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

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

So, the bad news is many of us are going to geteither cancer or Alzheimer's disease.

(Laughter) The good news iswe're probably not going to get both.

(Laughter) I'm a biologist at the Whitehead Institutein Cambridge, Massachusetts.

And I'm in a really fortunate position,I get to run my own research lab.

It's a little bit like doinga non-profit start-up company, but far fewer headaches.

What we get to do in my lab is we get to exploreour big scientific questions, and the main one that we havethat we're really focused on is trying to connect diseaseslike cancer and Alzheimer's disease that seem to havevery little in common at first glance, but try to understandthat 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 foras many as 70 million deaths per year, and it's going to cost the world economynearly 2 trillion dollars to treat.

On the other hand, Alzheimer's diseaseand diseases like Alzheimer's are going to affectmore than 115 million people and also cost the world economyover a billion dollars.

So by 2050, these two diseases are going to be the cause of deathfor nearly one out of three people, and one out of every 30 dollarsgenerated 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 diseasesas really being opposite, and we think of thisin a disease spectrum.

On the one hand, we have cancer, and cancer is, as we all know, when cellsgrow and grow and grow and grow.

So we think of it as a diseaseof 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 diseaseof not enough cell growth, and one is a diseaseof too much cell growth.

So they seem very different.

But there is actually somethingthat links these diseases.

We know this because,if we look at the population, we've seen a trendlike I alluded to at the beginning: people who get Alzheimer's disease have a much lower riskthan an average person of getting cancer.

And people who get cancer,even if they get cancer as a child, much later in life they havea much lower risk than an average person of getting a disease like Alzheimer's.

And it's not just Alzheimer's.

The same is truefor Parkinson's, and for ALS, and for other diseases of this nature.

So there is somethingconnecting these two diseases, What I'm going to arguefor the rest of the talk today is that this has to dowith protein folding.

What is protein folding? I think we're all on the same pagethat 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 levelis it codes for a protein.

I've drawn here this string of balls[in] different colors, and those representthe individual amino acids.

And each proteinis a string of amino acids.

But these proteinsdon't do anything in the cell when they're just a string of amino acids.

They have to fold up intoa very particular three-dimensional shape.

Only when they've attainedthis shape, they're functional.

So protein folding isthis absolutely vital process going from a string of amino acidsinto a functional protein.

OK, so this is great.

Proteins fold up and they do their thing.

The problem is thoughthat proteins don't always fold properly.

Many times they'll fold up spontaneously,and some proteins are very good at this.

But many proteinshave a tendency to misfold.

Misfolded proteinscan be very toxic for the cell because they are prone to aggregation,and protein aggregates are very toxic.

Many of us have heardof diseases like Alzheimer's, and one of the things we know is that they're characterizedby 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 gettingaggregated proteins all the time, why aren't they just dying all the time? Well, it turns out that cells havea way of coping with aggregated proteins.

And that's through thingsthat we call chaperones.

This is actually a technical term, a term of art that we use to describeagents in the cell that help to keep proteins from misfoldingand prevent aggregates.

Just like the chaperonesthat were at your high school dance (Laughter) these cellular chaperonesprevent aggregation.

(Laughter) They're vital to the cells.

So why then, if cells havethese chaperones, why do we ever getaggregated, misfolded proteins? And why do we ever get disease? There's a different metaphor that I liketo think [of] when I think of chaperones which is that they arethe cell's origami artists.

They are in there to make surethat proteins don't misfold, and a bit more than that, that they're folded exquisitelyinto their absolutely perfect shape, so that they can carry outtheir 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 levelof 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 diseaseslike Alzheimer's disease actually occur in brainswhen chaperone levels have dropped.

If that's the case,then there is a very simple solution, which is that, if we could just increasethe chaperone levels in the brain, then we could have a treatmentfor these diseases, and perhaps even reverse them.

So there is some hopeabout these neurodegenerative diseases.

I also promisedI was going to talk about cancer.

How do chaperoneshave anything to do with cancer? At the basic level, cancer occurswhen a single cell goes rogue, and that means it acquires a mutation that escapes the normal controlthat keeps the cells in check, and then instead of functioningas a part of the whole body, it decides it's just goingto grow and grow and grow, take the resources awayfrom 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 occurin genes, and many of these genes, like I said before, code for proteins.

So if you have a mutation in a genethat leads to a mutation in a protein, and mutations in proteinscan make proteins more difficult to fold.

It turns out that manyof the most cancer-causing mutations actually do cause proteinsto 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 outhow to highjack chaperones.

Cancer cells have figured out how to take the level of chaperonesand artificially raise them in order to bufferagainst the misfolding effects that might be caused by the mutations.

Cancer cells rely very heavilyon these elevated levels of chaperones.

Again, we have a very simple idea, which is that cancer cells requirechaperones in order to survive.

So if we could somehow decreasethe level of chaperones in cancer cells, then we could unmask these mutations,and their proteins could aggregate, and we could have a wayof cancer self-destructing.

It could really bean Achilles heel for cancer.

Cancer and Alzheimer's disease actually have somethingfundamentally in common at the root, and that isan opposite requirement for chaperones.

In diseases like Alzheimer's,chaperone levels drop, misfolded proteinsaccumulate and aggregate, and that leads to cell death.

Whereas in cancer, cancer has mutationsthat it needs to buffer against, so it figures out how to raisethe 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 thisas a whack-a-mole problem.

(Laughter) You can imagine if we tried to knock down the level of chaperonesto 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 lowthat in the brain they drop, and then we get misfolded proteinsand get neurodegenerative diseases.

So rather than takingthis sledgehammer approach, what we really needis a Goldilocks approach.

We need the porridge not to be too hotor too cold, but to be just right.

What that means is we need to figure outhow to fine-tune chaperon levels, and we need to do this in a targeted way, to target to the cell typesthat really need them.

In thinking about this, we really think this isan Achilles heel for all cancers.

All cancers rely on mutations, all cancers have increased levelsof misfolded proteins, and all cancersseem to rely on chaperones.

Of course, there areexceptions to any rule, but all subtypes of cancers are going to have somethingthat can be treated this way.

We think if we could figure outhow to target chaperone levels in cancers, it wouldn't just be a curefor breast cancer or pancreatic cancer, but it could potentially be beneficialfor all different types of cancer.

On the other hand, if we thinkabout diseases like Alzheimer's where we have not enough chaperones, if we could increasethe level of chaperones and specifically in the brainand specifically as we age, then we think we could havea treatment not just for Alzheimer's, but for Parkinson's, for ALS,for Huntington's, et cetera.

We really hope that we've founda fundamental process that's related to bothof these different types of diseases.

What we're studying in my labis just how do we do this.

How do we fine-tunethese chaperone levels? We've figured out alreadyhow we can slam down on them or increase them way too much, but the fine-tuning mechanismis 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 thisin a fine-tuned and targeted way, then we could dialthe appropriate level of chaperones for an individual personin an individual case.

And we could dial it to ALS, or dial it down a bitif there is a bit of cancer, and hope to get this in the right place, so that rather than gettingeither cancer or Alzheimer's disease, we get neither of these diseases.

Thank you very much.


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