̽��ֱ�� of Cambridge - nerve

Robotic nerve ‘cuffs’ could help treat a range of neurological conditions

sc604 — Fri, 26 Apr 2024 08:55:34 +0000

̽��ֱ��researchers, from the ̽��ֱ�� of Cambridge, combined flexible electronics and soft robotics techniques to develop the devices, which could be used for the diagnosis and treatment of a range of disorders, including epilepsy and chronic pain, or the control of prosthetic limbs.

Current tools for interfacing with the peripheral nerves – the 43 pairs of motor and sensory nerves that connect the brain and the spinal cord – are outdated, bulky and carry a high risk of nerve injury. However, the robotic nerve ‘cuffs’ developed by the Cambridge team are sensitive enough to grasp or wrap around delicate nerve fibres without causing any damage.

Tests of the nerve cuffs in rats showed that the devices only require tiny voltages to change shape in a controlled way, forming a self-closing loop around nerves without the need for surgical sutures or glues.

̽��ֱ��researchers say the combination of soft electrical actuators with neurotechnology could be an answer to minimally invasive monitoring and treatment for a range of neurological conditions. ̽��ֱ��results are reported in the journal Nature Materials.

Electric nerve implants can be used to either stimulate or block signals in target nerves. For example, they might help relieve pain by blocking pain signals, or they could be used to restore movement in paralysed limbs by sending electrical signals to the nerves. Nerve monitoring is also standard surgical procedure when operating in areas of the body containing a high concentration of nerve fibres, such as anywhere near the spinal cord.

These implants allow direct access to nerve fibres, but they come with certain risks. “Nerve implants come with a high risk of nerve injury,” said Professor George Malliaras from Cambridge’s Department of Engineering, who led the research. “Nerves are small and highly delicate, so anytime you put something large, like an electrode, in contact with them, it represents a danger to the nerves.”

“Nerve cuffs that wrap around nerves are the least invasive implants currently available, but despite this they are still too bulky, stiff and difficult to implant, requiring significant handling and potential trauma to the nerve,” said co-author Dr Damiano Barone from Cambridge’s Department of Clinical Neurosciences.

̽��ֱ��researchers designed a new type of nerve cuff made from conducting polymers, normally used in soft robotics. ̽��ֱ��ultra-thin cuffs are engineered in two separate layers. Applying tiny amounts of electricity – just a few hundred millivolts – causes the devices to swell or shrink.

̽��ֱ��cuffs are small enough that they could be rolled up into a needle and injected near the target nerve. When activated electrically, the cuffs will change their shape to wrap around the nerve, allowing nerve activity to be monitored or altered.

“To ensure the safe use of these devices inside the body, we have managed to reduce the voltage required for actuation to very low values,” said Dr Chaoqun Dong, the paper’s first author. “What's even more significant is that these cuffs can change shape in both directions and be reprogrammed. This means surgeons can adjust how tightly the device fits around a nerve until they get the best results for recording and stimulating the nerve.”

Tests in rats showed that the cuffs could be successfully placed without surgery, and formed a self-closing loop around the target nerve. ̽��ֱ��researchers are planning further testing of the devices in animal models, and are hoping to begin testing in humans within the next few years.

“Using this approach, we can reach nerves that are difficult to reach through open surgery, such as the nerves that control, pain, vision or hearing, but without the need to implant anything inside the brain,” said Barone. “ ̽��ֱ��ability to place these cuffs so they wrap around the nerves makes this a much easier procedure for surgeons, and it’s less risky for patients.”

“ ̽��ֱ��ability to make an implant that can change shape through electrical activation opens up a range of future possibilities for highly targeted treatments,” said Malliaras. “In future, we might be able to have implants that can move through the body, or even into the brain – it makes you dream how we could use technology to benefit patients in future.”

̽��ֱ��research was supported in part by the Swiss National Science Foundation, the Cambridge Trust, and the Engineering and Physical Sciences Research Council (EPSRC), part of UK Research and Innovation (UKRI).

Reference:
Chaoqun Dong et al. ‘Electrochemically actuated microelectrodes for minimally invasive peripheral nerve interfaces.’ Nature Materials (2024). DOI: 10.1038/s41563-024-01886-0

Researchers have developed tiny, flexible devices that can wrap around individual nerve fibres without damaging them.

̽��ֱ��ability to make an implant that can change shape through electrical activation opens up a range of future possibilities for highly targeted treatments

George Malliaras

XH4D via iStock / Getty Images Plus

Illustration of the human nervous system

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Campath: from innovation to impact

bjb42 — Sat, 01 Aug 2009 00:00:00 +0000

̽��ֱ��journey taken by Campath-1H from the laboratory to its imminent use as a new treatment for multiple sclerosis (MS) is deeply rooted in fundamental research and illustrates the role that academic research plays throughout the development of new innovations. In the late 1970s, Professor Herman Waldmann, then a lecturer in the Department of Pathology at the ̽��ֱ�� of Cambridge and now Head of the Sir William Dunn School of Pathology, Oxford, was applying for his first Medical Research Council programme grant. ‘I was interested in understanding immunological tolerance [see Glossary below],’ remembers Waldmann, a process that was poorly understood at that time, as were many other aspects of the human immune system.

̽��ֱ��immune system is a network of many cell types that protect the body from bacteria and other disease-causing organisms (pathogens). When a pathogen enters the body and infects human cells, immune system cells that circulate in the blood called T and B lymphocytes detect its presence by binding to pathogen-specific molecules called antigens and become activated. ̽��ֱ��activated T lymphocytes kill the pathogen-infected cells directly or help the activated B lymphocytes make antibodies, secreted proteins that recognise specific antigens. These antibodies coat the pathogens, which labels them for destruction by other immune system cells through processes that immunologists call effector mechanisms.

Although a person’s immune system responds quickly to pathogens, it usually ignores self antigens, molecules that are present in the person’s own body. This lack of response is called tolerance. In 1978, says Waldmann, ‘people thought that to make a good immune response, lymphocytes had to cooperate with each other and that if there wasn’t good cooperation between lymphocytes, the default state was tolerance.’

One way to investigate tolerance, therefore, might be to reduce the number of lymphocytes in an experimental animal and then expose the animal to a new antigen. If this theory about tolerance was right, the animal should become tolerant to the antigen. But how could the number of lymphocytes in an animal be reduced?

̽��ֱ��approach Waldmann took was to make an anti-lymphocyte antibody using a technique that had recently been developed by Dr César Milstein at the nearby Laboratory of Molecular Biology. By fusing myeloma cells (cancer cells that develop from B lymphocytes) with cells from the spleen, Milstein had managed to make cell lines that indefinitely produced large amounts of a single antibody. Such monoclonal antibodies were ideal for Waldmann’s experiment.

‘ ̽��ֱ��immediate medical applications of this experiment were very clear,’ says Waldmann. ‘If it worked, it would provide a way to improve bone marrow transplants.’ These transplants are used to ‘rescue’ cancer patients whose blood system has been destroyed by radiotherapy. Donated bone marrow rescues these patients because it contains stem cells, precursor cells that can provide the recipient with a new blood system. Unfortunately, donated bone marrow also contains mature lymphocytes, which can attack the patient. Waldmann reasoned that, by using a monoclonal antibody to remove mature lymphocytes from the donor marrow, this potentially fatal ‘graft-versus-host disease’ could be avoided. Importantly, however, Waldmann also saw his work as a way to investigate basic immunological mechanisms.

Campath antibodies and bone marrow transplants

Late in 1979, Waldmann and his team immunised a rat with human lymphocytes and fused its spleen cells with a rat myeloma cell line. Over Christmas, Waldmann isolated several antibody-producing cell lines from this Campath-1 fusion (‘Campath’ stands for Cambridge Pathology) and his team set to work to identify an antibody that could kill mature T lymphocytes without damaging the bone marrow stem cells. In particular, the researchers looked for an antibody that could activate complement, one of the immune system’s effector mechanisms. ̽��ֱ��monoclonal antibody that best met these criteria was an ‘IgM’ antibody. B lymphocytes can make several different types of antibody (isotypes), each of which behaves differently in terms of which immune effector mechanisms it interacts with to destroy pathogens. This particular IgM (Campath-1M) activated complement efficiently and almost completely eliminated T lymphocytes in test tubes.

̽��ֱ��first bone marrow transplants that used Campath-1M for T-lymphocyte depletion were performed in the early 1980s. Bone marrow taken from donors was treated with Campath-1M in test tubes and the T-lymphocyte-depleted bone marrow was then injected into the graft recipients. This procedure successfully reduced the incidence of graft-versus-host disease but a new problem soon became evident. Some of the bone marrow recipients rejected the transplant. Their immune system had recognised the marrow as foreign even though the patients had been given drugs before the transplant to suppress their immune responses. Clearly, a better method was needed to suppress the patient’s immune response.

An obvious way to do this was to treat both the donor bone marrow and the transplant recipient with a T-lymphocyte-depleting antibody but the researchers knew that Campath-1M worked poorly in patients so they returned to the laboratory to find another antibody isotype that would be more effective. Their results suggested that an IgG2b antibody was likely to work best. Unfortunately, none of the antibodies produced in the Campath-1 fusion had this isotype. However, monoclonal-antibody-producing cell lines sometimes spontaneously start to make antibodies of a different isotype. So, the researchers painstakingly screened a cell line that was making an IgG2a antibody until they found a cell that had switched to making an IgG2b antibody – Campath-1G. Like the original Campath-1M (and Campath-1H; see below), Campath-1G binds to a molecule called CD52 that is present on lymphocytes and some other human cells.

Campath-1G and Campath-1H go into patients

‘Once we knew we had an antibody that worked in patients, we started to talk to a variety of clinicians who might be interested in using an anti-lymphocyte antibody,’ explains Waldmann. Some of these clinicians were treating patients who had lymphocytic leukaemia, a blood cancer in which lymphocytes replicate uncontrollably. Two patients with this type of cancer were duly treated with Campath-1G and initially responded well although both patients subsequently relapsed. In one patient, their immune system had recognised Campath-1G – a rat antibody – as foreign and destroyed it.

Clearly, a more-nearly human antibody was needed that would be ignored by the human immune system. Fortuitously, another Cambridge scientist, Professor Sir Greg Winter, had just developed a way to ‘humanise’ antibodies. Humanisation is the replacement of some regions in an animal antibody by the equivalent human regions; the animal regions that determine which antigen the antibody recognises are retained in humanised antibodies. Dr Mike Clark, who had joined Waldmann’s laboratory in 1981, started to make a set of fully and partly humanised antibodies from Campath-1G and, together with other team members, tried to determine which human isotypes would work in patients. Campath-1H, a humanised IgG1, was the result of all this basic research although, says Clark, who is now a Reader in Therapeutic Immunology in the Department of Pathology, ̽��ֱ�� of Cambridge, ‘these days, we think that a partly humanised antibody that retained some more of the rat regions would probably have worked just as well.’

Campath-1H was very successful for the treatment of lymphocytic leukaemia and of non-Hodgkin lymphoma (another type of blood cancer), and for use in bone marrow and solid organ transplants. Clinicians also started to use it to treat several autoimmune diseases including vasculitis (inflammation of the blood vessels), rheumatoid arthritis and MS. ̽��ֱ��clinical-grade material needed for these studies was produced in the Therapeutic Antibody Centre (TAC) that Waldmann set up in Cambridge in 1990 with Professor Geoff Hale, a biochemist who had joined Waldmann’s group at the beginning of the Campath-1H story and who is now Visiting Professor of Therapeutic Immunology at the Sir William Dunn School of Pathology, Oxford. ̽��ֱ��TAC moved to Oxford in 1995. ‘Without Geoff’s critical contribution and the support of both Cambridge and Oxford ̽��ֱ��,’ says Waldmann, ‘we would not have been able to initiate many of these studies, including our long-standing collaboration with Alastair Compston in MS.’

Pharmaceutical company involvement

̽��ֱ��development of a drug for clinical use is a highly regulated, long and expensive process, so drugs only get to market if pharmaceutical companies become involved in their development. In the early 1980s, the Cambridge researchers assigned the rights for the Campath-1 cell lines to BTG, originally a government body set up to facilitate the exploitation of inventions from UK academics but now an international specialty pharmaceuticals company. In 1985, BTG licensed Campath-1M to Wellcome Biotech, a subsidiary of the Wellcome Foundation. ‘Many people were very sceptical in the mid-1980s about the commercial future of antibodies and other biotech drugs but Wellcome was excited by the potential of this new area,’ comments Dr Richard Jennings (Director of Technology Transfer and Consultancy Services, Cambridge Enterprise Ltd).

When the basic research being undertaken by Waldmann’s team suggested that Campath-1G and Campath-1H were more likely to have a clinical future than Campath-1M, these antibodies were also licensed to Wellcome Biotech. Indeed, once Campath-1H had been handed over, the company abandoned its work on the earlier antibodies and started a programme of clinical trials of Campath-1H in rheumatoid arthritis, leukaemia and lymphoma. Meanwhile, the academic scientists continued with their basic research, refining and extending their understanding of how Campath-1H was working in various diseases by collaborating closely with the physicians who were giving the antibody to patients. This research was helped along by the development of new molecular techniques and by improved understanding of the human immune system.

Then, in 1995, Wellcome (which merged with Glaxo that year to become Glaxo-Wellcome) decided to abandon its development of Campath-1H, fearing that Campath-1H would not have a billion-dollar market after all. Although the antibody worked well in some types of leukaemia, it did not work in all leukaemias and, in the rheumatoid arthritis trials, Campath-1H had permanently suppressed patients’ immune systems. This decision was very disappointing for Waldmann and his colleagues, who strongly believed in the clinical potential of Campath-1H. ‘We looked at things from a different point of view,’ says Waldmann. ‘As academic scientists, when Campath-1H caused unexpected side effects or did not work as well as expected, our response was to look at the evidence, figure out what had gone wrong, and find ways to put it right rather than giving up.’

In 1997, after protracted negotiations with BTG and Glaxo-Wellcome, LeukoSite Inc. took on the licence to develop Campath-1H. LeukoSite, which merged with Millennium Pharmaceuticals in 1999, partnered with ILEX Oncology to complete the development and obtain US approval in 2001 for Campath-1H to be used for the treatment of B-cell chronic lymphocytic leukaemia (CLL) in patients who had failed to respond to conventional chemotherapy. ̽��ֱ��licence for Campath-1H was then transferred to ILEX Oncology before, finally, in 2004, Genzyme Corporation acquired ILEX Oncology and the production rights to Campath-1H.

Says Mark Enyedy, Senior Vice- President at Genzyme, ‘Campath-1H has had a particularly tortuous commercial history. I think the many changes of commercial support for this product have impeded the realisation of this drug’s commercial potential even though products like this always take an enormous time to develop.’

MS – Campath-1H’s new market?

Last year, the revenue from the use of Campath-1H for the treatment of CLL was around US$100 million but this income may eventually be dwarfed by the revenue generated from the treatment of early relapsing–remitting MS with Campath-1H (the generic name for the drug is alemtuzumab; its registered name is Campath®). As in other diseases, the development of Campath-1H for the treatment of MS has relied on academic researchers willing to do the basic research needed to understand how Campath-1H is working in patients and how to make it more effective.

MS is an inflammatory neurological disease that is caused by damage to myelin, a substance that forms an insulating sheath around the nerve fibres in the central nervous system (CNS; the brain and spinal cord). Electrical messages pass along these nerve fibres to control conscious and unconscious actions. If the myelin sheath is damaged these messages can no longer pass smoothly and quickly between the brain and the body.

Most people with MS are initially diagnosed with relapsing–remitting MS. In this form of the disease, symptoms (which include muscle spasms and stiffness, tremors, bladder and bowel control problems, and pain) occur in episodes that are followed by periods of spontaneous recovery (remissions). Relapses can occur at any time, last for days, weeks or months, and vary in their severity. Most people who have relapsing–remitting MS eventually develop secondary progressive MS in which the occurrence of relapses wanes but overall disability slowly increases.

Early attempts to treat MS

By the late 1980s, it was becoming clear that MS is an autoimmune disease (a disease in which a person’s immune system attacks the person’s own tissues) in which activated T lymphocytes move into the CNS and damage myelin. As Professor Alastair Compston (Professor of Neurology and Head of the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge) explains, ‘we began to wonder whether we could help patients with MS by preventing the movement of activated lymphocytes from the bloodstream into the brain.’ Treatment with Campath-1H looked like one way that this could be achieved and, in 1991, Compston started an 18-year-long collaboration with Waldmann and his team by trying this approach for the first time in a woman who had developed MS some years earlier. ‘At that time, there were no licensed treatments for MS,’ says Compston, ‘and this individual seemed to be facing a particularly grim future. Alarmingly, she actually got much worse for a day or two after receiving Campath-1H but then picked up and remained very well for some years. She even seemed to get back some of her lost functions.’

Keeping in close contact with Waldmann’s team, Compston and colleagues carefully followed the progress of their patient for about 18 months before treating another six people. ‘By 1994, we had satisfied ourselves that Campath-1H treatment could stop the development of new inflammatory lesions in the brain,’ says Compston. In addition, ‘it seemed as though our patients had fewer new attacks after the treatment.’

By 1999, Compston and a clinical trainee, Dr Alasdair Coles, had treated 27 patients, all of whom had already entered the secondary progressive stage of MS. ‘We paused then to analyse our results,’ says Compston. &lsq

uo;We realised that, although we had stopped disease activity in terms of new inflammatory brain lesions and had reduced the number of attacks that people were having, most of our patients were continuing to deteriorate.’ ̽��ֱ��problems that the patients had had when they started Campath-1H treatment were slowly progressing. This observation puzzled the researchers. If MS is an inflammatory autoimmune disease, why was Campath-1H treatment failing to help people in the progressive phase of the disease even though the treatment seemed to turn off inflammation?

̽��ֱ��answer to this conundrum, the researchers realised, is that there are two separate processes going on in MS – inflammation and degeneration. Inflammation causes the attacks in relapsing–remitting MS but also triggers nerve degeneration. Eventually, the degenerative component of the disease gains a momentum of its own and continues even in the absence of inflammation, which results in slow progression and the accumulation of disabilities that don’t get better. ‘Until we used Campath-1H in patients, this separation between inflammation and degeneration was not appreciated,’ says Compston, ‘but its implications were obvious. If this drug was going to be of any use to people with MS, we would have to use it much earlier in the disease process than we had so far.’

Campath-1H for the treatment of relapsing–remitting MS

Compston and Coles now began to treat some of their patients with relapsing–remitting MS with Campath-1H. As before, the treatment almost completely stopped new attacks occurring but, in addition, many of these patients actually began to get better. Their various disabilities began to improve. It was time to take Campath-1H into formal clinical trials to prove the drug’s efficacy and to prepare the way for marketing the drug for the treatment of MS.

With the support of ILEX Oncology (and, from 2004, of Genzyme), a Phase 2 clinical trial was started in December 2002. Patients enrolled into the trial had to meet strict entry criteria and were treated with up to three annual doses of Campath-1H. ̽��ֱ��effects of the drug were measured three years after the initial treatment and, unusually for a Phase 2 trial, its effects were compared with the effects of another drug – interferon beta-1a, the current gold standard treatment for MS. ‘We set the bar high in this trial,’ says Enyedy. ‘Most studies of treatments for MS compare the new treatment with a placebo and only last a year.’ Genzyme, adds Compston, ‘has been fantastically committed to the development of Campath-1H for use in MS.’

̽��ֱ��results of the trial, which were published in 2008 in theNew England Journal of Medicine, showed that there were 70% fewer relapses and that the risk of accumulated disability was 70% lower among the patients receiving Campath-1H than among those treated with interferon beta-1a. Furthermore, as in the patients treated before the trial started, the disability score of patients treated with Campath-1H actually improved; by contrast, it worsened in the patients given interferon beta-1a.

Two large Phase 3 trials are now under way that will finish in 2011. If all goes well, Genzyme expects to apply for marketing approval in 2012, 21 years after the first patient with MS was treated with Campath-1H (and 33 years after Waldmann’s team started the research that produced Campath-1H). ‘So far, ‘ says Compston, ‘we have spent 18 years carefully observing treated patients and learning from our mistakes… With more secure funding for our basic and clinical research in the 1990s, we might have been able to move more quickly. But with a disease like MS, which was then poorly understood, it was always going to take a long while to develop a new drug.’ Importantly, adds Enyedy, ‘if the Phase 3 trials are successful, I think we can stake a claim for a new standard of care for a large subset of patients with relapsing–remitting MS,’ a prospect that, Compston says, is ‘very rewarding for a clinical neurologist who has seen so many young people lose the ability to perform simple aspects of everyday living as a result of this difficult disease.’

Glossary

Antibody: a secreted protein made by the immune system that binds to a specific molecule called its antigen. Antibody binding to an antigen on the surface of pathogens (disease-causing organisms) recruits other parts of the immune system to kill the pathogen. Antibodies are members of a family of proteins called immunoglobulins (Ig).

Antigen: any molecule that can bind specifically to an antibody.

Autoimmune disease: a disease in which the immune system mounts a response against self antigens.

B lymphocyte: a type of white blood cell that makes antibodies.

Bone marrow: the spongy material inside bones where all the cells in the blood, including red blood cells and lymphocytes, are made.

Complement: a set of blood proteins that form one of the immune system’s mechanisms for killing pathogens.

Isotypes: different classes of immunoglobulins such as IgG and IgM. Some of the isotypes have subclasses. For example, there are four human IgG subclasses – IgG1, IgG2, IgG3 and IgG4.

Monoclonal antibodies: antibodies that are made artificially in the laboratory.

Self antigens: molecules that are in an individual’s own tissues.

T lymphocytes: a type of white blood cell that helps B lymphocytes make antibodies and that also directly kills pathogen-infected cells.

Tolerance: the failure to respond to an antigen. ̽��ֱ��immune system is usually tolerant to self antigens.

̽��ֱ��path from innovation to impact can be long and complex. Here we describe the 30-year journey behind the development of a drug now being used to treat multiple sclerosis.

As in other diseases, the development of Campath-1H for the treatment of MS has relied on academic researchers willing to do the basic research needed to understand how Campath-1H is working in patients and how to make it more effective.

Photograph: Greg Smolonski

Waldmann, Clark and Hale

A tale of two innovations

We are often taken aback by the sudden appearance of a new innovation that has clear economic or clinical impact. Just how did these innovations arise?

Academic scientists working in universities are driven to do their research for many reasons. Some see their research as a way to develop new drugs or to build more powerful computers, for example. Many academic scientists, however, are simply curious about the world around them. They may want to understand the intricacies of the immune system or how the physical structure of a material determines its properties at a purely intellectual level. They may never intend to make any practical use of the knowledge that they glean from their studies.

Importantly, however, even the most basic, most fundamental research can be the starting point for the development of materials and technologies that make a real difference to the everyday life of ordinary people and that bring economic benefit to the country. Indeed, said Dr Richard Jennings, Director of Technology Transfer and Consultancy Services at Cambridge Enterprise Ltd, ̽��ֱ�� of Cambridge, ‘what universities are good at is fundamental research and it is high-quality basic research that generates the really exciting ideas that are going to change the world.’

But it takes a great deal of time, money and commitment to progress from a piece of basic research to a commercial product, and the complex journey from the laboratory to the marketplace can succeed only if there is long-term governmental support for the academic scientists and their ideas as well as the involvement of committed commercial partners and well-funded technology transfer offices.

Two particular stories illustrate the long and complex path taken from the laboratory to commercial success by two very different ̽��ֱ�� of Cambridge innovations. In the case of Plastic Logic, basic research on materials called organic semiconductors that started in the 1980s and that continues today has led to the development of a new type of electronic reader that should be marketed in early 2010 and, more generally, to the development of ‘plastic electronics’, a radical innovation that could eventually parallel silicon-based electronics. For Campath, the journey started just before Christmas in 1979 in a laboratory where researchers were trying to understand an immunological concept called tolerance. Now, nearly three decades later and after a considerable amount of both basic research and commercial development, Campath-1H is in Phase 3 clinical trials for the treatment of relapsing–remitting multiple sclerosis.

‘Both innovations are likely to have profound impacts over the next two years and it is important to recognise the deep temporal roots of both,’ said Professor Ian Leslie, Pro-Vice-Chancellor for Research.

Professor Leslie highlighted that an important lesson to draw from these stories ‘is the need for universities and other recipients of public research funding to implement and develop processes to support the translation of discovery to impact or, more generally, to develop environments in which the results of discovery can be taken forward and in which external opportunities for innovation are understood.’

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Yes

A brain chemical changes locusts from harmless grasshoppers to swarming pests

bjb42 — Fri, 30 Jan 2009 00:00:00 +0000

A collaboration between a team of scientists in Cambridge and Oxford, UK and Sydney, Australia has identified an increase in the chemical serotonin in specific parts of the insects' nervous system as initiating the key changes in behaviour that cause them to swarm.

Desert Locusts are one of the most devastating insect pests, affecting 20% of the world's land surface. Vast swarms containing billions of locusts stretching over many square kilometres periodically devastated parts of the USA at the time of the settlement of the West, and continue to inflict severe economic hardship on parts of Africa and China. In November 2008 swarms six kilometres (3.7 miles) long plagued Australia.

Locusts belong to the grasshopper family but unlike their harmless relatives they have the unusual ability to live in either a solitary or a gregarious state, with the genetic instructions for both packaged within a single genome.

Locusts originate from barren regions that see only occasional transient rainfalls. While unforgiving conditions prevail, locusts eke out a living as solitary individuals with a strong aversion to mingling with other locusts. When the rains come, the amount and quality of vegetation expands and the locusts can breed in large numbers.

In deserts, however, the rains are not sustained and food soon becomes more and more sparse. Thus large numbers of locusts are funnelled into dwindling patches of remaining vegetation where they are forced into close contact with each other. This crowding triggers a dramatic and rapid change in the locusts' behaviour: they become very mobile and they actively seek the company of other locusts. This new behaviour keeps the crowd together while the insects acquire distinctly different colours and large muscles that equip them for prolonged flights in swarms.

As Steve Rogers from Cambridge ̽��ֱ�� emphasises: " ̽��ֱ��gregarious phase is a strategy born of desperation and driven by hunger, and swarming is a response to find pastures new."

Solitary and gregarious locusts are so different in looks and behaviour that they were thought to be separate species until 1921. But the realisation that crowding triggers swarming posed a new problem: how can the mere presence of other locusts have such a dramatic effect?

̽��ֱ��new research, which was funded by the Biotechnology and Biological Sciences Research Council, the Natural Sciences and Engineering Research Council of Canada and the Royal Society, solved this 90 year old question by identifying an increase in the chemical serotonin in specific parts of the locust's nervous system as launching the fundamental changes in behaviour that lead to the gregarious phase.

In the laboratory, solitary locusts can be turned into gregarious ones in just two hours simply by tickling their hind legs to simulate the jostling that locusts experience in a crowd. This period coincides with a threefold but transient (less than 24 hours) increase in the amount of serotonin in the thoracic region of the nervous system. Experiments were then designed to show that serotonin is indeed the causal link between the experience of being in a crowd and the change in behaviour.

First, locusts were injected with specific chemicals that block the action of serotonin on its receptors: when these locusts were exposed to the same gregarizing stimuli, they did not become gregarious. Second, chemicals that block the production of serotonin had the same effect. Third, when injected with serotonin or chemicals that mimic serotonin, locusts turned gregarious even in the absence of other locusts. Finally, chemicals that increased the natural synthesis of serotonin enhanced gregarization when locusts were exposed to the tickling stimuli. This indicates that it is the synthesis of serotonin that is driven by these specific stimuli and in turn changes the behaviour.

Dr Michael Anstey, an author of the paper from the ̽��ֱ�� of Oxford, said:

"Up until now, whilst we knew the stimuli that cause locusts' amazing 'Jekyll and Hyde'-style transformation, nobody had been able to identify the changes in the nervous system that turn antisocial locusts into monstrous swarms. ̽��ֱ��question of how locusts transform their behaviour in this way has puzzled scientists for almost 90 years, now we finally have the evidence to provide an answer."

Dr Swidbert Ott, from Cambridge ̽��ֱ��, one of the co-authors of the article, said: "Serotonin profoundly influences how we humans behave and interact, so to find that the same chemical in the brain is what causes a normally shy antisocial insect to gang up in huge groups is amazing."

Professor Malcolm Burrows, also from Cambridge ̽��ֱ��: "We hope that this greater understanding of the mechanisms causing such a big change in behaviour will help in the control of this pest, and more broadly help in understanding the widespread changes in behavioural traits of animals."

Professor Steve Simpson of Oxford and Sydney Universities said: "No other biological system is understood from nerve cells to populations in such detail or to such effect: locusts offer an exemplar of the how to span molecules to ecosystems - one of the greatest challenges in modern science."

Photo by Tom Fayle (Cambridge ̽��ֱ��) and provided by Science.

Scientists have uncovered the underlying biological reason why locusts form migrating swarms. Their findings, reported in today's edition of Science, could be used in the future to prevent the plagues which devastate crops (notably in developing countries), affecting the livelihood of one in ten people across the globe.

Up until now, whilst we knew the stimuli that cause locusts' amazing 'Jekyll and Hyde'-style transformation, nobody had been able to identify the changes in the nervous system that turn antisocial locusts into monstrous swarms.

Dr Michael Anstey

Leo-seta from Flickr

Grasshopper

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Yes

New hopes for the nervous system: multiple sclerosis

amb206 — Thu, 01 Jan 2009 00:00:00 +0000

Multiple sclerosis (MS) affects almost 100,000 people in the UK and several million worldwide, many of whom develop the illness between the ages of 20 and 40. Individuals at first experience episodes that transiently disturb functions that healthy people take for granted: seeing, walking, feeling, thinking and emptying the bladder. Later, the episodes are replaced by secondary progression and, as the disabilities mount up, the illness begins to threaten many aspects of daily living.

MS results when the body mounts an autoimmune attack on nerve fibres, particularly targeting the myelin sheath that envelops them and interfering with the passage of the nerve impulse through the spinal cord and brain. ̽��ֱ��prime orchestrator of this damage has been identified – a type of white blood cell known as the T cell – but exactly how tissue injury occurs, why there is a characteristic relapsing–remitting pattern followed by secondary progressive disease, and how to treat the illness effectively, have remained elusive.

Made in Cambridge

̽��ֱ��results of a recent study raise new hopes for patients with MS. A three-year, Phase 2 clinical trial with Alemtuzumab (also known as Campath), in which over 300 patients were treated, showed that not only was the advance of disease halted but, remarkably, many patients started to get better – perhaps due to brain repair. Professor Alastair Compston and Dr Alasdair Coles in the Department of Clinical Neurosciences found that the drug reduced the relapse rate by an additional 74% compared with the standard treatment, and the risk of accumulating fixed disability also fell by 71%.

These results provide a new installment in what has been a fascinating history for an antibody made in Cambridge in 1979 by Professor Herman Waldmann in the Department of Pathology. Campath was the first antibody to be ‘humanised’ – a technique pioneered by Dr Greg Winter at the Medical Research Council Laboratory of Molecular Biology that minimises the risk of the drug being rejected as foreign when given to patients. Because the drug destroys white blood cells, it has been principally used to treat adult leukaemia, a disease in which abnormal white blood cells build up and fatally ‘crowd out’ normal, healthy blood cells. This lymphocyte-destroying ability is now being exploited to destroy the perpetrators of havoc in MS.

Surprisingly, given that the drug is known to destroy white blood cells, infections were only slightly more common after treatment with Campath. Instead, the development of another autoimmune disease – usually affecting the thyroid gland – proved to be the major, and unexpected, complication.

All in the timing

Although Campath’s potential as a treatment for MS was first considered 18 years ago in Cambridge, early attempts to treat patients who had already reached the secondary progressive stage failed to improve their worsening disabilities. It seems that it’s all in the timing. ̽��ֱ��results of this latest study have shown that the drug must be given early, before the destruction of the myelin sheath has advanced to the point that secondary damage to the underlying nerves continues unabated. Not only does this strategy head off sustained accumulation of disability but it also allows some existing damage to get better, a factor not seen in any previous clinical trials. Expectations are high that the Phase 3 trials, now in progress, will lead to drug registration within a few years.

For more information, please contact the author Professor Alastair Compston (alastair.compston@medschl.cam.ac.uk) at the Department of Clinical Neurosciences. This research was published in New England Journal of Medicine(2008) 359, 1786–1801 and was funded by Genzyme and Bayer Schering Pharma AG.

Cambridge neurologists have shown that an antibody used to treat leukaemia also limits and repairs the damage in multiple sclerosis.

̽��ֱ��results of this latest study have shown that the drug must be given early, before the destruction of the myelin sheath has advanced to the point that secondary damage to the underlying nerves continues unabated.

Jon Heras, Equinox Graphics

Nerve cell

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Cambridge graduate wins Nobel Prize for Chemistry

bjb42 — Wed, 08 Oct 2008 00:00:00 +0000

Professor Roger Tsien, who completed his PhD at the university in 1978, has been awarded a share in the prize for increasing understanding of the bright green fluorescent protein GFP. He also extended the range of colours that scientists can use allowing them to watch numerous cellular processes at the same time.

He shares the prize with two other scientists, Osamu Shimomura and Martin Chalfie, for their work identifying and developing the fluorescent protein GFP. It was first found in the jellyfish Aequorea victoria in 1962.

GFP can be tagged onto proteins providing scientists a window into the cell. They can now watch the actions of thousands of proteins that regulate a diverse range of processes; from how we feel pain to controlling hunger and providing further insights to diseases such as cancer and Huntington's. Before this technology the actions of the thousands of proteins used by humans were invisible to scientists.

Roger Tsien took his Bachelor's degree at Harvard then came to Churchill College, Cambridge to study for a PhD in the Department of Physiology. He spent much of his time working in the Department of Chemistry where he was supervised by Professor Jeremy Sanders:

"Roger decided that it was important to know the concentration of calcium in cells, and he had a entirely novel idea about how to measure it," said Professor Sanders.

"His idea was to design a molecule that could get into cells and change colour when it contacted calcium ions. It was a brilliant conception, combining chemistry and biology. He made the compound in chemistry, then he went back to Physiology and proved his idea worked. Roger's original compound, and its descendants, have transformed our understanding of cell biology. He has continued his work in this area, and is an inspiration to everyone who reads his work or hears him speak."

After completing his PhD he was the Comyns Berkeley Unofficial Fellow at Gonville and Caius from 1977 to 1981, before moving back to the USA. Professor Tsien is now based at the ̽��ֱ�� of California San Diego.

̽��ֱ�� ̽��ֱ�� of Cambridge has more Nobel Prize winners, 83, than any other institution.

Announcing the prize the Nobel Foundation stated: "With the aid of GFP, researchers have developed ways to watch processes that were previously invisible, such as the development of nerve cells in the brain or how cancer cells spread."

̽��ֱ��Nobel Foundation awards the prizes each year for achievements in physics, chemistry, medicine, peace and literature.

A ̽��ֱ�� of Cambridge graduate is one of three winners of the 2008 Nobel Prize for Chemistry.

Roger's original compound, and its descendants, have transformed our understanding of cell biology.

Professor Jeremy Sanders

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Chemistry

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