David Pincus – TRANSCRIPT
So, the bad news is many of us are going to get either cancer or Alzheimer’s disease. The good news is we’re probably not going to get both.
I’m a biologist at the Whitehead Institute in Cambridge, Massachusetts. And I’m in a really fortunate position, I get to run my own research lab. It’s a little bit like doing a non-profit start-up company, but far fewer headaches. What we get to do in my lab is we get to explore our big scientific questions, and the main one that we have that we’re really focused on is trying to connect diseases like cancer and Alzheimer’s disease that seem to have very little in common at first glance, but try to understand that at the fundamental level what’s going on in these diseases.
OK, so what’s the problem? By the year 2050, cancer is going to account for as many as 70 million deaths per year, and it’s going to cost the world economy nearly 2 trillion dollars to treat. On the other hand, Alzheimer’s disease and diseases like Alzheimer’s are going to affect more than 115 million people and also cost the world economy over a billion dollars. So by 2050, these two diseases are going to be the cause of death for nearly one out of three people, and one out of every 30 dollars generated in the world is going to go to treating these diseases. So it’s a really big problem, especially as our population ages. Like I said, we tend to think of these two diseases as really being opposite, and we think of this in a disease spectrum. On the one hand, we have cancer, and cancer is, as we all know, when cells grow and grow and grow and grow.
So we think of it as a disease of unchecked cell growth; cells grow when they are not supposed to. On another hand, we have diseases like Alzheimer’s, which have the opposite problem: cells in the brain are dying, and they are dying prematurely. So, one is a disease of not enough cell growth, and one is a disease of too much cell growth. So they seem very different. But there is actually something that links these diseases.
We know this because, if we look at the population, we’ve seen a trend like I alluded to at the beginning: people who get Alzheimer’s disease have a much lower risk than an average person of getting cancer. And people who get cancer, even if they get cancer as a child, much later in life they have a much lower risk than an average person of getting a disease like Alzheimer’s. And it’s not just Alzheimer’s. The same is true for Parkinson’s, and for ALS, and for other diseases of this nature. So there is something connecting these two diseases. What I’m going to argue for the rest of the talk today is that this has to do with protein folding.
What is protein folding? I think we’re all on the same page that we’ve all heard of genes, and genes are parts of DNA. There is a sequence of DNA, and that sequence is a gene, and what that gene does at the basic level is it codes for a protein I’ve drawn here this string of balls in different colors, and those represent the individual amino acids. And each protein is a string of amino acids. But these proteins don’t do anything in the cell when they’re just a string of amino acids.
They have to fold up into a very particular three-dimensional shape. Only when they’ve attained this shape, they’re functional. So protein folding is this absolutely vital process going from a string of amino acids into a functional protein. OK, so this is great. Proteins fold up and they do their thing.
The problem is though that proteins don’t always fold properly. Many times they’ll fold up spontaneously, and some proteins are very good at this. But many proteins have a tendency to misfold. Misfolded proteins can be very toxic for the cell because they are prone to aggregation, and protein aggregates are very toxic. Many of us have heard of diseases like Alzheimer’s, and one of the things we know is that they’re characterized by plaques in the brain.
What these plaques are are actually aggregated, tangled up, misfolded proteins. And it’s not just in Alzheimer’s disease, but in ALS, in Huntington’s, in mad cow disease, and in Parkinson’s disease. All of these neurodegenerative diseases have aggregated, misfolded proteins as a hallmark. So, you know, if the cell is just getting aggregated proteins all the time, why aren’t they just dying all the time? Well, it turns out that cells have a way of coping with aggregated proteins. And that’s through things that we call chaperones.
This is actually a technical term, a term of art that we use to describe agents in the cell that help to keep proteins from misfolding and prevent aggregates. Just like the chaperones that were at your high school dance these cellular chaperones prevent aggregation. They’re vital to the cells. So why then, if cells have these chaperones, why do we ever get aggregated, misfolded proteins? And why do we ever get disease? There’s a different metaphor that I like to think of when I think of chaperones which is that they are the cell’s origami artists. They are in there to make sure that proteins don’t misfold, and a bit more than that, that they’re folded exquisitely into their absolutely perfect shape, so that they can carry out their essential function.
So these chaperones are absolutely vital. Bacteria cells have them, human cells have them, they are very ancient. Why then do cells ever have problems? Well, it turns out that the level of chaperones drops as we age, and, in particular, they drop in the brain. So in a young, healthy brain, there’re plenty of origami artists, all the proteins are perfectly folded, but, as we age, the levels of chaperones drop, the misfolded proteins can accumulate, and then this can lead to aggregation. This leads us to a very simple idea, which is that diseases like Alzheimer’s disease actually occur in brains when chaperone levels have dropped.
If that’s the case, then there is a very simple solution, which is that, if we could just increase the chaperone levels in the brain, then we could have a treatment for these diseases, and perhaps even reverse them. So there is some hope about these neurodegenerative diseases. I also promised I was going to talk about cancer. How do chaperones have anything to do with cancer? At the basic level, cancer occurs when a single cell goes rogue, and that means it acquires a mutation that escapes the normal control that keeps the cells in check, and then instead of functioning as a part of the whole body, it decides it’s just going to grow and grow and grow, take the resources away from the rest of the body, and this is how tumors form. So at the fundamental level, cancer is caused by mutations.