Cancer, Alzheimer’s & Protein Origami | David Pincus | TEDxBeaconStreet


Translator: Ilze Garda
Reviewer: Muhammad Ramadan So, the bad news is many of us are going to get
either cancer or Alzheimer’s disease. (Laughter) The good news is
we’re probably not going to get both. (Laughter) 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 (Laughter) these cellular chaperones
prevent aggregation. (Laughter) 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. How do mutations affect protein folding? Well, these mutations occur
in genes, and many of these genes, like I said before, code for proteins. So if you have a mutation in a gene
that leads to a mutation in a protein, and mutations in proteins
can make proteins more difficult to fold. It turns out that many
of the most cancer-causing mutations actually do cause proteins
to become much less stable and rely much more heavily on chaperones. So why then,
don’t the cancer cells self-destruct if they have these mutations? Well, cancer has figured out
how to highjack chaperones. Cancer cells have figured out how to take the level of chaperones
and artificially raise them in order to buffer
against the misfolding effects that might be caused by the mutations. Cancer cells rely very heavily
on these elevated levels of chaperones. Again, we have a very simple idea, which is that cancer cells require
chaperones in order to survive. So if we could somehow decrease
the level of chaperones in cancer cells, then we could unmask these mutations,
and their proteins could aggregate, and we could have a way
of cancer self-destructing. It could really be
an Achilles heel for cancer. Cancer and Alzheimer’s disease actually have something
fundamentally in common at the root, and that is
an opposite requirement for chaperones. In diseases like Alzheimer’s,
chaperone levels drop, misfolded proteins
accumulate and aggregate, and that leads to cell death. Whereas in cancer, cancer has mutations
that it needs to buffer against, so it figures out how to raise
the chaperone levels. OK, so what do we do here? Well, it leaves us with a simple solution,
but it’s actually kind of a catch-22. We’d like to think of this
as a whack-a-mole problem. (Laughter) You can imagine if we tried to knock down the level of chaperones
to try to treat cancer cells, we can drop them down and, sure,
maybe we’ll unmask the cancer cells, and the cancer cells will self-destruct. But at the same time, we could drop the levels so low
that in the brain they drop, and then we get misfolded proteins
and get neurodegenerative diseases. So rather than taking
this sledgehammer approach, what we really need
is a Goldilocks approach. We need the porridge not to be too hot
or too cold, but to be just right. What that means is we need to figure out
how to fine-tune chaperon levels, and we need to do this in a targeted way, to target to the cell types
that really need them. In thinking about this, we really think this is
an Achilles heel for all cancers. All cancers rely on mutations, all cancers have increased levels
of misfolded proteins, and all cancers
seem to rely on chaperones. Of course, there are
exceptions to any rule, but all subtypes of cancers are going to have something
that can be treated this way. We think if we could figure out
how to target chaperone levels in cancers, it wouldn’t just be a cure
for breast cancer or pancreatic cancer, but it could potentially be beneficial
for all different types of cancer. On the other hand, if we think
about diseases like Alzheimer’s where we have not enough chaperones, if we could increase
the level of chaperones and specifically in the brain
and specifically as we age, then we think we could have
a treatment not just for Alzheimer’s, but for Parkinson’s, for ALS,
for Huntington’s, et cetera. We really hope that we’ve found
a fundamental process that’s related to both
of these different types of diseases. What we’re studying in my lab
is just how do we do this. How do we fine-tune
these chaperone levels? We’ve figured out already
how we can slam down on them or increase them way too much, but the fine-tuning mechanism
is not revealed, and that’s what we’re working on. The hope is that with enough information, if we can figure out how to do this
in a fine-tuned and targeted way, then we could dial
the appropriate level of chaperones for an individual person
in an individual case. And we could dial it to ALS, or dial it down a bit
if there is a bit of cancer, and hope to get this in the right place, so that rather than getting
either cancer or Alzheimer’s disease, we get neither of these diseases. Thank you very much. (Applause)

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10 thoughts on “Cancer, Alzheimer’s & Protein Origami | David Pincus | TEDxBeaconStreet

  1. Hope we find a cure to both retro virus diseases and prion diseases as soon as possible. Enough people died from them already!

  2. Hundreds of millions of dollars have been donated to cancer and other diseases, where is the money going? Why is the progress so slow? We have three main techniques or treatments if you will for cancer- chemotherapy, radiation, and slowly emerging, immunotherapy. Immunotherapy is in my opinion the most effective/promising, so why did it take so long?

  3. it was really helpful. I would like to put your information in the my report regarding the correlation of Alzheimer's and cancer. and I would like to reference and cite some of your finding. How will I get this information online? please reply asap

  4. and also if you have any journals or articles on the correlation of cancer and Alzheimer's that would be helpful. thank you

  5. want to know how to prevent cancer and alzheimer's ? exercise,plant based nutrition and intermittent fasting . you're welcome

  6. Oxygenate cells by correct breathing and cut out sugar and starches and both syndromes can be reversed or prevented. But hey! No research grants or profits for Big Pharma in that!

  7. Quit meat starch milk eggs carrots spinach soy it’s more I can help you figure this out email me we could talk more

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