Though innovation is generally a gradual, even painstaking process, it is most conveniently recorded in terms of apparently sudden leaps. One such landmark for neuroscience was the operation performed recently on a 25-year-old Swede whose left arm was paralyzed in a motorcycle accident. A surgical team at the Karolinska Hospital in Stockholm reimplanted two of the four nerve roots that had been torn from the man's spinal column and made medical history. The procedure was the first of its kind done on a human being.
Prominent amongst the players in this drama was hand surgeon Dr Thomas Carlstedt, who headed the Karolinska team. Carlstedt implanted the first of the dislodged nine roots, keeping it in place with biological glue until axons could shoot through the spinal lesions and re-enervate the muscles. The second and third nerve roots were too damaged for implantation. Finding that the fourth nerve root was salvageable but too short, he removed a nerve from the leg, cut it into strands to make a cable, spliced this on to the original nerve, and attached it to the spinal cord. Nine months after the operation, the first signs of re-enervation appeared in the patient's shoulder. Six months later, the man could bend his elbow slightly. Today, his hand remains paralyzed, but he has been able to return to his work as a car mechanic.
Important as Carlstedt is in this success story, his role is actually part of a vast and rambling plot, peopled by an international cast of researchers and clinicians working on their own, overlapping themes. Paving the way for the operation on the car mechanic were successful procedures of the same kind on animals, and before them, years of essential research into axonal regrowth, cell signaling, and so on.
The Karolinska hospital team was in a particularly good position to draw on this accumulated wisdom because of its close relationship with the prestigious Karolinska research institute (Kl), also in Stockholm. The association between the two is not simply an accident of proximity. 'There's an understanding here that research questions have to be approached from both sides,' says Walter Frontera, a guest researcher at the institute. 'I've noticed a great capacity and desire to exchange views and ideas about what's happening at the basic level, and to understand its importance to the clinical world.'
To fund their work, scientists at the institute often must be able to describe possible clinical implications. 'I think we're pretty good at that,' says Lars Olson, a professor in the institute's Unit of Development, Growth Factors, and Transplantation. Sten Grillner, Chairman of the Department of Neuroscience, agrees. 'Large parts of our biomedical research are of relevance to health care and various illnesses,' he says. 'That's why we're always trying to improve our cooperation with relevant clinical institutions.'
The Royal Karolinska Medico-Surgical Institute, founded in 1810, is Sweden's largest center for medical research and is responsible for all state medical-care training in the Stockholm region. It has a vast international research network, which has developed partly through its annual task of awarding the Nobel Prize in Physiology or Medicine - a responsibility it shouldered reluctantly at the turn of the century but which has since proved useful in cultivating international contacts, attracting prominent guest researchers, and obtaining international funding. The institute's hall of fame includes Ragnar Granit, who received the 1967 Nobel Prize for discovering specific color sensitivity in the sensory elements of the retina, and Ulf von Euler, who received the prize in 1970 for identifying noradrenaline, the active agent in the sympathetic nervous system.
The Department of Neuroscience was created in as part of wide-ranging organizational change at
the institute. Eight research units were set up, with scientists from the former departments of anatomy, histology, neurobiology, and neurophysiology. 'Neuroscience is so broad, you really need to understand the nervous system at the molecular, the cellular, the physiological, and the behavioral level,' Grillner says. 'And you must bridge all those levels in order to understand the functioning or malfunctioning of the nervous system.' Department researchers can measure the energy spent on a thought and tell you where it stirs the brain. They can draw conclusions about chronic pain from the whiskers of a rat. They study the eel-like lamprey to learn about the neural networks that guide our motor skills.
The department's research has applications in fields as diverse as computer science, teaching, psychology, and robotics. It has contributed to the development of such technologies as the confocal microscopes now being produced in Silicon Valley, the United States. Ericsson, the Swedish communications company, supports the department's research, with the expectation of new possibilities in computer networks capable of learning through experience. The department pays special attention to the processes that control the growth of nerve cells, and their regeneration and degeneration during Parkinson's disease, Alzheimer's disease. and after spinal injuries.
Tomas Hökfelt, head of the Unit for Chemical Neurotransmission, is best known for his groundbreaking work on peptides. His group debunked the belief that brain cells use only one transmitter, showing that brain cells often use, for example, one monoamine along with one or two peptides as CO-transmitters. With the salivary gland as a model, Hökfelt's group showed that peptides are often released when nerve cells are highly active. This suggested that peptides enhance information transfer during nerve damage, stress, and other emergency situations when cells are pressured. If correct, the hypothesis could clear the way for peptide pharmaceuticals. 'You won't find neuropeptides at the clinics,' Hökfelt says. 'It takes time to find a good peptide antagonist without side effects. One problem is to know when and where to use peptides. We're seeking indications in animal experiments to determine what systems to attack, but we have no definite answers so far.'
Hökfelt attributes his achievement to the good fortune of collaborating with the legendary peptide researcher Victor Mutt at the institute's Department of Biochemistry. In 1983, Mutt discovered the peptide galanin, which has since been of special interest to the Unit for Chemical Neurotransmission. In rats, galanin coexists with acetylcholine in the same neuronal group that degenerates in Alzheimer's disease. That, along with its proven role in memory, makes galanin a promising substance for research: inhibiting the peptide could help slow down the loss of learning capacity in Alzheimer's disease patients. 'There are some data that suggest galanin can influence learning,' Hökfelt says cautiously, 'but the problem with peptides is that they're active in several systems that converge in the brain.
If you inject the peptides, it's not clear what systems you're affecting. If you activate several systems, they can inhibit one another. We still know too little about the specificity of galanin.'
Hökfelt and other KI neuroscientists working with demyelinating diseases such as Alzheimer's and Parkinson's benefit greatly from the extensive collaboration with colleagues at clinics associated with the institute. 'We couldn't have accomplished half of our work without it,' Grillner says. Whereas most departments for basic research are situated on the KI campus, the clinical departments are located in seven hospitals. Two of these - Karolinska Hospital and Huddinge Hospital - are regional hospitals, with more than 1,OOO beds, which also serve as teaching hospitals for KI researchers. Huddinge Hospital, 5 minutes south of the campus, is especially strong with regard to Alzheimer's disease.
In 1974, Bengt Winblad, the current director of Huddinge's Department of Clinical Neuroscience and Family Medicine, co-wrote a report describing for the first time the reduction of neurotransmitters in the brains of deceased Alzheimer's patients. He now also heads the Center for Alzheimer Research, which is studying more than zoo families with inherited Alzheimer's disease. 'If we understand the generic factors,' says Lars Lannfelt, assistant professor in neurogenetics at Huddinge Hospital, 'it's easier to understand the environmental factors.' One of the prime clues is the peptide beta amyloid - a part of the amyloid precursor protein APP - which is always found in the brains of those suffering from Alzheimer's disease.
The Center for Alzheimer Research, like many other research centers worldwide, has sought the gene that produces the peptide. In 1991, the British researcher John Hardy found a point mutation in the APP gene. Soon afterwards, Lannfelt's group found yet another mutation of the same gene in a large Swedish family. 'If you understand what kind of protein the gene is producing,' says Lars Edström, head of Clinical Neuroscience at Karolinska Hospital, 'you can start to understand the process that will eventually lead to the degeneration of nine cells. When you know that much, there's a reasonable chance of identifying potential victims and finding remedies.' The identification of the APP mutation led to a recent discovery at Huddinge Hospital that young, healthy individuals from families with heritable Alzheimer's have as much amyloid in their blood as their relatives struck with the disease. 'That means the amyloid is present long before the symptoms appear,' says one of Lannfelt's researchers. The discovery could help clinicians make early diagnoses and perhaps develop a drug to block amyloid production in an effort to slow down progress of the disease.
Although Huddinge is Sweden's foremost hospital for Alzheimer's research, KI neuroscientists collaborate more extensively with Karolinska Hospital, partly because it is only a short walk from the KI campus. Founded in 1940, Karolinska Hospital is also an older institution, with a longer tradition and record of neuroscientific discoveries. The neuroradiology section of the Department of Clinical Neuroscience has done pioneering work in the imaging of the central nervous system. Crucial parts of the positron electron topography (PET) camera were developed here in the late I970S, enabling scientists to study cerebral blood flow and metabolism. PET has been especially valuable to the internationally renowned psychiatrists at KI involved in the study of schizophrenia and psychoses. They use the PET research center to examine receptors in live human brains and to measure the effects of psychopharmaceuticals.
Karolinska Hospital is the only hospital in the world performing operations on epileptic patients using a combination of the magneto-encephalograph (MEG) and the gamma knife. The 20-ton gamma knife, created by the neurosurgeon Lars Leksell in the I960S, is more commonly used to destroy deep-seated vascular malformations and brain tumors once considered inoperable. The neurosurgery group at Karolinska Hospital, which performs 3,000 gamma lesions annually, has cooperated for years with Lars Olson at the KI Unit of Development, Growth Factors, and Transplantation to understand Parkinson's disease. In the I970S, Olson discovered that cells from the adrenal medulla can be converted to neurons. His research team, together with colleagues in the United States, demonstrated that fetal tissue could counteract symptoms of Parkinsonism in rats.
In 1982, with a group of Karolinska Hospital neurosurgeons, Olson carried out the first graft of adrenal tissue to a human brain affected by Parkinson's. 'That was a long time ago,' Olsson says, 'but it takes a long time for basic discoveries to be transferred to clinical uses - if they ever are. But, more important than these various firsts are the results you can achieve. In the long run, I think grafting in the central nervous system will have limited applications, if any, and that treatment with atrophic factors will be more important.' Orson has studied atrophic factors since the early 1960s, and helped discover neurotrophin 3. Every neuron needs one combination of atrophic factors to develop, another combination to stay alive, and perhaps a third combination to be rescued after various forms of stress, injury, or disease.
Neuroscientists spent years searching for atrophic factors that act on the dopamine-producing brain cells which degenerate in Parkinson's. When a clone finally was developed in 1993, Olson quickly obtained the Glial Cell Line-Derived Neurotrophic Factor (G DN F). 'Now we're asking whether Parkinsonian patients have something wrong with either their GDNF production or receptors,' he says. 'Maybe GDNF mediated mechanisms are involved in the etiology of this disease. we, and others, have shown that, in different models of Parkinson's disease in mice, rats and monkeys, you can counteract the symptoms very efficiently with GDNF treatment. I hope that, after another round of animal experiments - within a year, perhaps - we'll be able to try it on human patients.'
Researchers who, like Olson, hold a medical degree, are common at the institute and a key to its success. Former KI president Bengt Samuelsson, who won the Nobel Prize for his work on prostaglandin's in 1982, often said that his dual MD/PhD degrees helped him understand the basic science of prostaglandin's as well as their clinical relevance. Staffan Cullheim, a KI associate professor at the Unit for Neural Regeneration and Autonomous Functions, says: 'Our success is a consequence of the fact that so many students doing their PhD theses here are medical students. That provides a background that makes our brains work in the clinical direction.' The crossover works both ways, with basic researchers sometimes going into clinical research laboratories. All six doctors working at the PET research center at Karolinska Hospital, for example, are former neuroscientists.
Thomas Olsson recently left his post at Huddinge Hospital to head KI's Department of Molecular Medicine, running a laboratory devoted to neuroimmunological diseases. A neurologist by raining, Olsson also works part-time at the Karolinska Hospital. 'Traditionally,' he says, 'you have clinicians working only in the clinics, basic researchers working only in their labs, and a big barrier in between. With our set up, it's easier to get a rapid exchange and application of ideas from basic research to clinics.' Olsson, who studies multiple sclerosis, is an authority on cytokines, mediators from the lymphoid cells engaged in promoting or downregulating inflammation. 'We've been successful in defining a number of cytokines that either promote or downregulate disease in experimental models,' he says. 'Those are key findings. Now we've got data in human patients that show the same thing. We've seen that patients with severe disease tend to have very much of the disease promoting cytokines and too little of the immunodownregulatory cytokines. We think that's important to take into account when testing new therapies.'
Such detailed knowledge of inflammatory responses presents a number of targets that can be attacked with immunotherapy or even simpler drugs. Yet Olsson is cautious about dramatic advances. 'Multiple sclerosis has been considered an enigmatic disease with causes that are totally unclear,' he says. 'That's wrong. There's no riddle that will suddenly be solved. It's a continuous development. We'll understand more and more about the disease, and find more and more applicable treatments. In three or four years, we could have a new regimen that dampens the disease to 50%, then 75%, and in 15 years we hope we'll be down to zero.'
Olsson's detailed understanding of cytokines has been of much help to Cullheim at the Unit for Neural Regeneration and Autonomous Functions. And it was Cullheim's basic research in axonal regrowth that helped rehabilitate the arm of that accident victim operated on by Thomas Carlstedt. More than 10 years ago, Cullheim developed an intracellular staining technique which revealed the complex dendritic urges of motorneurones. With his colleague Mårten Risling, he gained a sufficient understanding of severed axons from spinal motorneurones to help restore some strength to patients. Yet Cullheim, whose work is funded largely by the International Spine Research Trust, is still puzzled as to why injured motoneurones regrow. After observing that glia cells change after injury and come to resemble the Schwann cells of the peripheral nervous system, Cullheim wonders if those changes are caused by substances carried by the blood. Macrophages, for example, are known to release cytokines into spinal scar tissue.
Cullheim is now trying to learn which, if any, cytokines activate the glia cells that stimulate the injured neurons. The research is at an early stage. 'We're still mapping the presence or absence of the various cytokines,' he says. 'We're not yet asking specific questions. But, since cytokines have been involved in so many other circumstances involving lesions in the nervous system, we're eager to detect patterns and deduce interrelationships and possible regulatory mechanisms.' As for the car mechanic and others who suffer from plexus injuries, Cullheim hesitates when asked to predict the clinical relevance of cytokines. 'Of course the reason we're looking at this is that we hope to find something of relevance to future patients, but we till can't tell in what way,' he says. 'We have a lot more basic science to do.'
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