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Permalink 05:53:21 am, by Tom, 673 words, 1762 views   English (UK)
Categories: Information

Returning control to paralyzed limbs one nerve cell at a time.

A few months ago we reported on a fascinating study undertaken by Andy Schwartz and colleagues at the University of Pittsburg, who developed a brain-machine interface that when implanted into the motor cortex, the part of the brain responsible for controlling voluntary muscle movements, of monkeys allowed then to control a robot arm with surprising precision. This week Chet Moritz and colleagues at Washington National Primate Research Center have published another exciting paper (1) online in the journal Nature that describes an alternative approach to the use of brain-machine interfaces to overcome paralysis.

Rather than use an implant that monitors the activity of groups of nerve cells in the motor cortex and then use complex algorithms to decode this activity and calculate appropriate control signals for external devices, the approach used by the University of Pittsburg group, Chet Moritz and colleagues used a brain implant that could detect the activity of a single nerve cell and then home in on it and measure its activity. These implants were placed in the part of the monkey motor cortex responsible for controlling the wrist muscle and used implanted wires to directly stimulate the wrist muscles using a technique known as functional electrical stimulation (FES). Monkeys whose wrist muscles had been temporarily paralyzed by injection of anaesthetic to the nerves that control them, quickly learned to control their wrist muscles again using the brain implant-FES system. The wrist muscle movements in turn controlled the location of a cursor on a screen and by moving the cursor to particular locations in a screen the monkeys could gain rewards in the form of a tasty snack. More surprisingly the scientists found that monkeys could also learn to use motor cortex neurons that were not normally involved in controlling the wrist muscles to control the wrist muscles.

This research has caught the attention of the mainstream press, and it's good to see that the welcome it has received is accompanied by cautionary notes. There's no doubt that this is a significant advance, the Washington National Primate Research Center team have shown that a relatively simple device can be used to restore control to paralyzed muscles, but they have so far only demonstrated control of one muscle group whereas a useful limb will require the simultaneous and accurate control of many muscle groups by many nerve cells. I'm optimistic that this won't be as much of a problem as it may initially appear since this study, the previous work at the University of Pittsburgh, and indeed the frequently observed ability of patients with brain damage to recover lost functions, all demonstrate that the brain is surprisingly adaptable. Whether using individual nerve cells to control muscles or groups of nerve cells to control robots will prove must useful in the clinic several years down the line is impossible to say right now. It's quite likely that elements of both techniques will be used in future systems and that he decision as to which approach should be used in an individual paralysis patient will be determined by the nature of the injury and duration of subsequent paralysis.
Several scientists involved in this work have also stressed the importance of sensory feedback, the ability of a patient to "feel" what a paralyzed or robotic limb is doing, and this is an area under investigation by several research groups that will no doubt see further advances in the coming years. Even without the ability to feel objects, and consequently the ability to more precisely manipulate objects, I'm of the opinion that the ability to use a robotic arm, or even a patients own arm, has the potential to greatly increase the independence of paralysis patients. For that reason I expect that we will see this technology in the clinic sooner than many people think, and will be a therapeutic advance that many paralysis patients will welcome.


Paul Browne

1) Moritz C.T., Perlmutter S.I. and Fetz E.E. "Direct control of paralyzed muscles by cortical neurons" Nature. 2008 October 15. DOI: 10.1038/nature07418 [Epub ahead of print]


Permalink 09:09:15 am, by Tom, 875 words, 4776 views   English (UK)
Categories: Information

Jellyfish, worms and research revolutions

At first glance the jellyfish Aequorea victoria seems an unlikely candidate to spark a revolution in medical research, but thanks to the work of the marine biologist Osamu Shimomura that's exactly what it did. In their decision to award the Nobel Prize in Chemistry to Osamu Shimomura, Martin Chalfie and Roger Y. Tsien for their work on the Green Fluorescent Protein (GFP) the Nobel Foundation has recognized how research in apparently esoteric areas of biology can ultimately transform the biomedical research.

This revolution began in the early 1960's when Osamu Shimomura and Frank Johnson at the University of Princeton, intrigued by the ability of Aequorea victoria to glow green when disturbed, set out to isolate the proteins responsible. They succeeded in isolation two proteins, a blue luminescent protein they named aequorin and another green protein that glowed when exposed to UV light. In the 1970's Osamu Shimomura studied the green protein, later known as GFP, and found that unlike aequorin GFP did not need a supply of energy to glow, a useful property for a molecule being used to label proteins in a cell.

GFP was clearly a very interesting protein but there was a problem, it could only be obtained from jellyfish, so obtaining useful quantities of it was next to impossible. A scientist named Douglas Prasher working for the National Cancer institute had the answer, if the gene for GFP could be identified and cloned it could be inserted next to a gene that scientists wished to study so that the protein produced by that gene would be labeled by a GFP molecule. This label would then allow the scientists to follow what that protein was doing in a cell or organism. With this in mind Douglas Prasher identified and sequenced the gene encoding GFP, publishing his results in 1992. Unfortunately at this point his funding ran out, but he did send copies of the gene to several researchers, including Martin Chalfie at Colombia University.

Martin Chalfie's research concerned the development of the nematode worm Caenorhabditis elegans, and he was excited by the possibility that bioluminescent proteins could be used to follow twhat proteins and cells were doing and where they were doing it. C.elegans is an organism favoured by many scientists who study animal development and genetics, and has played a decisive role in research leading to two other recent Nobel Prizes, that awarded to Sidney Brenner, John Sulston and Robert Horvitz in 2002 for their discoveries concerning genetic regulation of organ development and programmed cell death, and that awarded to Andrew Fire and Craig Mello in 2006 for their discovery of RNA interference. Martin Chalfie himself worked with Sidney Brenner and John Sulston while at the Laboratory of molecular Biology in Cambridge a few years earlier. What Martin Chalfie and his colleagues did was to prove that GFP could be expressed in the bacteria E. coli and in C.elegans, and then to place the GFP gene under the control of a gene that is active in only six nerve cells in the worm. The resulting worm with six cells that glowed green under UV light caused a sensation when it was published in the journal Science (1) in 1994, if GFP could be function in organisms as diverse as bacteria, jellyfish and nematode worms why shouldn't it work for other species?

While scientists around the world started to employ GFP in their research its versatility was greatly increased by the work of Roger Tsien who used the techniques of molecular biology to increase the numbers of colours available to scientists from just one colour, green, to a palette that covers the visible spectrum. A dramatic demonstration of the potential of the expanded palette of GFP proteins cane in 2007 with the publication of a paper that used different colour GFP labels to enable scientists to follow the fates of thousands of cells simultaneously in a portion of the mouse brain (2), a technique quickly dubbed the brainbow. Just this week another paper in Science described how scientists at the European Molecular Biology Laboratory used GFT labeling to track all the cells in the zebrafish embryo during the first 24 hours and use this information to construct a digital 3D model, allowing early embryonic development in vertebrates to be studied in unprecedented detail (3).

Scientists now use GFP widely in the laboratory, and its uses are as diverse as determining when and how proteins bind to each other in cells in vitro to following the fate of individual nerve cells in the developing brain of living organisms. The importance of GFP to biological and medical research today cannot be overstated.

We salute the winners of the 2008Nobel Prize in Chemistry on their magnificent achievements.


Paul Browne

1)Chalfie M., Tu Y., Euskirchen G., Ward W.W., and Prasher D.C. “Green
fluorescent protein as a marker for gene expression.” Science Volume 263,
pages 802-805 (1994).

2)Livet J., Weissman T.A., Kang H., Draft R.W., Lu J, Bennis R.A., Sanes
J.R., Lichtman J.W. "Transgenic strategies for combinatorial expression of
fluorescent proteins in the nervous system." Nature Volume 450(7166) pages
56-62 (2007).

3) Keller P.J., Schmidt A.D., Wittbrodt J., Stelzer E.H.K. "Reconstruction of Zebrafish Early Embryonic Development by Scanned Light Sheet Microscopy " Science, Published Online October 9 2008, DOI: 10.1126/science.1162493


Permalink 06:42:49 pm, by Tom, 835 words, 2464 views   English (UK)
Categories: Information

From the Nobel Prize to the clinic through animal research

The winners of the Nobel Prize in Physiology or Medicine for 2008 have been announced today, and this year the prize has been split between three scientists whose epidemiological work lead to the identification of viruses responsible for two deadly diseases. Luc Montagnier and Françoise Barré-Sinoussi were given the award for their discovery of the human immunodeficiency virus (HIV) while Harald zur Hausen was recognized for his discovery that the human papillomavirus (HPV) causes nearly all cases of cervical cancer. This years awards will get a lot of people talking, the decision not to award a share in the Nobel Prize to Robert Gallo cannot fail to be controversial, since he played an important role in the discovery of HIV and provided the bulk of the early evidence showing that it caused AIDS. Aside from that I think we can look forward to some interesting debates as every HIV/AIDS denialist and and anti-vaccine crank out there jumps on the Nobel Prize committee's decision. Amusing as such debates can be is it would be a shame if they distracted from the achievements of Montagnier, Barré-Sinoussi and zur Hausen, because make no mistake about it their discoveries were of great importance to modern medicine, leading to effective tests and treatments for HIV and more recently vaccines against HPV. We offer our heartfelt congratulations to each of them!

At this point you're probably wondering what any of this has to do with animal research? This is one of those years when the discoveries for which the Nobel Prize was awarded did not depend directly on animal research, but we do not have to look far to see where animal research played its part. Identifying the cause of a disease is just the start, you next have to work out how to prevent or cure it. Where HIV is concerned much has been written about the role of animal research in developing antiviral drugs and vaccines, and rather than going into that now I'll direct you to which is an excellent introduction to the topic. The role of animal research in the development of HPV vaccines is less well known, so that's what I'd like to discuss here.

Once it had been established that HPV was the cause of most cases of cervical cancer work began on developing vaccines to protect against the virus. As with any vaccine there was a need to ensure that the vaccine was both safe and capable of stimulation the immune system to protect against the virus, and animal models of HPV infection were sought. While HPV is specific to humans other papillomaviruses infect species such as cattle, rabbits and dogs, and these provided a good model for the study of papillomavirus vaccines. Early work on the vaccines proved discouraging. Immunization with whole papillomavirus protected against infection but was simply too dangerous to try in humans since there was a risk that the virus used to immunize could itself cause cancer, it was after all the same virus. This study did however show that a vaccine was possible. The next approach tried was to immunize animals using fragments of virus protein, a common method in vaccine design, but this failed to provide any significant protection (1). It seemed that the whole virus was required to elicit a strong immune response. The breakthrough came from scientists who were studying the bovine papillomavirus capsid protein L1, a protein that forms the outer shell of the virus. They found that when the L1 protein was expressed in vitro it could self-assemble to form a virus-like particle (VLP), which when injected into rabbits stimulated the immune system to produce antibodies antibodies that bound strongly to bovine papillomavirus (2).
The discovery that the bovine papillomavirus VLP could stimulate antibody production was good news, but the presence of such antibodies does not necessarily confer protection against the virus, so they next examined if bovine papillomavirus VLPs could protect cattle against bovine papillomavirus, and if VLPs made from the papillomavirus specific to their species could protect dogs and rabbits against the canine and rabbit papillomavirus's. The animals were protected, and no adverse effects were noted (1), a success that lead directly to the development of VLP vaccines against HPV. So far two HPV vaccines have been approved for clinical use, Merck's Gardasil and GlaxoSmithKline's Cervarix, and many states are now considering if they should make immunization against HPV part of their vaccination schedule. Hopefully, if their price tag does not prove too high, these vaccines will go on to prevent many cervical cancer deaths.

So as usual medical progress is made by scientists working in a variety of disciplines, each playing their part to make breakthroughs possible.


Paul Browne

1) Schiller J.T. and Lowy D.R. "Papillomavirus-like particles and HPV vaccine development." Seminars in Cancer Biology, Volume 7, pages 373-382 (1996) PubMed: 9284529.
2) Kirnbauer R. et al. "Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic." Proc Natl Acad Sci U S A., Volume 89(24), pages12180-4 (1992) PubMed: 1334560.

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