And another JNNP podcast

This time we are talking about intravenous trombolysis as a treatment for acute ischaemic stroke and we discuss distress, disability and employment in neurology outpatients with organically unexplained neurological symptoms. You can find the podcast here.

My first official podcast!

I am currently working at the British Medical Journal as part of my Masters in Science Media Production at Imperial. Here you can listen to the first fruits of my efforts! In the podcast we discuss a potential link between prenatal testosterone levels and ALS, as well as the usefulness of psychotherapy as part of the treatment for unexplained dizziness.

Mobilising the immobile

DARPAs dream?

Would you be happy to stay on-board a plane if you were told that the pilot was flying it whilst sitting in his armchair flying the plane with only his thoughts? This may sound like science fiction, but the Defense Advanced Research Projects Agency (DARPA) in the US has already spent millions of dollars on research that focuses on the interaction between the human brain and machines, and mind-controlled aeroplanes are high on their wish list, together with battle robots.

While armies of robots may still be well ahead into the future, immense progress has been made in research that could have a tremendous impact on the lives of people who suffer from paralysis. Often caused by diseases such as spinal cord injury after an accident, or by stroke, paralysis can be, at its most extreme, virtually complete, leading to locked-in syndrome. One of the most famous cases of paralysis after spinal cord injury is perhaps the late actor Christopher Reeve, who became paralysed from the neck down after a fall from a horse. Over the past couple of decades, research into paralysis has focused on the development of a brain-machine interface that allows people to control muscles and even prosthetic limbs using thought alone. 

Wilder Penfield

To understand the magnitude of this development, we have to go back into history. Wilder Penfield laid an important part of the foundation when he was working at McGill University in Canada in the 1950s.  Penfield, who studied neuropathology at Merton College in Oxford, became well known for the way in which he treated epilepsy patients by destroying the neurons in the foci of the seizures. Before each surgery, he would electrically stimulate the brain of his conscious patients to localise brain function. This allowed him to guide his surgery more precisely and prevent damage to other cognitive and motor functions. It also enabled him to draw a complete map of the motor cortex, or motor homunculus. The sizes of the body parts on the cortical map correspond to the complexity of the movements that those parts perform. Our ability to use such fine scale movements required to speak or to use tool is clearly reflected in Penfield’s map.

Penfield's motor homunculus

 Further exploration into motor functioning led Eberhard Fetz and colleagues to discover that monkeys were able to voluntarily control neural activity through operant training, as long as they were given biofeedback. The monkeys, who had electrodes implanted in their brain, were looking at a meter that showed their own neuronal activity. Whenever the needle of the meter was pointing to the right side, the monkey received a reward. As soon as monkeys had learned that there was a link between the meter and the reward, they were able to adjust their neural firing patterns for more rewards (Fetz, 1969; Fetz and Baker, 1973).  In the beginning the neuronal activity still resulted in active movement of the monkeys’ limbs, but over time, while the monkey still voluntarily controlled the neuronal activity, the overt movements extinguished (Fetz and Baker, 1973).

In the early 1980s, researchers began to slowly adopt the idea that ensembles of neurons spread across the brain, and not just single neurons, create physiological activity in the central nervous system of mammals (Gerstein and Aertsen, 1985). Donald Hebb had already suggested this in 1949, but research in this area was delayed by the persistent idea that single unit recordings would provide us with the answer to the neural code, because it was believed that only a few specific neurons controlled a particular movement. Since there are over a 100 billion neurons in our brain, finding those specific neurons would be like looking for a needle in a haystack. Thus, the discovery that ensembles of neurons were responsible for movements made looking for the target areas a lot easier.

By using different imaging techniques to look at this widespread brain activity, Jeannerod and colleagues made an interesting discovery. They compared activity in the brains of participants as they were imagining making a specific movement and compared these activations with the activity observed when the participants were actually making the movement. They found a striking resemblance between the observed activations, leading to the conclusion that imagining a movement may not be so neurally different from actually performing the movement.  This result provided a significant step in brain-machine interface research (Jeannerod, 1995; Jeannerod and Frak, 1999).

In parallel, Nicholelis and Chapin managed to train rats to receive rewards for activating lever press related activity in their brain. First, they trained thirsty rats to press a lever to get a drink of water. As they were pressing the lever, the researchers recorded the patterns of activity from 46 neurons in the rats’ brains, which they used in the next stage of the experiment. The lever was disconnected from the water supply and the rat no longer received water from a lever press. However, the rat went on pressing and the scientists gave the rat water whenever its brain produced the command for pressing the lever. After a while, the rat stopped pressing the lever altogether, but kept producing the press lever command in its brain. The external machine that delivers the reward is now directly operated through the command ‘press lever’ in the rat’s brain (Nicholelis et al., 1998).

The next step was to attempt something similar in primates and make the movements more intricate. Using a similar method as in the rats, Nicolelis and his colleagues managed to let a monkey swing an artificial arm from left to right, just by using thought. Then it was time to allow the monkey to make more complex movements. They first learned to use a joystick to drag a cursor onto a target on a computer screen while the researchers recorded the patterns of activity like before. Soon, the monkeys learned that the command for ‘drag cursor’ resulted in reward, and they stopped actively dragging the cursor onto the target. This was swiftly followed by an ability to reach and grab, trained in similar ways (Nicholelis et al., 2003).

Thus, scientists are now able to create communication pathways between the brain and an external machine (e.g. a computer cursor or an artificial limb). The first human trials have already successfully shown that paralysed patients were able to directly control computer cursors (Hochberg et al., 2006). However, they have also raised issues about safety and reliability of the intracranial electrodes that need to be addressed before clinical trials can extent to larger patient populations.

Sensory feedback is essential

Another limitation of current-generation brain-machine interfaces is a lack of sensory control. To successfully sip from a cup of tea requires more than just reaching and grabbing movements. The touch sensors that send signals from our hand to our brain allow us to pick up the cup without knocking it over. However, an artificial extremity has no such sensors. Thus, we need feedback of information from the external device to the brain. The only feedback currently available is visual feedback, which gives insufficient control over artificial limbs. A recent article in the Journal of Neuroscience showed that adding sensory feedback information would increase control greatly and that is the next challenge researchers are currently focusing on (Suminski et al., 2010; Nicholelis and Lebedev, 2009).

Research is also currently focusing on the striking finding that the brains of the monkeys that participate in these studies become structurally adapted to the external devices. Thus, different areas within the motor cortex of these monkeys now seem to be representing the robot, as if the robot was a part of their own body. If further research proves this to be right, the implications can be unprecedented. It would allow the patient to perceive the prosthetic device as an actual part of their body (Nicholelis and Lebedev, 2009).

A global team of neurophysiologists, computer scientists, engineers, roboticists, neurologists and neurosurgeons are now working together in the “Walk Again Project” to do no less than develop a generation of neuroprosthetic devices that can restore full-body mobility in patients with severe paralysis. Thus, while DARPA is dreaming of creating armies of robots, their money has been well spent on research that could mobilise the immobile in the not too distant future.

References:
Fetz EE. (1969). Science 163, 955-958.
Fetz EE, Baker MA. (1973).  Journal of Neurophysiology 36, 179-204.
Gerstein GL, Aertsen AM. (1985). Journal of Neurophysiology 54, 1513-1528.
Jeannerod M. (1995). Neuopsychologia 33, 1419-1432.
Jeannerod M, Frak V. (1999). Current Opinion in Neurobiology 9, 735-739.
Nicolelis MAL et al. (1998). Nature Neuroscience 1, 621–630.
Nicolelis MAL et al. (2003). Proceedings of the National Academy of Sciences 100, 11041-11046.
Hochberg LR  et al. (2006). Nature 442, 164-171.
Suminski AJ et al. (2010). Journal of Neuroscience 30, 16777-16787.
Nicolelis MAL, Lebedev, MA. (2009). Nature Reviews Neuroscience 10, 530-540.


This article appeared in the Trinity Term issue of 'Phenotype' in a slightly modified form. Phenotyope is the termly science magazine published by the Oxford University Biochemical Society. Here you can read this issue of the magazine in its entirety.

In the neutral zone: is there an ethical side to science?

"I promise to work for a better world, where science and technology are used in socially responsible ways. I will not use my education for any purpose intended to harm human beings or the environment. Throughout my career, I will consider the ethical implications of my work before I take action. While the demands placed upon me may be great, I sign this declaration because I recognize that individual responsibility is the first step on the path to peace."

The above is the text of a ‘Hippocratic Oath for Scientists’ proposed by the physicist and Nobel Peace Prize laureate Sir Joseph Rotblat in Science in 1999 (1). Rotblat, a British physicist who grew up in Poland and moved to England just before the Second World War, was originally part of the Manhattan Project that created the atom bomb. When in 1944 it became obvious that the Germans were themselves not capable of building such a device, Rotblat was the only member of the group – which included many of the finest physicists of the 20th century such as Niels Bohr and Richard Feynman – who decided he no longer wanted to be part of the creation of such a powerful weapon of mass destruction. Throughout the rest of his life, he advocated that scientists had the responsibility of protecting the environment and humankind and should be main players in the quest for world peace.

Rotblat did not see science as amoral; he felt that scientists had a clear responsibility to the public and if the results of certain lines of research could lead to adverse effects for humanity and the environment, scientists should decide against conducting those experiments. But many have argued that, while the misuse of scientific knowledge can certainly have dangerous consequences, the scientific process itself is, and has to be, ultimately neutral.

Arguably the strongest advocate for such a position is Lewis Wolpert, Emeritus Professor in Cell and Developmental Biology at University College London. In 2000, in a published exchange of letters (2) between Wolpert and the environmentalist and founder of The Ecologist, Edward Goldsmith, he argued that “it is the very nature of science that it is not possible to predict what will be discovered, or how these discoveries could be applied”, and suggests that one should not confuse knowledge gained by scientific research with the (technical) application that follows. While he also argues that “scientists have neither the right nor the skill to make ethical decisions about the application of their work”, he does suggest that scientists have a responsibility to provide the public with the tools to make informed decisions about the application of science: they should explain their research to the public, explore possible consequences – positive and negative – of their scientific results, and make sure that the research is trustworthy (3). This then would allow for informed debates amongst policy makers and the general public such that society as a whole would be involved in decisions as to how scientific progress is applied.

The debate about the ethical responsibilities of scientists came to the fore again in May this year when the controversial American scientist, Dr Craig Venter, announced that researchers at the J. Craig Venter Institute, a private organisation run by a board of which Dr Venter is President, had been able to create ‘synthetic life’ - a notion disputed by some scientists who say that rebooting a living cell with synthetic DNA is not equal to the creation of new life - by replicating DNA from a bacterial cell artificially and replacing the original DNA of the cell with the artificial DNA (4).

While the technical advancements of this study are largely undisputed, it has been the ethical questions surrounding this research that have caught the headlines. Some of the more controversial reactions to Venter’s research came from Professor Julian Savulescu of the Uehiro Centre for Practical Ethics, who is quoted in the Times Online saying that “Venter is creaking open the most profound door in humanity’s history, potentially peeking into its destiny”, and even goes on to say that “he [Craig Venter] is going towards the role of a God: creating artificial life that could never have existed naturally … the risks are also unparalleled. These could be used in the future to make the most powerful bioweapons imaginable.” David King, director of the Human Genetics Alert watchdog also criticised Venter for playing God: “what is really dangerous is these scientists’ ambitions for total and unrestrained control over nature.” Although these statements seem extreme and guided by emotion rather than reason, they do illustrate an important issue: that there is a discrepancy in understanding of scientific research between scientists and lay-audiences – even highly educated ones – that needs to be addressed.

This research has also grabbed the attention of environmentalist groups who are calling for a moratorium on the release of any synthetic life forms into the environment. They argue that artificial life forms may threaten existing wild life and could lead to hastened extinction, resulting in diminished biodiversity. At the UN Conventional on Biological Diversity held in Kenya at the end of May this year, the Action Group on Erosion, Technology and Concentration (ETC Group) - an international civil society organisation that researches the impact of new technologies on marginalised peoples and is based in Ottawa, Canada - helped formulate a ‘de facto moratorium’ on synthetic biology, which calls for a total ban on any experiment where artificial life forms are released into the wild (5). Environment ministers of the 193 member countries of the Biological Convention will meet in Japan later this year to decide whether to adopt such a moratorium.

Browsing through the popular media coverage, it might seem as if Rotblat would not have approved of Craig Venter’s experiments; however, as Venter himself has pointed out, the ability to create synthetic life allows us to start understanding the function of the fundamental components of life. This may ultimately lead to cures for genetic diseases, such as cystic fibrosis and Alzheimer’s disease by replacing damaged DNA with synthetic DNA that does not have mutations. The environment may benefit significantly too. Synthetic cells may be used to develop synthetic fuels that could address our need for fossil fuels and the large amount of carbon emission in our atmosphere. Such technologies therefore have huge potential for business; BP and Exxon Mobil are already large funders of Dr. Venter’s research.

To a young scientist, it might seem quite straightforward to sign up to Rotblat’s proposed oath, but what would it practically mean to adhere to this code? How do you decide where your personal responsibilities lie? Are you always aware the possible effects of your research? These are particularly difficult questions to answer, especially in a scientific world where high profile publications are ever more important as a token for research money. 

As Wolpert argues, scientific discovery is not necessarily predictable, and the suggestion that controversial results can be avoided by not carrying out such experiments seems naïve. Furthermore, while some findings may be used in harmful ways, often their benefits far outweigh their risks. For example, 14% of the world’s electricity needs (30% in the EU alone) are provided for by nuclear power (6,7). Thus, despite its major image problem, this positive use of nuclear fission is of vital importance in today’s society.

While the argument for the scientific process being neutral seems well founded, it is harder to conceive exactly how the application of science should happen democratically. There are only a few scientific minds in the current UK parliament. The crucial question is whether we would really want to leave decisions about the application of synthetic life or genetically modified crops up to politicians or groups of activists. Many comments on Venter’s study came from philosophers, and they could potentially play a pivotal role in democratising the application of scientific progress. In the current era, where major scientific discoveries follow each other in rapid succession, there is a need for ethicists to guide scientists and policy makers on how to use controversial results responsibly. This need is beginning to be widely acknowledged and has already led to the founding of numerous centres dealing with the ethical side of scientific discovery worldwide. Scientists could, or maybe even should, play a major role in this process by helping ethicists and policy makers understand the science behind discovery.

While it may seem that the media increasingly represents scientific advances as lead to increasing a threats to our existence, such fears are by no means new. An image of the “mad scientist”, tinkering with the natural world, can be seen as far back as Aristophanes’ comedy ‘The Clouds’. Mary Shelley’s famous 19th century novel ‘Frankenstein’ expressed the uneasy feelings many people might have about science. However, one has to bear in mind that controversial advances have always led to criticism and ethical questions, but equally, controversial advances in science as well as literature, art and society, has made our society the way it is today.

References
1.    Rotblat, J. A (1999). Hippocratic Oath for Scientists. Science 286: 1475
2.    Wolpert, L. and Goldsmith, E. (2000). Letter exchange: Is science neutral? The Ecologist 30 No. 3 (May).
3.    Wolpert, L. (1999). Is science dangerous? Nature 398: 281-282.
4.    Gibson, D.G., Glass, J.I., Lartigue, C. et al., (2010). Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome. Science 329: 52-56.
5.    Etc Group (2010). Synthia is Alive … and Breeding: Panacea or Pandora's Box? http://www.etcgroup.org/en/node/5142
6.    International Energy Agency (2009). Key world energy statistics. http://www.iea.org/publications/free_new_Desc.asp?PUBS_ID=1199.
7.    European Commission (2009). Eurostat. http://epp.eurostat.ec.europa.eu/portal/page/portal/product_details/publication?p_product_code=KS-SF-09-055.

This article appeared in the Science and Society section of the Michaelmas Term issue of 'Phenotype', the termly science magazine from the Oxford University Biochemical Society. Here you can read the magazine its entirety.

Finally ...

I know - months have gone past without fresh words on this blog. I have not been entirely idle during this period, but few of my energies have been directed towards writing (evidently!).

Moreover, I have also recently been moonlighting online elsewhere and have just posted a piece on Science Oxford Online provoked by the pointless nature-nurture argument on a recent edition of The Today Programme following the announcement of a possible genetic component to ADHD (Attention Deficit Hyperactivity Disorder).

This comes as part of my increasing involvement with Science Oxford, a charitable organisation for the promotion of local science to the general public and also more generally to educate and inspire children and adults about science from across the globe.

For the younger generation, they provide what is called a "Discovery Zone", essentially a large, educative and interactive play pen, which provides seemingly hours of distraction and fun while also quietly demonstrating some of the laws of magnetism and gravity and the like.

While many adults also seem to gain as much enjoyment from these toys as their children, Science Oxford also organises events more specifically tailored to their age group on Thursday evenings. Over the past year, I have helped out at talks on topics ranging from sustainable farming to Alzheimer's disease via a celebration of the contribution of black scientists. They even allowed me an evening to consider how memory and identity interact. For those of you not in Oxford, many of the events are streamed and archived on the website and can be downloaded as video podcasts via iTunes (search for Science Oxford in the iTunes store). Their recent event on everything you always wanted to know about sex (whether or not you were afraid to ask) should be up there shortly and there will soon be talks on the universe and the atom (quite some change in scale!) along with a seasonal take on the science of fireworks.

But don't worry, Science Oxford has not entirely taken over my life and I shan't be forsaking this blog entirely.  I hope shortly to write about some of the science that has caught my eye over the summer months.  Without a 4 month delay this time, I promise.

Double blind & placebo controlled, but where are the statistics?

For those of you who missed this morning's The Today Programme on BBC Radio 4, listen here to a fragment where homoeopathy-sceptic Simon Singh and conservative MP David Tredinnick take opposing views on the healing powers of homoeopathic remedies. Based on a couple of studies published recently, Tredinnick feels it is worth re-opening the debate on whether or not the NHS should fund homoeopathic remedies; Simon Singh explains why this would be a mistake. The latter's description of a French homoeopathic flu medicine that contains one crushed and highly diluted duck that serves millions of people - and therefore earns the company who created the remedy millions of Euros - as the ultimate quack remedy is a wonderful and almost perfect put-down for the values of homoeopathy.

Reading between the lines

Whenever we compare human and animal behaviour, one major difference that always comes up is our ability to use words to communicate with our fellow human beings. We can use words to order food in a restaurant and chat about everything and nothing over coffee with our friends, and the act of talking has become so normal to us that we don't even give much thought as to how extraordinary speech really is. And now researchers have discovered that our use of language gives away more than just the literal meaning of the words: there are hidden clues about ourselves in our words, in the frequency with which we use certain words, in the number of different words there are in our personal vocabulary and in the richness of our sentences.

In 'Vanishing Words', a recent episode of my ever favourite science-based radio programme Radiolab, Jad and Robert talk about those hidden messages. Drs Ian Lancashire, Kelvin Lim and Serguei Pakhomov are all interested in how characteristics of our personal vocabulary may be an indication of our likelihood of developing memory related diseases such as Alzheimer's. Moving from analysis of the crime novels of Agatha Christie to a comparison of how the linguistic content of teenage essays by a group of nuns relates sixty years on to their cognitive function, these researchers have found surprising associations between the richness of our language and our later susceptibility to cognitive decline.

And more messages can be found in this blog post on the British Psychological Society's Research Digest blog. Dr Paul Rozin of the University of Pennsylvania showed in a study published in Cognition and Emotion that our existential feelings about positive and negative events are reflected in our language. Analysing the frequency of positive and negative words in our language, the researchers found a large prevalence of the former type of utterance, mirroring, they claim, the preponderance of positive events that occur.  Nonetheless, while negative words are comparably scarcer, they exist in greater variety, which the authors argue again is typical of how such events occur in our everyday environment.

Perhaps this latter is not so surprising.  Even at its most gossipy or mundane, language is partly a translation of our needs and desires, and partly a reflection of our environment.  Slips-of-the-tongue have endlessly been interpreted, not just as mistakes, but as windows onto our souls (see, for instance, the furore when Gordon Brown once accidentally said that he had "saved the world" rather than just the monetary crisis). Similarly, the past fifty years have seen fierce battles over Whorfian linguistic relativism, questioning how language affects thought, perception and behaviour.

All this does give the phrase 'reading between the lines' quite a different meaning!