with Geoff Watts 

Geoff Watts: This week in Leading Edge,genetics for historians,maths for biologists,and new cells for old. 
(Sound of miniature circular saw) 

Doctor : Okay that's the noisy bit over.Forceps please. 
Newsreader : For the first time in Britain,two patients suffering from Parkinson's disease have been given a new treatment,which involves receiving transplanted brain cells. 
Doctor : So all we have to do now is put the material in,okay? 

Geoff Watts: Transplant surgery for Parkinson's disease is now 10 years old.A report on the current state of brain repair,later in the programme. 
[Genetic Heritage segment omitted] 

Geoff Watts: Now have you ever wondered why a moving millipede doesn't trip over it's own legs? Unlikely I guess,but if you have,you'll most likely have asked a biologist.Well Ian Stewart [Ref: Red File: Inourtmu.wri;I.Stewart "Nature's Numbers";"Does God Play Dice?;Video: BB14:RI Lecture] is a mathematician,but that hasn't stopped him writing to the magazine "Nature" to put forward some ideas not just on millipedes but on animal movement in general.It's an illustration of how maths can offer new an sometimes surprising insights into all sorts of features about the world around us.First though to animals.All of them whether blessed with two,four,six,eight or scores of legs,have to move them at the right moment, and in the right direction.Groups of cells in the animal's nervous system,must be controlling this pattern of coordinated movement.In fact,these groupings have even got a name,the central pattern generator.The only problem is that biologists can't find them,this makes them rather hard to study,so what to do? Enter the mathematician,Ian Stewart. 

Ian Stewart : We use mathematics.We look for the patterns,we look at the patterns in the movements of the legs and sort of try and work backwards from those to the structure that ought to produce those patterns.The important thing in the legs is there are very regular patterns in the timing of the foot falls.For example in a walk,an animal will walk left rear,left front,right rear,right front over and over again,it's a completely regular pattern.An animal that's trotting,diagonal pairs will alternate,and you have a list of eight or ten of these patterns,and so mathematically you can look at this list,work out what the patterns are in some very stripped down abstract form and then say,"What kind of structure could produce that range of patterns and only that range of patterns?",and our assumption,which is based to some extent on the actual structure of the patterns is that Nature makes some unit,some circuit out of nerve cells,and then it makes copies of that unit,which is very easy to do,and so the question is,"How many copies and how are they linked up? " [As a mathematician you ought to be able to see that's two questions,not one! -LB],and this is what we work out mathematically,and in fact we found to our surprise that with four legged animals you need eight copies of the unit to make everything work properly. 

Geoff Watts: Why is that? 

Ian Stewart : It doesn't work with four.The problem with too few units is that certain gaits,certain patterns of movement that ought to be different from each other,particularly the trot and the bound and the pace,the one's where legs move in pairs,two legs then the other two legs,but different groups of two,mathematically those are too closely related to each other with only four units to produce them.But if we allow ourselves eight units,we have a hidden set of four extra ones where lots of differences subtly and cryptically can come into play,and so we were forced into this structure,we didn't want it,we started out thinking it's got to be four units,because you've got four legs.Roughly it's two units per leg.You can think of that perhaps as one to push and one to pull. 

Geoff Watts: It's possible I suppose then that if you could observe certain forms of movement that would upset your theory,because they didn't fit in with this notion of the number of central pattern generators.What sort of movement? 

Ian Stewart : Oh that's good.....for example,suppose four legged animals had a central pattern generator with just four units,then one of the predictions from that is that if the animal can walk and trot then it will also pace.The pace is where the left legs move then the right legs move,this is like a giraffe does or a camel.Now horses trot,but very few horses pace,camels pace but don't trot,but if it was four units,the theory would say that if it can do one of them,it should be able to do the other one as well,and it's just not the case. 
[Maybe it can but just doesn't bother as it prefers the other method which it uses.We theoretically could use both hands for writing,but we use a preferred one,even though we could be ambidextrous-LB] 
So we rule out four units on those grounds.With twelve units their would be two many patterns for a four legged animal.There would be some very funny patterns where it will perhaps move the back legs then the front legs,then pause for a beat,back legs,front legs,nothing happens for a beat (Geoff laughs), and that's not observed,so we rule out twelve,and eight is kind of sandwiched in between,as the only one that works. 

Geoff Watts: I think..it will probably strike many people,listening to this,that to start of with maths and go to a theory about biology is a fairly strange way of proceeding.I mean it seems almost as if you're producing something which is,you know,works very nicely on paper.Do you ever have any doubts in your own head about this kind of approach? 

Ian Stewart : I think all mathematicians are gratified when they do this kind of calculation or prediction and then you go and look at the real world and it does what you think it ought to do. 

Geoff Watts: But this is quite a mild example by comparison with starting with maths and then talking about the physical world.I'm thinking for example that if you start with maths,and you can start assuring people that aren't just the three dimensions that we're aware of but there are four and five and six,and goodness knows how many,now this may be mathematically very satisfying,but it's jolly difficult to believe what mathematicians tell you because you just have no sense of the reality of this. 

Ian Stewart : Perhaps the extreme case at the moment,is in particle physics where we're being told that the universe has,let's say 11 dimensions,7 of which are all curled up,and 4 of which you see as space and time,and no one's quite sure whether this is true,and we'll have to wait until the physicists do the experiments to find out.But the maths of this stuff says "if the way the physicists are currently thinking is remotely like the truth,then this bizarre story of 7 curled up dimensions,in a sense 7 quantities which are very,very tiny and you can't normally measure,must in fact be what's going on".What maths does is it let's you draw necessary conclusions.It let's you say,"If certain things are true,and we're pretty sure of those,then gosh well what a surprise,certain other things follow",and the things that follow may not be at all obvious,and this is the job of the maths,it's to draw these conclusions. 

Geoff Watts: You'll not be surprised when people are prepared to go with you when you're commenting on the way that an animal might move,and perhaps less keen to follow you when it comes to saying that there are 11 dimensions! (chuckles) 

Ian Stewart : Yes! When I can go and watch a dog walking along the street,you think "oh look what the dog's doing,it's exactly what we say", I feel pretty confident.But I can't pick up an atom and look at it and spot it's 7 extra dimensions. 
[That's not reason to say that they aren't there,since the conclusions drawn are based on things which are observable -LB] 
So this is definitely a more abstract and something I'm not as confident about. 

Geoff Watts: Well,it's nice to know that even mathematicians have their moments of doubt [Why is there something more certain about what a mathematician says? -LB].That was Ian Stewart,Professor of maths at the University of Warwick. 
Well,Roger Highfield has been listening to that as well.Roger,maths and animal movement first,any profound thoughts on that? 

Roger Highfield : Well I had a gossip with one of Ian Stewart's colleagues,Dr Bwono (??) about this and in fact he pointed out that all this work emerges from something called the Curie Principle,and that's actually named after Pierre Curie,the husband of the legendary Marie Curie,and it did strike me at the time,this is rather sad and ironic,because poor old Pierre Curie was trampled to death by a horse in 1906.I'm not sure what he would have thought if he knew that it was a quadruped that now thanks to this work had 8 nominally identical sub-circuits,arranged in an essentially unique manner according to this nature paper (Geoff chuckles),but there we go.It's a sort of rather bizarre connection between a rather sad event in 1906 and this fascinating paper. 

Geoff Watts: Yes,yes, a nice symmetry there,it might not have mad much difference to him! (Roger laughs).More troublesome is the point that I was raising there at the end with Ian Stewart.This question of maths and the real world,I mean I really do have trouble with the extent to which maths sometimes seems to live in sphere apart from everything else.Do you....does that trouble you as well? 

Roger Highfield : Oh it does,I think it's an absolutely fascinating question.I mean I tend to think of physicists as sort of grazing round this mathematical supermarket,just pulling mathematical ideas off the shelves and you know,using them and hoping that they work to explain the real world.But when you look into maths,you realise that there's some very spooky things out there. 
For instance the work of Alan Turing [Ref: [Maths 2] Turing;[Maths 2] Bletch;Video:N45:Station X;N27: Breaking the Code;BC1: Horizon;M3:Granada Reports] suggested to us there might be processes in the natural world whose complexity is beyond the simulation capabilities of one of his universal computers (see R.Penrose),you know this mathematical abstraction of a computer. 
There's the work of Greg Chaitin at IBM that shows that even the simplest mathematics can contain randomness [[Science 1]Front 4] and there are classes of mathematical problems that can only be solved by someone with a eternity of free time.So when you say to yourself ,"Why does maths work?" [Ref: PAM p526 EP.Wigner "The Unreasonable effectiveness of maths...."],we really don't know,and that is spooky [You might not but I do,and it's not spooky -LB],because it seems to suggest to me that the greatest engine of cultural change,the scientific revolution and world view,rests on a mathematical foundation tat in many respects you can regard as religious,it's an act of faith that it works [Arrrrgghhh,no there is no faith in the precepts,they can be tested -LB]. 

Geoff Watts: I think at which point we'd better get back to things that are more tangible,biology! (Roger laughs) 

Many bits of the body which have stopped working for whatever reason can,to some extent,be repaired, I mean it's why we have doctors! So far though,their efforts at brain repair have been less than impressive,but if the hopes of the people at a meeting,held this week in London are anything to go by,that could soon begin to change.Organised by the Novatis Foundation,the meeting brought together doctors and scientists with an interest in neural transplantation.In essence grafting fresh nerve cells into the brains of people who've suffered disease or damage to their nervous system. The disorders they're targeting range from Alzheimer's to strokes.The replacement cells can be taken from other parts of the body,other humans or even from animals.This is a branch of biomedicine littered with scientific and ethical booby traps,in which even the experts aren't always certain what separates science fact from science fiction.Doctor Geoff Razeman for example is trying to find a way of repairing breaks in the chains of cells which go to make up the central nervous system.Damage of this kind leaves victims partially or wholly paralysed,even though the nerves themselves are doing their best. 

Geoff Razeman : It's a fact that when nerve fibres are damaged,they always attempt to grow,so they have the innate ability or in fact potential for trying to grow.What we can hope to do is make the pathways available to them,so they can reach their correct destinations. 

Geoff Watts: And what from does it take...what do you actually do to encourage this process? 

Geoff Razeman : Well,it's what we might do in the future,we don't have a repair at the moment.But we know their is only one part of the nervous system where nerve fibres continually grow throughout life, and those are the nerve fibres connected with the sense of smell.So if we could transfer something from that system to other parts of the brain and spinal chord and the limb nerves,we may be able to convey the ability to repair,to those other part.So we're talking about getting something from the nerves in the nose,and transferring it to nerves,for example,in the spinal chord. 

Geoff Watts: Erm...when you say "you put them where the damage is",I mean....you literally grow up a collection of these cells,and how do you actually introduce them where they're required? 

Geoff Razeman : The methods we're thinking of are putting them onto some kind of membrane,which can then be used to form a repair,a physical repair. 

Geoff Watts: And you actually place this membrane into the area of damage? 

Geoff Razeman : You would use it as a "bridge" to connect two damaged areas.So to make...to restore a pathway,in the same way as if there was....if part of a motorway had collapsed,you might place a bridge across it,so that the cars travelling up the motorway could go onto the bridge and re-enter the motorway on the other side. 

Geoff Watts: Dr Geoff Razeman of the National Institute for Medical Research in North London.As we heard at the beginning,Parkinson's Disease in which certain cells die off and stop making an essential chemical messenger called "Dopamine" has long been the favourite for attempts at brain repair.Doctors can replace these cells with fresh tissue taken from human foetuses.Some 250 patients have now been treated in this way.Neurologist Professor Olay Lindval (???) from Sweden has used the procedure himself and is well pleased with the results. 

Olay Lindval : We can,beyond doubt,have survival of the grafted neurons,they survive,they grow,they form these specialised contacts with the patients brain and they also release this single molecule Dopamine,which is missing,and they are probably under some kind of influence from the host brain.In the most successful case,patients have been able to withdraw medication completely.We have had three patients who have been able to do that,and two of those patients have been without L-Dopa which is the standard treatment for three and a half and for and a half years,respectively.So in the best cases you can have dramatic improvements.I would say that with the current procedure,you have improvement of value,of therapeutic value in about 2/3 of the patients.On the other hand,I think one should also be aware that with the need for foetal tissue in every....in each Parkinson patient today,and in order to have a major improvement,we need tissue from several donors,human embryonic donors,that will never be a treatment for a large number of patients.It's very important scientifically to develop this strategy,to prepare the ground for the use of other cells like precursor cells,stem cells,maybe xeno grafts. 

Geoff Watts: Animal cells, in other words.That was Professor Olay Lindval .Although it's the surgeons who implant the new cells,it's the brain and the cells themselves that do the really clever work,says Dr Helen Hodges of the Institute of Psychiatry. 

Helen Hodges : The brain is telling the cells where to go,and the brain is also,if you're using,for instance,very early cells called stem cells,the brain is telling those cells what to become to fit in with the cells that have been lost. 

Geoff Watts: So there's a sense in which the system is repairing itself in a way that you couldn't possibly do? 

Helen Hodges : That's right, it's making use of the tissues that we give it and integrating it into the whole structure. 

Geoff Watts: As Helen Hodges said,she uses what are called stem cells,ideal for this kind of work because they have the potential to give rise to mature cells of any type.Her cells have also been cunningly engineered to incorporate a new gene,this allows them to grow and proliferate indefinitely in the cool conditions of the laboratory,to become immortal in other words,but stops them dividing at the warmer temperature they'll experience inside the brain.So Doctor Hodges cultivates as many cells as are needed,what then? 

Helen Hodges : We then inject them into the brain and there,they will actually stop dividing and the signals from the brain you're putting then into,they will turn into mature type cells depending on what instructions they're given. 

Geoff Watts: Why do you want them to not go on dividing when they are in the brain? 

Helen Hodges : Because then they would form tumours,wouldn't they? And that would be highly dangerous. 

Geoff Watts: And so what stage as this work got to? 

Helen Hodges : Well this work has got to quite considerable proof of their effectiveness of these cells in animal models..... 

Geoff Watts: You know they go where they're wanted? 

Helen Hodges : We know that they go where they're wanted,they're very migratory.We know that in the brain they can turn into different types of cell.We know that they can repair several different types of brain damage,including damage in stroke,where there's quite a big volume of brain loss,and the way they integrate in the brains of old rats which haven't had obvious damage,is absolutely marvellous,they simply align themselves around existing structures in a very natural looking way. 

Geoff Watts: And these old rats are healthy old rats,it's just that they're suffering from old age and some of their capacities have been lost? 

Helen Hodges : That's right,yes they can move around they're quite healthy,but some of them find difficulty in learning. 

Geoff Watts: And they get a new lease of life,from having these extra cells? 

Helen Hodges : Just like us yes. 

Geoff Watts: So it does seem to be quite effective in animals,can you see any reason in principle why it wouldn't also work in humans? 

Helen Hodges : There's the initial difficulty in humans of getting the cells what's called "immortalised", so that they do switch off their expansion.Because you have to have human foetal cells,and you have to play around with them a bit.But once that critical step is taken,really I don't see why not. 

Geoffrey Gray :The signs are increasingly that one can do things with tissue transplanted into the brain,which 5 years ago,10 years ago we would have believed to be impossible. 

Geoff Watts: That was Professor Geoffrey Gray,a colleague of Helen Hodges at The Institute of Psychiatry,although optimistic about these treatments,he does emphasise caution. 

Geoffrey Gray : There are millions of people out there who are suffering from intractable and very distressing diseases and we know that whenever a programme of this nature is broadcast,many of those people will immediately and quite understandably be saying,"There's something there for me now,tomorrow".It's unlikely to be there tomorrow.It probably is going to be there in 5 or 10 years time,possibly even 2 or 3 years time,and in principle any damage to the brain is probably capable of being approached by the methods of neural transplantation that we're talking about this week. 

Geoff Watts: Professor Geoffrey Gray finishing that brisk chop through some of the prospects opened up by the development of neural transplantation.Roger,that meeting at the Novatis Foundation has only just finished,but I gather you've got news of an even more recent development in this field? 

Roger Highfield : Yes,that's right in tomorrows issue of "Science" where Elizabeth Gould and Charles Gross of Princeton University report that contrary to popular belief,adult brains do actually generate new brain cells in the most complex regions.Now the regions they're talking about ,the cerebral cortex,which is responsible for highest level decision making,recognising and learning about the world,and it's an interesting result because it shows that unlike the discussion that we've just heard,where we're talking about transplanting things into the brain,we might by the use of growth factors,exploit natural repair mechanisms to treat brain injuries.But I must echo some of the sentiments there,that,you know,the brain is the most complex known object in the universe,it's not going to be easy,and I think routine brain repair,even though we've had some encouraging results for Parkinson's disease,are still probably a matter of decades away,rather than years away. 

Geoff Watts: Sounds as if the brain is making an effort to repair itself but not very successful,and the hope is really that we could give this process a boost and make it work more effectively. 

Roger Highfield : Absolutely,and in fact you know this dogma goes back,you know,I mean everyone will quote you,how if you drink too much or bang your head you lose your brain cells and that's it, you've had it,and then they found in studies of canaries and birds and other things.There was some neural regeneration,then in some of the lower centres of the human and primate brain they found that,and now of course,we're finding that it seems to be taking place in higher centres,not at a big rate,but if it's happening it makes you think "gosh,if we can harness those natural mechanisms,then rather than,particularly harvesting foetal tissue,we could,just by injecting some special growth factors into the right bit of the brain,stimulate the growth of the appropriate family of nerve cells that you need ". 

Geoff Watts: Roger thanks.Roger Highfield from "The Telegraph".That's all from Leading Edge this week.Next week wandering poles,when South becomes North.