Dr. Maurice Curtis, Malvinder Singh-Bains, Auckland University
Professor Richard Faull and Dr. Maurice Curtis from Auckland University have set up a bank of frozen human brains. This contains hundreds of brains from Huntington's disease patie nts and also, healthy controls from the general population. Their PhD student Malvinder Singh-Bains took me on a tour of the research facilities.
Malvinder - Okay, and now we’re going to go into the Neurological Foundation of New Zealand Human Brain Bank. Long title but we call it the Human Brain Bank over here. If you just walk this way, through the music and we have all our brain bank freezers isolated in rooms.
Hannah - We’ve entered into the brain bank room. So, it’s got a massive freezer in here which is humming away. You might be able to hear it and there's also a fume cupboard over there where I'm presuming some dissection can take place under very clean conditions. Can you open up the brain bank and show us some of the samples?
Malvinder - I can, indeed.
Hannah - And the freezer is opening up now and it’s minus 80 degrees centigrade. So, it’s keeping the brains in a very cold condition to preserve the tissue and all the proteins and the genes that are there.
Malvinder - Absolutely and we have a few of these freezers. So, we have the tissue stored in these columns that are kept in the minus 80 freezer and they're all designated with a number and they're all coded specifically. We don't know who these cases belong to for security purposes and also for patient confidentiality. The tissue is kept in these biohazard bags. I'll just open up one of them. So here, we have one tissue block. We’ve designated it a case of H131. So, in this case, I've picked out a normal one and we’ve also got the block number on it. So, SM4 stands for sensory motor block 4.
Hannah - So, that's sensory motor cortex. So it's the band of your brain which runs kind of from ear to ear. If you imagine having a hair band on, or an Alice band, that's roughly about where the sensory motor cortex would be. The sensory motor cortex is involved in processing all of the sensory information that comes in through our bodies. So for example, sense of touch, sense of temperature and sense of self as well I think.
Malvinder - Absolutely. Sensory motor cortex is probably one of the most important cortical regions.
Hannah - So, can we open the sample without jeopardizing the integrity of the tissue, but open it and just have a quick look?
Malvinder - Absolutely. So, we have each of our blocks that are wrapped in foil. So, we snap freeze them using dry ice. I think this one has a few layers on it.
Hannah - We’re unravelling now the block of human brain tissue.
Malvinder - So, this is a fresh piece of tissue and you can actually see the gyri.
Hannah - Yeah. So, the human brain has these folds in it which almost make it look like a walnut and I can see now all of the gyri. So, those like little folds coming into the brain which almost look like – I don't know – like a river bed that's flowing into the brain with little bits of blood which – that's how the brain gets its blood supply and the oxygen rushing to it and I can see that really intricate details there in this frozen block of tissue. It’s quite awe-inspiring actually.
Malvinder - It’s very real. When you see the brain this way, you know that this is such a precious gift from a person. You can even see the little tiny vessels on the top of the meninges. If you look very carefully, you can see the little capillaries.
Hannah - And that's how the brain gets its oxygen through this vasculature which lies on almost the surface of the brain.
Malvinder - You can even see the separation between the grey and white matter. The grey matter contains all the bodies of the cells of the neurons and then the white matter contains all their processes. So, all of the connections come through the white matter here and it’s just very distinct. We haven’t even stained the tissue. You can get so much information just from one block.
Hannah - It’s beautiful. Would you donate your brain for medical research for this type of study?
Malvinder - Absolutely. I think the care that we take into the processing of every single block of tissue and just the brain as a whole, we treat these brains like as if it was our grandparents or our parents and I would certainly donate my brain with the knowledge of how well we treat the tissue here.
With the Indian culture, certain different cultural groups amongst Indians, the Indian population, we have beliefs that the blood of our body is sacred and our organs are sacred, that the tissue is sacred. This is why when a person passes away, we practice the art of cremating so in other words, giving everything back to the earth, so sending our ashes into the ocean and then passing on to the other side. So, the sensitive topic of tissue donation i.e. leaving a part of yourself on Earth is very, very different for Indians. So for me, I've actually had an internal cultural battle as well. I actually wasn’t allowed to donate blood at a point.
Hannah - Because of your family’s wishes.
Malvinder - Yes, because of the cultural commitments and also, the family understanding that blood is sacred. I've brought my parents to the centre and shown them firsthand what we do and also, my parents can see how precious the information is, it’s as almost as if that knowledge has armed them with the understanding that we can actually learn so much from what we have.
Hannah - Thanks, Malvinder. Now, over to Dr. Maurice Curtis, Deputy Director of this brain bank on some of the results from the samples to date.
Maurice - One of the things I've been interested in are the stem cells in the brain. These are cells that have the capacity to divide and become any other cell type in the whole body actually. But in this case in the brain, they would normally go on to become either glial cells which are the supporting cells of the nervous system or neurons which are kind of the active unit of the brain. These stem cells we’d always thought were very important during the development of the brain. In fact, it’s those stem cells that produce about 160 billion neurons in the course of about 4 or 5 weeks when we are developing in utero. But once you're born, the thought has always been that you don't have any more stem cells in the brain.
Hannah - So, the number of cells in your brain that you are born with, people used to think that that was it for life. So, if you have any trauma or if you do any damage to your brain then you can't replace those cells. That was the traditional hypothesis.
Maurice - That's right. That's what I was taught when I first started at the university. Only a few years later and I can still remember where I was standing when I read the paper in 1998, which indicated a paper that showed unequivocally that the brain produces new brain cells. That was staggering to me and I thought I have to know more about this. And so, we were actually interested in the Huntington's disease brain for the reason that the area that the stem cells reside is exactly next door right – they're neighbours – right next door to the area that actually degenerates in Huntington's disease.
So, you've got this interesting situation where in Huntington's disease, the regenerative area and the degenerative area are neighbours. They're right next to each other. So, the areas that we’re referring to when we say the stem cell area is an area called the subventricular zone, it sits right next to the lateral ventricle in the brain that's the fluid-filled space in the middle of the brain. Just next to the subventricular zone is the caudate nucleus. The caudate nucleus is the area that degenerates in Huntington's disease and it normally is involved with mood and movement and hence people with Huntington's disease of problems with movement and also, they can have mood disturbances. And so, we were interested to see whether or not the area that is responsible for regenerating the brain at least during development was upregulated or whether more stem cells were born in that area, in response to the area next door, the caudate nucleus degenerating. And so, we used some special stains and what we found was that the more degeneration that was occurring in the caudate nucleus, the more regenerating cells or the more stem cells we found in the area next door, the subventricular zone.
Hannah - So, it’s kind of almost the opposite of what you might expect.
Maurice - Yeah, that's right. So, you might naturally think it would go the other way, but if you think about how skin repairs itself, when you cut yourself, you'd think, well, that's going to kill off the cells. But actually, what it does is it gets the stem cells engaged and they come along and they repair it and within a few weeks, you're left with just a small scar, but not an open wound anymore. Of course, the brain isn’t nearly as able to cope with insults, but the process is similar just on a smaller scale.
Hannah - So, what's going wrong with the patients with Huntington's disease then? So, they're having more degeneration in this particular area of the brain, but they're trying to compensate with this regeneration. But why isn’t it happening properly so that those regenerating cells are properly getting down into that region, making the circuits and replacing those lost cells?
Maurice - Yeah, so there's a couple of problems there I suppose that the brain has to overcome. Unlike skin which are relatively simple cells, the neurons are highly specialised, very, very specialised and they've actually done their job successfully for 40, 50, 60 years, and they've learnt it. We're then asking stem cells to come along and just replace these cells that have done their job well for a long time and asking these stem cells to find the right place to connect up with is actually quite a big ask. It’s a case of too little too late. So, we don't really get the true regeneration that would be nice to be seen there.
Hannah - Is it also something to do with this CAG repeat that Russell was mentioning earlier? Is there some genetic reason for why these new regenerating cells aren’t re-circuiting or getting into the circuit properly as well? Is that something to do with the genetics of Huntington's?
Maurice - We don't know. We certainly don't have a lot of information about that. What we do know is that some of the abnormalities that occur in cells with Huntington's disease actually affects stem cells less. So for instance, the Huntington protein which abnormally accumulates in Huntington's disease, that normally is a real problem for neurons. It accumulates because the neurons are very old and they don't have such good ways of being able to get rid of those abnormal proteins, the Huntington. In stem cells, they actually don't accumulate the Huntington. Cells that are dividing don't seem to accumulate these abnormal proteins that occur later in life with diseases like Alzheimer's, Parkinson's and Huntington's. So, the stem cells seem to have a window of being immune to these problems and part of it is just the fact that they're regenerating.
Hannah - So is this finding, will it lead to maybe a treatment where you can start using these stem cells which wont accumulate these misfolded or improper proteins and somehow make sure that they do make the proper connections and kind of get themselves in place in the circuit properly in order to help cure or treat Huntington's and other disorders as well like Alzheimer's?
Maurice - That's certainly always been the desire, is to be able to get new cells in there, a cell replacement therapy essentially. What I guess we’ve learned from other cell replacement therapy approaches is that getting one group of cells that you put into the brain to connect up with the right target cells is actually quite tricky. It certainly has been done a lot in the past and the hope is that using endogenous stem cells, the brain can direct it themselves and we just help the brain out. So, that's certainly one of the goals. We want to know more about how is it that you actually get the brain cells to do what they would naturally do and connect up in the right places. But part of that is actually understanding what it is that drives a stem cell to make a projection to actually look for a place to connect up with elsewhere. And so, we’re studying those features currently.