Warriors Within/Training Our Special Forces

[Sparky]

An interview:

Robyn Williams: Could you point to your thymus gland please?

Ellen Rothenberg; a professor of biology at Caltech.:"This is where it has been,-"

Out of order for clarity and edited ....

Robyn Williams: And you pointed to just below your throat-

Ellen Rothenberg: -they usually atrophy pretty much by the time that anyone is as old as I am now.- They get smaller in terms of their actual lymphocyte producing domains, and the intermediate parts of the organ that aren't being used anymore tend to get filled up with connective tissue and fat.- in the '60s and they were still ripping people's thymuses out during cardiac surgery and throwing them away. So it's a good thing that we use our thymuses to produce a lot of the T cells our body is going to need before we are even born and before the surgeons can get their hands on us.-"

Robyn Williams: Tell me the story of the T cells and how they come to be and what you are studying.

Ellen Rothenberg: T cells are a progeny from the same stem cells that give rise to all your other blood cell types, so they are distant cousins of red blood cells, of the macrophages which are major infection fighting cells. But the T cell precursors don't grow up in the same environment as these other cell types, they migrate out of the bone marrow where the other kinds of blood cells are generated to the thymus which is a school for T cells, it's kind of an academy for T cells. The cells that first come into the thymus are not committed to become T cells, and there is a fantastic analogy with a real human education; it's like taking a young student and enrolling them in a religious seminary before they are actually certain whether they have a religious vocation not. And over the next little while they have to decide whether they really have this vocation, and they are certainly influenced by the environment.

Finally they become committed to it, and then they still have to undergo training. So the commitment process is really what we study in my lab. They do this through a very error-prone and random receptor-generating process that has the potential for creating a great deal of trouble for the body unless it is very well filtered. And so the cells go through an extraordinary selection process, and the thymus is a really relentless purifier of the population, selecting only those cells that have happened to get receptors that are potentially useful and not harmful for the body. And that's a remarkable process. Also it's coupled with making professional subspecialty choices on the parts of these developing T cells. They finally come out from this process maybe after a month, and they then go out into the body and they then begin their function.

Robyn Williams: Isn't that amazing, making life so difficult to these poor little buggers, these poor little T cells...well, it does seem nature could have done it in a simpler way, which implies there might be some sort of purpose behind making it so difficult, as I said.


Ellen Rothenberg: Yes, I think there are a number of ways of thinking of the purpose. First, there are two big strategies of dealing with infections. One of them is the strategy that T cells and their cousins the B cells use and that is a divide and conquer strategy. Every individual T cell or B cell recognises a different thing in the universe than any other one. But that means it is only useful to the body if that one thing...-That one germ, that one bit of a germ is being recognised. And so every one of those cells is different from every other, and that means that in order to get defence against everything you might be exposed to, you need many, many different ones of them. And so the population diversity becomes a huge strength of the system. If you have only ten different kinds of T cells that all recognise the same ten things, it you are unprotected against a great number of other things.

The alternative strategy is the one that is used by other kinds of defence system cells like macrophages, and their job is basically to express all of them, the same group of receptors, but those would be tried and true things, they may be less precise but they are things that you will tend to find on most pathogens or most invaders. So those are cells with a less precise function and more generic function, and they don't have to go through this kind of selection process.

The price that the T cells and B cells pay for their huge specificity is that it is the generation of all these different receptors, each one to a different cell, involves a kind of a random receptor mutation mechanism actually, and some of the mutant receptors that come out are useless. Some of the mutant receptors that come out can actually attack one's own body, and so those are actually a danger to the system. And the way the system is set up is these cells are going to be rewarded if they can be useful, but they are going to be punished if they are not useful. So it is estimated that over 95% of each generation of T cells in training are killed in the thymus without ever being allowed to come out, every generation, which means every few days you are killing massive numbers of these acolyte T cells.

Robyn Williams: What a process! It's almost like a science-fiction movie, isn't it, but that's what you have to do...if you imagine all the thousands of different germs, diseases that you could be exposed to, and most of us go through life without having terribly much trouble. You know, it shows that the system works. What, however, does trigger the commitment in the thymus that makes a T cell want to be permanently a T cell? You found out what might be involved.

Ellen Rothenberg: The first thing that triggers the commitment process is what the thymus environment provides to the cells, and there is a very famous signalling system that is used actually in many parts of biology again and again for different purposes, but in blood cell formation it's really used to instruct blood cells to become T cells, but it's a very important switch mechanism that the environment uses to tell the developing possible T cell 'turn on these genes, don't turn on those genes'. And it takes a beating on the cells again and again and again by this notch pathway to the cell to get closer and closer towards the decision.

My own labs found a molecule called BCL11B which is a gene that's expressed in the developing T cells after being beaten on by this notch signal. And the specific role of this factor in the developing T cells seems to be to make its decision irreversible. And so we're very interested in understanding all the molecular details of how that works. But it only comes on as part of this program of the cell in dialogue with its environment, having the notch signal saying 'you will, you will, you will' and the cells says 'are you sure, are you sure, are you sure' and then the BCL11B says 'okay, I'll do it'.

Ellen Rothenberg: We try to make use of it. I think one of the things which is most provocative about this is that if you look at the comparison between how far the cells get in the T cell program with BCL11B and without it. Without it they get stuck in a kind of an arrested adolescence, and it's really very striking. They can go on growing very happily but they don't ever complete their development, and instead they cling to their childish stem cell like properties, and they will keep on expressing a number of genes which normally they should have turned off. And so these cells are actually refusing to grow up.

So it becomes a discovery which points in two directions, one is what does it say about what it means to be a T cell, but also it sheds a spotlight on the fact that cells have to actually stop being stem cells, that this is an actual decision they make, and that may be part of the connection with leukaemia because a lot of these stem cell genes, if you keep them on artificially, will cause leukaemia...

Robyn Williams: They go berserk.

Ellen Rothenberg: They go berserk, but the question of what is the boundary between being a stem cell and being a committed specialised cell that never goes backwards again.

Robyn Williams: One thing you said in the beginning really worried me. If your thymus may have gone away, certainly my thymus has...but don't I need T cells anymore? What's going on?

Ellen Rothenberg: Your thymus hasn't really stopped and neither has mine. The zones in the thymus that are devoted to making new T cells have shrunk down but they still are there. However, it turns out that we actually have the ability, our mature T cells, to keep growing a little bit, keep the stock going. What they are bad at is making really fresh T cells with receptors that are new to the repertoire. So remember that all the T cells in our body, to a first approximation, have different receptors, but that is only when they first come out of the thymus, and afterwards, if they have been growing in response to a challenge, fighting an infection, they will make the whole clone of T cells all with the same receptors. And as we get older and older, more and more of the T cells in our bodies really have more or less repeats of the same receptor over and over again. And that is bad for us.

[Sparky]

I am not a biologist nor chemist, and i have read about the immune system, but i found this interview very interesting... I am surprised that others have not commented on this function of our bodies.