creating for the clinic is figuring the best way to accomplish something, and that means not just activating a process, but insuring there is a way to regulate that process, and, so importantly, turn it off when the job is done. The most remarkable fact about our discovery was that the tail regenerated perfectly (size, shape, anatomy, timing), in response to a very simple "switch" that we flipped and that the organism recognized and knew how to use.

  10. #10
    Dr. Adams. If you need any human spinal cord injured subjects to try this out on, I'm only 45 minutes away from your institute in Rhode Island. I see you are near fenway park where the red sox play, it would be great, after the procedure I could walk over to the park and take in a baseball game. I'll take you guys with me and hot dogs and beers are on me for curing me

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