Cell Death Nets 2002 Nobel Prize in Medicine

An anonymous reader writes "The recent press release at the Nobel website details the first of the 2002 Nobel Prizes. This year the Medicine prize goes to Sydney Brenner, H. Robert Horvitz, and John E. Sulston for their discovery of programmed cell death (also called apoptosis). Their seminal work in the model organism C. elegans established the foundation of cell suicide as a normal physiologic process. The implications are wide ranging including understanding organ development and cancer."

Comments

Re:Death?

[Trinition]

could understanding why cells die when they do help create ways to make us live longer?

Certainly. For example, there is a theory that free radicals (oxygen atoms sometimes released during the fuel generation accomplished by our mitochondria) cause damage to the DNA of a cell. There are "sweepers" in our cells that are supposed to suck up these free radicals, but som get away and damage our cells.

Studies have shown in laboratory animals that high-antioxidant diets extend the lifetime of animals. In one particular test, a very simple worm's life was DOUBLED compared ot the control population when a special, synthetic anti-oxidant was fed to it.

I don't know how related, if at all, programmed cell death is to free radicals and antioxidants, but as you suggested, once you figure out an effect, you can try to figure out a way to prevent or reverse the effect.

What was it G.I. Joe said? Knowng is half the battle

A practical example

[madcoder47]

After working for several years at an Immunology lab at Harvard, It's very nice to see people finally get credit for discovering apoptosis. I use it in the lab as a core immunosuppressive therapy, only in mice and monkeys as of yet -- and by harnessing the power of apoptosis (PCD) we have so far created a treatment which acts like a powerful immunosuppressant to transplanted allografcts, without all the harmful side effects.
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While it may sound pretty violent or harmful, Apoptosis is not only a natural process, but it has also opened up new gateways into research in many different fields.

Understanding Cell Death and Regulatory Switches

[Salis]

The next step is to quantify the signals (chemicals) responsible for triggering the series of events that are called apoptosis and to elucidate just how transcription switches work. All 'switches' in the body are based off the concentration of various molecules, be they enzymes, cofactors, structural proteins, minerals (Na+, K+, Ca+), etc. The most interesting exploration would entail studying how a concentration of a signal yields a binary switch, that an event either be triggered or not.

The cell widely uses feedback loops, both positive and negative, to exponentially increase and decrease the amount of signal that is being produced at any one time. This signal may interact with other signal-producers to give a multi-signal, multi-enzyme response system that, through the non-linear dynamics of the system, yields a definitive high and low concentration of signal that determines whether an event is to be triggered or not.

To fully understand the mind-boggling complexity of a single cell, imagine a system composed of 5000 enzymes (or more) all interacting with 10,000 molecules (or more) with thousands of possible reactions. Now try to simulate this all at the same time, using non-linear kinetics, and predict the outcome of an initial state.

A lot of crazy things happen, including shifts in entire groups of genes (responsible for protein & sRNA synthesis) caused by very tiny disturbances. The non-linear dynamics of the cell are set up so perfectly that its self-regulation is simply amazing.

My Two Cents...not meant to be a full explanation of why apoptosis is so cool or where the research is going from there.

Salis

Apoptosis 101

[DjMd]

People have asked and speculated as to the usefullness as to preventing or inducing apoptosis.

Cancer is caused by mutation on a single cell level. In order to divide, grow, resist the immune system, spread locally, develop a blood supply, and finally spread to distant sites a cell needs to mutate.

The list of mutations literally reads as check list of to-do's... Some of the first level requirements involve turning on the growth cycle, and turning off the mechanism of automatic cell death. Many cancers are 'immortal' cells. It is litterally one cell that grows and divides. Cloning itself over and over...

If you could force the cells to apoptose, (or disable their overide of the natural apoptotic cycle) you could defeat a great many cancers...

That is of course an over simplification, most cancers do the same thing but the method they use is very different (thus there is no magic bullet on the horizon)


How do I know? check the name djmd

Re:Cells not dying or over-multiplying?

[Idarubicin]

Isn't cancer caused by cells multiplying too rapidly?

It's a little bit of both. Cancer is the result of uncontrolled cellular replication due to genetic damage to cellular regulatory machinery. Apoptosis is supposed to kill off cells that have problems with their internal structure (for example, a genetic error causing a fault in the systems that regulate growth and proliferation) as well as cells at the end of their useful lifespan.

If we could make periodic adjustments to the way cells replicate perhaps this would work?

And you've just hit on the holy grail of oncology. Unfortunately, we can't just tell all the body's cells to commit suicide. Cures cancer--but results in unsatisfied customers. And some quickly replicating cells are supposed to be that way (bone marrow, gut lining, hair, etc.) so we can't even just mow down fast-growing cells. Actually, that's sort of what chemo and radiation therapies do in a very ham-fisted way--toast all the fast-growing cells, and hope that the cancer dies faster than the rest of the body. It's why chemo makes your hair fall out, and causes anemia and nausea.

Rest assured, however, that your tax dollars are hard at work on a solution.

I've also heard that hair/nails can still grow for some time after death? I suppose those cells keep on going. Creepy

This one is mostly an urban legend. Mostly, it's due to the slight dessication/dehydration the body underdoes after death. There's a bit of evaporation, and shrinkage. Contraction of surrounding tissue can force hair and nails to protrude further than before death, giving a perception of growth. Also, there were cases up until the last century or so that involved patients in deep coma states--still alive, but apparently dead. Yes, hair and nails grew on those 'dead' people. And they got pissed off when they got buried.

Apoptosis d/n = Free Radical theory

[MichaelPenne]

Uhh, AFAIK, the programmed cell death = why we age theory has nothing do do with the various free radical charlatans.

Rather, programmed cell death in the context of aging has to do with the loss of telomeric DNA, (non-coding 'tags' on the end of DNA molecules that form a place for DNA polymerase to bind when copying the DNA).

The part of the telomere where the DNA poly first binds doesn't get copied & eventually (after reaching a number of divisions known as the 'Hayflick limit') the cell has no more telomeres & so can't divide anymore, at which point it undergoes programmed cell death.

There are other signals that activate PGD, such as viral infections and early stages of cancer (where the sad association with vitamen C overdosing came in: if the cell was damaged by 'free radicals', it should undergo apoptosis, but this would be a symptom not a cause), but the type of PGD usually referred to in aging studies is this 'molecular clock' that keeps count of how many times the cell has divided in aging (of some tissues) is then caused by many cells of that tissue reaching the hayflick limit and self destructing.

This theory of aging doesn't seem to completely cover the issue, but it does have alot more backing in scientific research than the free radical stuff. More:
http://www.nature.com/nsu/020819/020819-13. html

Interestingly, many "Lower" animals, along with germ (sperm & egg progenitors) cells & cancer cells make an enzyme called telomerase which rebuilds the telomere, making these cells essentially immortal.

On the subject of aging, Geron is trying to find ways to reverse some effects of aging (at least those caused by PCD due to shortened telomeres) using telomerase:
http://www.geron.com/02.01_telomerase .html

Re:Apoptosis d/n = Free Radical theory

[aswang]

I agree, apoptosis and necrosis due to oxidation are not the same thing, but if you agree with the current elucidated mechanisms, they are not unrelated.

The point that they have in common is alteration of mitochondrial membrane permeability. In apoptosis, different signal transduction cascades (initiated by factors such as FasL found on cytotoxic T cells that can therefore kill virus-infected or tumor cells, TNF [tumor necrosis factor] secreted by macrophages in inflammation, and tumor suppresor genes like p53 and Rb which initiate apoptosis after sensing DNA damage) affect the balance between pro-apoptotic proteins (e.g. Bax and Bad) and anti-apoptotic proteins (e.g. Bcl-2 and Bcl-XL). (These proteins are analogs of the ced gene products found in C. elegans) If the pro-apoptotic proteins win out, mitochondrial membrane permeability is altered, cytochrome c gets dumped into the cytosol (essentially stopping ATP production), and the caspases (which are also proteins that are analogs of the ced gene products) are activated and proceed to effectively dismantle the cell. Similarly, oxidation of the cell membrane alters cell permeability, causing, among other things, a massive influx of calcium, which in turn also alters mitochondrial membrane permeability, once again dumping cytochrome c into the cytosol and activating caspases.

Another way that oxidation is linked to apoptosis is that free radicals damage DNA. The damaged DNA is sensed by products of tumor suppressor genes such as p53 and Rb, and apoptosis is initiated.

In most cases of pathological cell death, both necrosis (which is essentially the unregulated death of a cell due to loss of membrane integrity, inadvertant release of destructive enzymes, and destruction of critical regulatory proteins) and apoptosis (which is by contrast exquisitely regulated) are occurring simultaneously.

And while telomerase serves an interesting purpose in regulating the cell cycle, it is by no means the only cause of aging. Most of the pathology of aging is caused by mechanical and structural damage to cells: the accumulation of intracellular debris, wear and tear on the cytoskeleton, damage to the genome. While free radicals aren't the only factors that cause this damage, they undoubtedly do have a significant effect.

Telomerase is only important in cells that continue to divide, but the organ systems that are most affected by aging are typically populated by cells that don't really reproduce at all or at least reproduce very infrequently, such as neurons in the brain and myocytes in the heart.

Re:Unrelated to human death.

[ebuck]

So when all your cells die, you go on living?

If so, we've found the scientific foundation for defining the afterlife.

Seriously, some cell death is vital for correct development of the tissues and complex structures that we all carry around. But by understanding cellular death, we might better understand cellular stasis and cellular growth. Every piece of the puzzle hints at what is missing.