The Material World
with Quentin Cooper 

Quentin Cooper : There's no stemming the tide of stem cell applications. Harvests of organs for transplant,repairing nerve damage,new treatments for diseases such as Parkinson's and Multiple Sclerosis.All are on the cards if we can just figure out a few basics about stem cells and how they behave. In recent months two separate teams have managed to isolate all important "pluripotent" stem cells which have the potential to form virtually every type of cell in the human body,but we still know little about what it is that triggers stem cells to develop into particular tissues and organs.It's here that a great deal of work is going on at the moment,because if we can comprehend and manipulate the process,then we can,potentially produce tissues and organs to order,and begin to intervene against a range of degenerative conditions. Well to look at how far we've come in our understanding of stem cells,and how far we've got to go,I'm joined by two Professors of Biology at University College,London,Lois Wolpert,who's there Professor of Biology as applied to Medicine,and Bill Richardson,Professor at the University's Wolsten Institute of Biomedical Research. Bill Richardson,stem cells regularly spread into the press,we've touched on them several times on our programmes,there cells from which other cell's stem essentially? 

Bill Richardson : Well the ultimate stem cell is the fertilised egg,because that can give rise to an entire organism after fertilisation,but as the cells divide during early embryogenesis,they gradually lose their potential to give rise to different types of cells,and they change from being what we would call a "totipotent" or fully potent stem cell to a "pluripotent" or very potent,but not quite.... 
[This is the loss of plasticity that makes cells "commit" to making organs.This is not evidence of a step backwards from the capacity to regenerate,but evidence of the necessity of cells to have to commit to making specialised tissue. Regenerative power in worms is because they are more like a fertilised egg and less specialised in terms of requiring special tissues,or that they retain the latent power of stems cells. Why we are like/not like worms is explained by the rest of the programme -LB] 

Quentin Cooper : So totipotent can make anything,pluripotent can make most things. 

Bill Richardson : ....can make most things yeah...and then as they go on during development, they become even more restricted,and you would get cells that could only give rise to cells in the nervous system for example,or only cells in the blood system,and they would be pluripotent stem cells. 

Quentin Cooper : Lois Wolpert,do you just get these cells in the early stages of development or do you get them in adults as well? 
[Recent information suggests that teenagers go through a second stage of plasticity and "pruning back" of brain cells in order to accommodate social rules at the point of becoming adult,and possibly the mood swings associated with being a youth are due to this second wave of brain development and not hormone changes (or perhaps the brain changes are induced by the hormone changes) -LB] 

Lois Wolpert : No! You've got them in your blood system now.Your blood cells,your red blood cells are replaced,I can't remember - about every 30 days or so,and you've got a stem cell and I think a key feature of stem cell is a cell that both renews itself and can give rise to these...you know is pluripotent,and your blood is replaced,there are stem cells in your bone marrow,and when people do bone marrow transplantation,the real important bit is the stem cell. 

Quentin Cooper : Right,they're not just replacing a few cells,they're giving them the legacy of cells that will be replaced and replaced and replaced? 

Lois Wolpert : The key thing is to put in stem cells,sure. 

Quentin Cooper : So given... I mean so given that these stem cells each have the potential to become a lot of different cells and in some cases all different cells,is the mystery how different ones become different cells? What the decision making process is? 

Lois Wolpert : I think that would be fair to say we know some of the signals,but on the whole not.You can isolate from the early embryo,including the early human embryo,stem cells which you can grow in culture,and they become immortal,you know ,you can keep them in a culture dish and they'll divide and divide and divide,if you put them back into the right condition,if you put them back,let's say in a mouse embryo,you put them back into the early mouse embryo,they are almost totipotent and they can give rise to any tissue in the body.Now the question...the real point is you can also manipulate them in culture,and there is some success about manipulating them in culture,even human ones,so that you can get muscle,which could in principle...and heart muscle,which could be used for example with people with cardiac problems,that can give rise to ordinary muscle,that can give rise to neurones.There are great possibilities.On the whole,the way people are doing this are just putting on different factors, so-called "growth factors"-proteins,which can stimulate them to differentiate into different sorts of areas.But as far as neurones are concerned that's Bill's area. 

Quentin Cooper : Bill! Lois is pointing at you (Lois laughs) here,but yes this is your....you are particularly intercepted in how the brain and spinal chord develop? 

Bill Richardson : That's correct,yeah,and to get back to how cells know how to change into different types of cells during development,initially all cells in the nervous system for example are pretty similar,and would have the potential to give rise to probably all of the different kinds of neurones and glial cells in the central nervous system. 
[So there is a process of "differentiation" where cells undergo the metamorphosis into those specialised cells that make organs. There are mathematical models of this type of thing using cellular automata (see http:members.xoom.com/Templarser/algo.html and an excellent programme that demonstrates the principles is at http://www.mirwoj.opus.chelm.pl/ or http://psoup.math.wisc.edu/mcell/ contact Mirek at e-mail: mirwoj@homemail.com -LB] 
But they don't,because that would give you a complete mess,a brain that wouldn't work.You have to give rise to the appropriate types of cells in the appropriate places. 
[So in order to have the type of complexity we have,we have had to have specialised cells.These cells would not do their job if they were too "generic".Lack of regenerative power is not a sign of lack of evolution.On the contrary,our specialised cells indicate our particular developments with respect to worms that hold the latent power of regeneration.I don't know if it's the case,but possibly worms have cells that are more like stem cells,and thus possibly if the latent regenerative power is primordial it is indicative of how close worms are to early creatures and how developed we are -LB] 
And so how do cells know what to become? They know what to become because of were they are in the developing nervous system.
[Mathematical models such as "Conway's Life" show how a cell's action depends on where it is -LB] 
And the same thing goes for the embryo as a whole. Quentin Cooper : How do they know here they are? I mean that would be the next question that seems to come to mind. 

Bill Richardson : Exactly,and they know where they are in relation to certain signalling centres,and we're talking here...the signals are chemicals which are secreted from specialised groups of cells and diffused through the embryo and it's like the kitchen of the embryo,because the cells know here they are in relation to the kitchen according to how strong the smell is! (Quentin laughs) If you see what I mean. 

Lois Wolpert : (laughs) That's nice,I like that! 

Bill Richardson : So they don't have noses,but they have receptors on their cell surfaces which can bind particular signalling molecules and send signals inside the cell,ultimately ending up at the cell nucleus,and activating different kinds of genes.Genes for neurones or genes for glial cells or in a different part of the embryo,genes for blood cells and so on. 

Quentin Cooper : But aren't you only just getting one vector there,to stick to your kitchen metaphor,you only going to know how far you are from one particular smell,so if you are I don't know 5 microns away from smell central,then won't everything 5 microns away want to become a kidney or whatever? 

Bill Richardson : That's right,so this is one of the questions that we would like to know is "What limits the spread of these molecules?".Within the central nervous system,there might be barriers around the nervous system which prevents the....these specific nervous system signals from getting outside.One of the specific signals in the nervous system is a molecule called "Sonic Hedgehog",and that is .... 

Quentin Cooper : (sniggers) You have to answer why is it called "Sonic Hedgehog"? 

Bill Richardson : Why? 

Lois Wolpert : That's my witty friends in Harvard,because there's a gene.....really all the interesting genes that control our development are also in the fruit fly Drosophila. 

Quentin Cooper : Right. 

Lois Wolpert : And there's a gene in Drosophila called "Hedgehog" which when its mutated makes the little larvae a little "hedehoggy" and when the related gene was discovered in vertebrates,Cliff Tayborn and his colleagues called it "Sonic Hedgehog" because of the computer game. 

Quentin Cooper : Why all this worry about people patenting you know,bits of the Human Genome (Lois laughs),when we're come up with commercial names anyway for these things!? 

Lois Wolpert : Sorry. 

Quentin Cooper : Sorry. 

Lois Wolpert : Sorry,could I just go on with Sonic Hedgehog,because I don't want to think....because the nicest example,although the nervous system,I'm sure is very nice (laughter),but Sonic Hedgehog....what determines where your thumb is,compared to you little finger,really is largely determined by what the concentration of Sonic Hedgehog in the developing limb...there's a signalling region of the posterior margin of you limb... 

Quentin Cooper : Right. 

Lois Wolpert : ...which makes Sonic Hedgehog. If your close to that region you make the little finger,if you're a long way away you make the thumb. And the...going back to your original question...it's kitchens within kitchens. So you star with one kitchen,you can use the same smells,one they've learnt that....cells have good memories as to what's happened to them ,and that changes how they respond to smells,would that be a reasonable way of saying it ,Bill? 

Bill Richardson : That sounds very reasonable. (Lois chortles) I would just interject that the exactly the same molecule..signalling molecules are used in different parts of the embryo, because the Sonic Hedgehog which determines whether you get a thumb or a little finger,in a different context in the nervous system,will determine whether you get a motor neurone - a neurone that will move your muscles,and allow you to move,or a sensory neurone - one which will detect incoming signals and tell you what to do.So the same signals and signalling pathways are used in different contexts. 

Quentin Cooper : But,Lois it seems that every time one of these questions is answered it opens up more questions.Are we quite a long way down the line here,or are we just at the beginning of it. 
[One things for sure we're never going to be forever foxed by puzzles within puzzles in "God's creation" - LB] 

Lois Wolpert : It depends on how you want...it depends on how much you want to know. 

Quentin Cooper : Well I'm a "bottle half full" kind of a guy! So let's be optimistic. 

Lois Wolpert : No,no,no...that's no,no,it's not like that at all.What one has to understand about development is the real complexity that lies within the cell itself.It's not the signals that are complicated.The same signals exactly as we've been discussing...there are only ...I don't know...5 or 6 families of different molecules that really play the key signalling.It's how the cells...what the cells remember and how they change their responses,and knowing precisely what's going on inside the cell is really quite complicated. I think that's where the complexity lies.In fact my normal joke....it's not a joke,is the real triumph of evolution was the cell.Once you have the cell it was downhill all the way,it was trivial,and I really mean that,because the cell is really...is really a very complicated and remarkable organism,I don't know whether Bill would agree with me.

Bill Richardson : Well I think I would have to agree with that! (laughter) 

Quentin Cooper : I seem to remember.... 

Lois Wolpert : Bill and I agree...! 

Quentin Cooper : I seem to remember a line of yours Lois,about how the most important thing in life isn't birth marriage or death it's gastrilation,but I don't know if we've got time to go into.... 

Lois Wolpert : No,no it's actually the cell! (laughs) That's in development we shouldn't get involved in that! 

Quentin Cooper : Okay but Bill how far...but we have got a lot of knowledge here and maybe if the triumph if you like, is the complexity of the cell and we're beginning to understand it,how far are we from being able to actually manipulate these processes and actually not just say "Let's just see what happens here" but to actually change thing s to order,to grow things to order? 

Bill Richardson : Well we can grow these stem cells isolated from either embryonic or adult tissues,and we make them do limited sorts of things in culture.We can make them turn into neurones,but we can't direct what kind of neurone,we can make them turn into astrocytes,but it's more difficult to make them turn into olicadendrocytes and so on.So we're really at the beginning of an uphill incline,in figuring out how to manipulate these cells in culture. 

Quentin Cooper : So that's still a way from having direct medical applications? 

Bill Richardson : Well in some instances. 

Lois Wolpert : I'd like to ask Bill if I may,through you.... 

Quentin Cooper : Please do. 

Lois Wolpert : ...and that is there are report after report about people taking these stem cells,putting them into animals and curing all sorts of damage to the spinal chord and the brain and I'd love to know what Bill really thinks of those experiments. 

Bill Richardson : Well they're empirical and they're a little bit primitive at the moment because basically we don't know what do do to the cells to make them behave in exactly the way we'd like them to behave.So we take cells and we bung them in and see what they do,and there are some diseases for example Parkinson's Disease,or Multiple Sclerosis,where we have a pretty clear idea about what cells are damage or missing,and where those cells are...where the damage is,where we could start and indeed are beginning to start already thinking about putting stem cells into human patients to address those very specific diseases. But this is... 

Quentin Cooper : But its a long..it's a big gap... 

Bill Richardson : It's a big gap.

Quentin Cooper : ...between starting to think about and having practical stem cell therapy. 

Bill Richardson : Absolutely yeah. 

Quentin Cooper : And any idea of a time scale here? 

Bill Richardson : Well it's always a problem to think about time scales but things are moving so quickly now,and things that we accept now,three years ago were science fiction.So I would say in ten years it could be very possible that we'll be doing things with stem cells- stem cell therapy. 

Quentin Cooper : And if we could do this,Lois Wolpert,this would have an enormous impact on medicine? 

Lois Wolpert : Oh yes,it could be tremendous for all sorts of things. Many neuro degenerative conditions,heart disease,replacement of lost tissues,liver you know for example,in principle,if some body,instead of wanting a liver transplant,you could actually grow the liver cells,you might want to clone them and that's another story altogether,use embryonic cloning,and then replace liver cells.Yes it's very,very powerful,very exciting. 
[The BBC's online Scitech News this week reports that attempts to defeat Telomerase's capacity to curtail life,have resulted in increased propensity to create cancer -LB] 

Quentin Cooper : But I mean the stem cells for research for humans presumably come from human embryos,do they? 

Lois Wolpert : Yes. 

Quentin Cooper : And there are people in American Congress I think almost even as we speak, who are debating the ethics of this,I mean is there a possibility that somebody could just go "No,that's it,this is going to be off limits". 

Lois Wolpert : They'd be dotty if they did,if I might say.I find it...I must say I find most talk about bioethics bunk,and I fail to see what ethical issues there are involved here. 
[There's only an ethical issue if you think that something has been killed.Perhaps a religious view might posit that life is being removed before it gets started rather as contraception is regarded by some people.But no one has a problem with interrupting life by not having sex at all! I've heard Lois speak before,and he makes a very good case for use of cells with no ethical problem.If one has a "sanctity of life" view then one has to discern when actually something is alive and when not.Otherwise there would be an ethical problem about eating vegetables.The argument isn't as simple as merely saying that abortion or termination is a problem. In pure cellular terms there is no "person" to destroy,and it will never "know" one way or the other. The social stigma of utilising life or DNA structures in a dispassionate way has been biased by Promethian myths and Frankensteinian nightmares. No one has an ethical problem about mixing chemicals together or even building up long chain polymers. Life in terms of DNA is little different from those processes in that regard,and it is only because the structures are so complicated and we are made of them and give high value to them,that they become sources of ethical concern -LB] 

Bill Richardson : But in any case it might be possible to bypass that whole ethical issue,because recent work has shown that adult stem cells isolated from mature tissues like mature brain or bone marrow is more plastic and has more potential than we would ever have dreamed of in the past.So you can take adult stem cells from the brain of a mouse obviously,this has not been done on humans. 
[This is one of the follies of biotechnology.To me the similarity of creatures is over exploited.There is sufficient difference to warrant concern over what happens in a mouse as opposed to what happens in a human being.Our body environment is different. The problems of this were shown with Thalidomide (see Symmetry at Omegaman_UK Geocities.Moreover the underlying ethical problem is emphasised in the disregard scientists have for a full blown organism.If cells can be took from a foetus then how much less should they be took from an adult mouse,who should,if they are sufficiently similar to us,have the same rights to life and lack of suffering.It makes more sense to me to use a foetus,human or not, as a source of cells,than a full grown organism of any variety.In this I am not speciesist. Scientists by viewing a mouse as a living laboratory are viewing it as inferior,and perhaps this is what HRH Wales was concerned about.Richard Dawkins took issue with HRH Reith lecture at http://www.edge.org/3rd_culture/ -Open Letter to Prince Charles -LB] 
And it could give rise to blood cells in a mouse,or you can take stem cells from the bone marrow and they can give rise to certain kinds of brain cells if you put them into the brain or muscle cells in the right environment and so on.
[This was precisely the concern of Mai Wan-Ho with regard to GM food,that expression of cells/genes depends on environment (see Miller1 @fortunecity).What it does show is the latent capacity of stem cells to be reemployed -LB] 
And it's beginning to look as if the stem cells in our own bodies - our adult bodies,might, if you've treated them correctly,if you knew how to treat them correctly might actually be totipotent,you might be able to get totipotent cells from your own somatic (?) bodies.In which case you could donate your own tissue to repair yourself.
So having started with those nice clear definitions of what was pluripotent,totipotent and multipotent it may turn out there's some blurring there.I have to say Professors Bill Richardson and Lois Wolpert,many thanks for living up to your pluripotential. 
Next week,it's the origin of the word salary,it's great on celery,but just why is salt so important in terms of our bodies industrial chemistry and generating cheap electricity? All the salient saline facts on the Material World. 

16/6/2000