Tag Archives: nerve

The Portrait of a Superstar of Science – Drosophila melanogaster

Regular readers of this blog will no doubt have heard of Drosophila melanogaster, the fly that has played a key role in important discoveries about skin cancer, the innate immune system and the development of tissues, but we’ve never really given this tiny superstar of science enough prominence on this blog.  To help correct this I would like to invite our readers to hop over to the Wellcome Trust Blog, where science writer Michael Regnier has written two posts about his visit to the University of Manchester to see for himself how scientists there are using Drosophila to answer fundamental questions about animal biology.

In his first post Michael starts with a visit to the Fly Facility, and begins with a question:

For more than a hundred years, scientists have used the fruit fly (Drosophila melanogaster) to study the fundamentals of developmental biology and genetics.

But as biological understanding and techniques have improved, we are now able to do sophisticated genetic experiments in animals further along the evolutionary scale, such as mice.

What role, then, for the fly today?”

This question is quickly answered as he learns about past contributions of Drosophila to understanding development and the innate immune system, before moving swiftly to take a closer look at how Drosophila research is increasing our knowledge of the role played by different components of the cytoskeleton – the protein scaffolding found within cells – in the development of the nervous system.

Drosophila melanogaster – a fly whose small size belies it’s great importance to biomedical research.

In part 2 Michael joins Professor Richard Baines and his colleagues to learn more about the use of Drosophila to study disease, and in particular to see how Drosophila are being used to study the function of particular genes in the regulation of the nervous system, and even to screen potential treatments for epilepsy.

Drosophila: the model model organism; the humble fruit fly with a noble (not to mention Nobel) place in the history of science. Having learned about its importance in genetics and developmental biology, I wanted to see Drosophila in action.

At a lab in Manchester, I did just that and discovered that the relevance of such research to human health can be unexpectedly direct.”

All in all it is an excellent summary of what must have been a rather hectic – though fascinating – visit to the University of Manchester.

For anyone who would like to learn even more about Drosophila in medical research, I’m adding this video that the Wellcome Trust produced a couple of years ago.

Paul Browne

Swiss scientists restore voluntary locomotion in paralysed rats.

A study published yesterday in the journal Science, in which a team of scientists led by Professor Gregoire Courtine at the Swiss Federal Institute of Technology used a combination of electrical stimulation, drug treatment and a training regime that encouraged active participation to restore voluntary control of movement in paralysed rats, has received widespread media coverage over the past 24 hours, including reports on the BBC website and ABC news.

If this sounds familiar than it should, as this breakthrough builds on a technique pioneered by Professor V. Reggie Edgerton of UCLA that we reported on last year which enabled a man who had been paralysed in a car accident to stand and take a few steps on a treadmill. Prof. Edgerton wrote an article for Speaking of Research on the importance of animal research to the development of electrostimulation to overcome paralysis.

The key difference between the earlier work and that published by the Swiss team is that whereas in the earlier animal and clinical studies undertaken by Prof. Edgerton there was no conscious control by the rat or human over movement, Prof. Courtine and colleagues devised a training program that allowed the rats to learn to exercise conscious control over the previously paralysed limbs, eventually allowing the rats to run and climb.  In the video below Prof. Courtine discusses the important implications of his team’s work.

There is also an interview available as a podcast without subscription on the Science website in which Prof. Courtine discusses his work in more depth.

The importance of this study should not be underestimated, as it demonstrates that electrostimulation of the lower spinal cord has even greater potential to improve the lives of people with severe spinal cord injuries that was apparent in the earlier studies by Prof. Edgerton and colleagues, studies that were major medical breakthroughs in their own right.

Paul Browne

Not Difficult To Grasp

Paralysis can have tremendous negative consequences for a person’s quality of life.  In the US alone, there are more than 200 thousand people living with chronic spinal cord injury, which is a cause of immense suffering to them and their families.  The disease generates economic burden for society as well.   Thus, there has been a lot of interest in using our knowledge of how movement is coded in the brain to allow patients to bypass nerve injuries and communicate directly with the environment.  Moreover, when asked about their priorities in terms of regaining motor function the vast majority of patients rank regaining arm and hand function as most important.

It is thus encouraging to read in Nature today an update on how these efforts by scientists have allowed a paralyzed patient to reach for a cup, bring it to her lips, and drink from it.

Critical milestones in the development of motor prosthesis for paralyzed patients

As explained in a nice News and Views piece by Andrew Jackson that accompanies the article, this type of work builds on decades of previous research on the neural mechanisms that control arm movements (here, here and here) (blue on the Fig above), on the development of chronic multi-electrode arrays (orange), their recording properties in animals, and on feasibility studies of neural interfaces in monkeys (here, here, here and here) (green), which opened the way to clinical studies in humans (here and here) (purple).

The value of animal research should not be difficult to grasp. The knowledge that allows us to “read out” the planned movements of the patient from different brain regions in order to guide the movement of the robot is critical in the design of the system.  And it is an indisputable fact that such knowledge has been (and continues to be) obtained by experiments in awake, behaving monkeys.

And for those that doubt the true motivation of scientists for doing their work, it is worth noting what Dr. Leigh Hochberg (one of the leading authors of the study) had to say about their results — “The smile on her face … was just a wonderful thing to see.”   Do you want to see her smile too?  Watch this:

Of course the BrainGate system used by Dr. Hochberg and Dr. John Donoghue – director of the Institute for Brain Science at Brown University – is not the only brain-machine interface system under development to restore function in paralysis. In 2008 we wrote about a similar brain implant developed by Dr. Andy Schwartz at the University of Pittsburgh which enabled monkeys to manipulate robotic hands with unprecedented dexterity. Last year we wrote about how Dr. Schwartz’s team had used a different technology known as electrocorticography to enable a paralysed man to manipulate a robotic arm, while Dr. Chet Moritz and colleagues at Wachington National Primate Research Centre, have coupled readings from individual nerve cells to a technology called functional electrical stimulation to restore control to temporarily paralysed muscles in monkeys, an approach that may eventually supersede the use of robotic arms in some patients. It will be fascinating to watch this technology progress into more widespread clinical use over the next decade, and thrilling to think that, impressive as it appears today, we have barely begun to tap the potential of brain-machine interface technology to change lives.

How nerve cells reach their niche.

Developmental biology, the study of the processes through which organisms grow and develop, is an area of biomedical research where modal organisms – ranging from the slime mold Dictyostelium  discoideum to the chicken – play a crucial role, and one that has been honoured with several  Nobel Prizes in recent years.  For example, the 1995 prize for “discoveries concerning the genetic control of early embryonic development” was awarded for studies of the fruit fly  Drosophila melanogaster , and the  2002 prize for “discoveries concerning ‘genetic regulation of organ development and programmed cell death”, was awarded for research undertaken with the nematode worm Caenorhabditis elegans, while the 2007 prize for  “discoveries of “principles for introducing specific gene modifications in mice by the use of embryonic stem cells”” depended on studies of stem cells in the developing mouse embryo undertaken by Martin Evans.

Today on the Neurophilosophy blog Mo Costandi has another great example of how our knowledge of developmental biology is being advanced through animal research. In a post entitled “Astrocytes build blood vessel scaffolds for long distance neuron migrations” he discusses how a research team led by Dr Armen Saghatelyan  used  Green Fluorescent Protein labeling and genetic modification to track the processes that control the migration of nerve cells to their correct location in the developing mouse brain.

It’s fascinating work, and you can read about it on the Neurophilosophy blog here.

 

 

So what does this basic research in developmental biology mean to medicine?

Scientists have known for some time that the brain has a limited ability to repair itself following injury, for example after a stroke, and more recent studies have identified a critical role for adult neuronal precursor cells in this recovery.  But the process by these adult neuronal precursor cells migrate to the site of injury and integrate into the damaged brain circuitry is very inefficient, with only a small number of cells reaching the correct location, so scientists are working on a variety of approaches to boost the brain’s ability to repair itself.

One approach to doing this is the use of exogenous stem cells, such as the human embryonic stem cell derived neuronal precursor cells developed by the UK-based company ReNeuron that entered clinical trials for stroke in 2011.

Another avenue being pursued by several research groups around the world is to improve the efficiency with which the endogenous neuronal precursor cells migrate to and repair damaged regions of the brain. In order to develop therapies that improve endogenous brain repair scientists first need to understand the processes that drive – and limit – neuronal precursor production, migration and integration in the developing and adult brain, so that they can modify and enhance those processes to safely  optimize repair.  The work of Dr Saghatelyan and his colleagues has provided medical science with another important piece of a puzzle that when solved will benefit many thousands of stroke victims around the world.

Paul Browne

A paralyzed man stands again…thanks to animal research!

Yesterday an article appeared in the New York Times describing how scientists, supported by the National Institutes of Health and the Christopher and Dana Reeve Foundation, have used electrical stimulation of the lower spinal cord to enable a man who had been completely paralyzed below chest level to stand again,  and even to take steps on a treadmill. The good news has since spread around the world, being reported on the BBC, The Times of India, and Canadian TV .

While the reports have – perhaps understandably –focused on the fact that this breakthrough has for the first time enabled a man with complete paralysis to stand and take a few steps, the Lancet paper describing this work also reports “improved autonomic function in bladder, sexual and thermoregulatory activity that has been of substantial benefit to the patient”. Such improvements are important as they have a huge impact on the overall wellbeing of a paralysis victim.

In this video Professor V. Reggie Edgerton of UCLA, who lead the team that undertook this study, describes the background to this study, and how discoveries made in both animal and clinical research made it possible.

Regular readers of the  Speaking of Research science blog may recognize his name, in October 2009 Prof. Edgerton wrote an article for Speaking of Research  in response to media coverage of a study he and his colleagues had published on the use of implanted electrodes to restore motor function in rats whose spinal cord had been severed, allowing the rats to stand and walk again. This study in rats – which can be read in full in PubMed Central – proved that in the absence of input from the brain due to the spinal cord being severed, electrical stimulation of the caudal segments of the spinal cord could enable the nerve circuits in the lower spine to use input from sensory nerves to control movement, and led directly to the clinical breakthrough reported yesterday.

But as is almost always the case this advance did not come from only one study, many years of basic research in both animals, intitally in cats – where it was first shown that an animal can walk despite the complete transection of the spinal cord -and later in rats, provided the scientific basis for this work, as Prof. Edgerton himself wrote in 2009:

 It has been characterized as a major breakthrough in facilitating the level of recovery of locomotion following a severe spinal cord injury. This in itself implies that these findings were the result of a single experiment with rats. But the reality is that these experiments were based on 100s of other experiments by not only my laboratory, but many other scientists. All of the previous animal experiments relevant to our understanding of the control of movement, involving many different species ranging at least from fish to humans, have contributed to the evolution of the concepts that underlie our most recent publication.”

Only time will tell what this study will mean for the millions paralyzed by spinal injuries – breakthroughs like this are better viewed as the end of the beginning than as the beginning of the end – and much further research will be needed to evaluate and improve this technique before it can be considered for widespread clinical use.

Firstly, the electrode arrray used in this study was relatively basic, but was FDA approved for use in humans and so appropriate for this early clinical study. Prof. Joel Burdick of Caltech, an author on this weeks Lancet study, is working to improve the design of the electrode arrays and the patterns of electrical stimulation applied to the spinal cord. Improvements in the way in which the electrical stimulation is delivered should increase the effectiveness of the technique.

A possible second improvement could be the addition of drugs that activate the locomotor nerve circuts. In the 2009 rat study some animals were treated with agonists for the 5-HT2A and 5-HT1A/7 serotonin receptors – on the basis of earlier research in mice and rats – in addition to receiving electrical stimulation, and it was found that this combination was considerably more effective than electrical stimulation alone. Unfortunately the serotonin agonists used in the 2009 rat study are still experimental and not approved for human use, and so could not be used in the clinical study reported in the Lancet. Hopefully 5-HT2A and 5-HT1A/7 serotonin agonists suitable for use in humans will soon be developed and evaluated in clinical trials, perhaps this weeks result will encourage investment in such drugs.

Many avenues towards repairing spinal cord damage or restoring function are currently being studied, and it is possible that this approach might be superseded in some, or even most, cases by advances in stem cell and regenerative medicine, and of course the various brain machine interfaces that we’ve discussed earlier may prove more appropriate for some conditions and patients.

For today though, we offer Prof. Edgerton and his team our most heartfelt congratulations on an achievement that gives new hope to thousands.

Let’s also remember that this is but one of many examples of medical progress that animal rights activists would have prevented if they could have.  Fortunately, they did not succeed. It is up to us – medical researchers, health professionals and supporters of science and progress – to make sure it stays that way!

Paul Browne