“The Challenge of Stem Cells and Brain Diseases: Fact or Fantasy" - Professor Richard Faull

Richard Faull: Thank you, Linda. Thank you to the Bioethics Council for the invitation and for the opportunity to come here tonight to talk to you.

I want to give you an overview of stem cells. I have been involved with brain research for over 20 years. It has been an incredible challenge. It has been a passion. It has brought me into contact with families with Alzheimer’s, Huntington’s, Parkinson’s, epilepsy, Motor Neurone Disease, and so on. I have seen the tragedy of these brain diseases.

I am going to give you a scientific overview of stem cells from the perspective of brain diseases. I want to take you on a journey and let this unfold for you as to how I see the potential of stem cells. I am going to tell you some facts, and I am going to also tell you the fantasy. One of the fantasies I am going to tell you about is the fact that the hype in the media has taken us to a realm of expectation of what stem cells are going to do that is actually unrealistic. We are not going to have a cure around the next corner. It is going to be 5 or 10 years. We have enormous challenges.

I first want to tell you a little bit about the human brain. Then I want to tell you a little bit about brain disease, then put stem cells in perspective.

The human brain is the most fascinating and complex organ. You know, you all are special people, and you are special people because of this organ. Your special abilities, your personality, your special skills in life depend in many respects on your human brain. When we look at the brain from the side we see a whole series of folds, and we know from research over the years that all those folds have very specialised functions. The left side of the brain looks after the right side of the body, and we have got areas involved with movement and sensation. The back here is involved with vision, down here is involved with memory and listening. These functions are carried out by the most incredible cells in the human body –brain cells. If we have a quick look at the cells involved with movement or motor control, vision, and memory you will see the incredible complexity of these cells. That is a cell that is involved with the control of movement. There are millions and millions of them. They are the most beautiful cells, I think. Each of those cells gets upwards of 20,000 or 30,000 inputs from other cells. Even from the non-scientific, even from the artistic point of view, they are incredible. When we go to the visual area, the basic brain cell is still there, the cell body, the dendrites. But it is a different cell; it does a different job – it enables you to see a picture, consciously, through all the different interactions of other cells. It is like all the vehicles that we see outside. They are all modified to do different things, and so the brain cells are incredibly specialised.

We go to the cell that is involved with memory – the cells that die in Alzheimer’s disease. They are quite different again. Same basic pattern but they work in a different way. They have a whole different multitude of 20,000 to 30,000 inputs coming in to tell them how to form short-term, long-term memories.

So you see, as we walk around the brain we have essentially a collection of highly specialised cells, and that is what makes our brains unique, which makes us unique. The tragedy in brain diseases is that these cells start dying, and they die in different areas, and it depends on the disease which area of the brain is affected. Alzheimer’s disease, Parkinson’s, Huntington’s, epilepsy – they all result in different symptoms. They cause different tragedies. They are all tragic because what we can’t do is slow down the cell death.

Just take Alzheimer’s as an example. This is a side view of a person who died with advanced Alzheimer’s disease. They bequeathed the brain to us for research -the most precious gift you can give in the world. We interact with families. We get all the information about the symptoms that this person suffered, and so on. Each brain is different. The disease affects people in different ways. This brain weighs about 800 grams, compared with a normal brain, which weighs about 1500 grams. You see these folds are full – hopefully my brain looks just like that! Going back a slide, you can see the catastrophe here. You could almost drive a truck between these gaps in the folds, and that is because of the loss of cells. At least one-third more of the brain cells have been lost, and that is the tragedy of brain diseases.

That is why our research, and that of many groups overseas, has been directed to finding out whether there is any way that we can somehow slow the cell death or even replace the cells. Over the years there have been studies looking at the possibilities of forming new brain cells.

I am now going to give you an overview of stem cells, but first I have to take you on a kindergarten story of how we develop so that I can put it in perspective for you.

We all started life as a single cell when the sperm from your Dad fused with the ovum from your Mum – and that is your birthday. That is the day you should actually celebrate your birthday. It could be embarrassing, but it is actually important! Why? Because once that single cell is formed you have been born. You won’t be able to think back to that and remember that event, but that is actually the critical event in your life. From that day on, within hours you divide into two cells, and four cells, and so on. Four days old this is what you look like – a little wee cyst, a blastocyst, going along the Fallopian tube, just about to impart in the uterine wall, and in the side of that blastocyst are the cells that are going to grow and develop into all the organs of the body. At four days old these cells all look the same. You can’t tell the difference, but we know they are going to go along different lines. They are going to form parts of the brain. Some are going to form the liver and some are going to form the heart, and so on. These are the stem cells of life, the pluripotent cells, the magic cells. They are incredibly magic because they all look the same but they are going to do different things. Why? What tells them to do different things? We don’t know. If I knew I would be in Stockholm getting the Nobel Prize right now! But that is the challenge.

From there they continue to develop, and they go down different lines. At 10 weeks old this is what you look like. In these pictures, which are out of proportion, you can actually identify the major parts of the brain. The major organs are all identified, so those stem cells have gone off on their different routes, and they have done it in the most precise way. It is the incredible marvel and beauty of life that this actually works. At this stage the cells are still immature; they are still developing.

Then we are born at 40 weeks, then we grow up into our teens, then ultimately we are adults. That is the incredible story of life.

With brain diseases it has always been of interest whether there are opportunities to put new brain cells in. There have been studies on this over the last 30 years. There have been studies on animals, taking cells out of the adult brain of a rat and putting them into another rat. They die. Why? Because those cells, like the ones I showed you, are so specialised.

But about 15 or 20 years ago the studies started looking at taking tissue from embryonic rats where the cells were still immature. The most interesting thing that was found was that if you take cells from the embryonic rat where the cells are still maturing – we call them foetal embryonic neurones – and transplant them into another adult rat’s brain the cells will grow and develop over a series of weeks, and after 6 weeks to 8 weeks they develop into normal brain cells. They make the chemicals that were lost from the original cells. Models of Parkinson’s were made where you just kill in the adult rat brain those cells that die in Parkinson’s disease, and the animals develop symptoms. When they put the cells that they took out of a rat embryo back into the brain of those Parkinson’s rats, the symptoms disappeared. Marvellous, incredible, could not believe it. So over the past 5 to 10 years there have been studies done on human patients with Parkinson’s disease in certain circumstances where they have utilised the tissue from aborted foetuses, taken just from the area of the brain that would normally develop in the area that dies in Parkinson’s disease. The ethical implications are huge, but some patients showed remarkable benefits, showing that the cells would in fact replace the cells that were lost. As I speak, the USA and Europe are doing clinical trials on this type of therapy for Parkinson’s disease. The story coming back is that there are mixed results. It is not the miracle cure, that is for sure. When you consider that you have to use tissue from four aborted foetuses to do one transplant on one Parkinson’s patient, practically it is impossible. You would never utilise this therapy on a population basis. I could not go down this line. But that is one of the options being looked at.

Over the last 5 years suddenly the attention has turned to look at the stem cells and the blastocysts. Why has this happened? It has happened because reproductive technology has become so advanced that for couples who cannot have children by normal methods we can now take the sperm from the father and the ova from the mother - and this process can happen in the lab, which takes the fun out of life! – and you can let that single cell grow to a blastocyst, a four-day-old. Then you can freeze it down in liquid nitrogen and keep it for that couple for when they want to have the children. So it satisfies the real challenge for some couples.

Of course more blastocysts are frozen down than are ever utilised. So when this technology became developed the scientists said, “We know from animal studies you can take those stem cells, maintain them in the laboratory, and they will grow and develop and keep turning into the same type of cell, so why don’t we use some of those stem cells in the blastocysts that are going to be destroyed (after 6 or 10 years, depending on which country you are in) and form a stem cell line. And if you take some of those stem cells” – and this is the big challenge – “and if you can unlock the secret of what growth factors, what chemicals tell them to go down one line, theoretically you could encourage them to develop and form replacement cells.” So the interest in embryonic stem cells came alive. The challenge with them is enormous. Theoretically they will turn into a new cell in the body. It is just that we do not know how it is going to happen. That is the real challenge from a scientific point of view, regardless of what ethical or cultural value you like to put on this. But we are a long way from understanding that process. It is incredibly complicated. To take stem cells that look like this and turn them into the cell in the motor cortex in just the right number to provide a repair for a person with a stroke – not to get too many and form a tumour, as we know they can – or to form these cells in the visual area of the brain or the memory is an incredible challenge. We have got 10 years of research.

Stem cells offer an enormous opportunity. I believe the opportunity is challenging. We need to look at the potential of embryonic stem cells. I could never look at an Alzheimer’s patient and family and say we are not pursuing everything possible. But we need to do it in the right cultural and ethical context, and it is the challenge for you people to interact with us in every way to work it out. That is what this consultation is all about. However, our research is also taking us down a slightly additional way we never expected. I would never have dreamed when I was doing research on the human brain 20 years ago that I would be looking at stem cells, but we have been looking at stem cells which we have now found in the adult human brain. Each of you out there we know has stem cells lying in your brain. Let me just give you the background to that.

We knew right from the 1960s we have known that rats, monkeys, cats have stem cells in the brain. Once the animal had grown up it kept making new brain cells. I was told as a medical student that humans are so different, that our brain is so complicated we do not have stem cells in our brain, that once you mature that is it, that all we can look forward to is gradually losing brain cells for the rest of your life. That actually is not so. In the rat brain there is a little motorway going down through the brain, going up from the front of the brain where these stem cells lie in the middle. They keep dividing through the life of the adult rat, and they produce embryonic cells that then divide and multiply and run down this motorway, and as they go they are slowly developing, and when they get there they spend some additional days or a couple of weeks fully developing into new brain cells. So there is a turnover of brain cells. That is the actual motorway in the rat brain, and, of course, we thought “that’s the rat brain”, and dogma always taught us “not in the human brain”.

We have been interested in the human brain, and we have been interested because we looked at all these different diseases. Five years or so ago we started looking at Huntington’s disease. This is a section through a normal brain and this is a section from a person who died with Huntington’s disease. And this is where the stem cells lie in the rat. When we started looking at this area in more detail in the Huntington’s brain – the person who had this tragic disease caused by a gene, and there is massive cell death here – we always noticed that there were increased numbers of cells there. Suddenly we started to put two and two together. To cut a long story short, because I can’t keep you here all night, this is 5 years’ research and what have we found. We have found that lying in the normal brain, just under that area, we do have stem cells that multiply. When an area is affected by a disease like Huntington’s, these cells say, “We’ve got to try to fix this brain”, and they actually make new brain cells. The more advanced the disease, the greater the number of cells. The great majority of these cells, however, are glyle cells or support cells - only 5 percent of these cells we found were actually making new brain cells. So it is too little too late. But there are adult stem cells there, and that is incredible. Suddenly we realised that the adult human brain can make new brain cells. So there is another option here. You see life is full of options and opportunities, and all these stem cells are present not just in the embryo but they’re present in adults, in different tissues. The story I have got to tell you tonight is that we must look at all these options. We have to make sure we look at all the options so that we can help patients who have these tragic diseases.

And so, in conclusion, we found that the human brain does make new brain cells. We call that neurogenesis. That has got to be exciting! Neurogenesis is increased in the diseased human brain, but it is too little too late. When first I presented this at a conference some years ago, someone said, “Well that is no good because people still get brain disease.” I said, “But what you don’t know is that in the 85% of people who don’t have brain disease everything is working fine.” Our research has to be directed not only at looking at the embryonic stem cell lines but also at the adult stem cells to see how we can try to stimulate them to do their repair in a much more effective way.

The most fascinating thing, though, is that when you do animal studies and you look at what happens when you take animals and put them into an enriched environment, a challenging environment, where they have lots of things to do, compared with little rats that are not in that environment, the adult stem cells in the enriched environment get turned on. They make enormously increased numbers of brain cells. There are lots of factors that we know control the production of new cells – in this case, the brain. But it applies in general ways. So scientists have to try to look at all the options. We have got to look at the options of also trying to turn on the stem cells, which you and I have, which we don’t have to receive from anything else – these are your own cells – and study them in the lab and see how we can make them much more effective in treating brain disease, and treating other diseases.

In a final analysis, we must pursue all the opportunities but we must do it in a way that is culturally and ethically appropriate. We must make sure we always look at the options and do it in a way so we advance the quality of life. We must look and see how we can help patients with all the different types of diseases where there is cell death and try to utilise the normal repair processes as well as look at the options of using embryonic cells, which establish cell lines that have been achieved and received through appropriate cultural and ethical procedures. That is the challenge of science. When I was a third year medical student at Otago University I read about Christian Barnard doing the first heart transplant in South Africa on a Polish man - he died three or four days later. It was said, “This is interesting and real challenging stuff, and it is probably going to have no place in medicine whatsoever”, and there were all sorts of cultural aspects of it that are difficult – transplanting between different races and so on. Today in Auckland we do heart transplants every two weeks. It does not even reach the paper. These people are living long and fruitful lives. So perspectives change over the years, but we must always go forward, we must always push the barriers.

We have about 30 graduate students in our research programme in Auckland. When they come and say, “I have a problem with my research”, I say, “Fantastic. If you don’t have a problem with your research then you are not pushing the barriers, you are not discovering new knowledge. Every new fact you find creates a challenge and dilemma because you are finding new knowledge.” If we are not finding new knowledge and communicating that with the community we are not doing our job as scientists. It is important, though, to keep all the values in tact, but we must always seek and look for the vision for the enhancement of life.

Thank you.

Linda Clark: Thank you very much, Richard.

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