10 ms·

This article doesn't quite spell it out, but the current thinking is that the apparent paradox is explained by: 1. Bigger animals have larger cells, so the num

by Gatsky 4y ago

This article doesn't quite spell it out, but the current thinking is that the apparent paradox is explained by: 1. Bigger animals have larger cells, so the number of cells does not scale linearly with the mass of the animal. 2. Cells from larger animals are more resistant to cancer development in various ways (eg more copies of TP53, more propensity to die after DNA damage). 3. Large animals have non-linear metabolic scaling. So a cell in an elephant sees fewer metabolic cycles per unit time than a cell in a mouse. Some of this is due to the greater thermal efficiency of large animals. Now that we have more detailed data on animals, I think this paradox is a bit less interesting, albeit generally true. For example, there are some animals that just don't seem to get cancer (eg the blackbuck and the Patagonian mara, from several hundred autopsies each) [1]. Cancer is also very rare in Zebras. This is fundamentally interesting because it shows that being free from cancer is possible in an otherwise normal looking mammal. In theory therefore, we could consider engineering humans to be cancer free. To me, given the high incidence of cancer, the progressively increasing incidence in an ageing population and the incredible amount of misery it causes, this is the most ethically palatable reason to consider widespread genetic modification of humans. I think all anti-ageing efforts will ultimately bump up against cancer as the limiting factor. The technology to safely genetically engineer humans is nowhere near ready for prime time. The association between height and cancer is not thought to be due to 'more cells'. It only applies to some types of cancer and not others. It is believed to be due to growth factor signalling eg growth hormone and insulin-like growth factors. [1] https://www.nature.com/articles/s41586-021-04224-5 https://www.nature.com/articles/s41586-021-04224-5

mistrial9 4y ago
> we could consider engineering humans to be cancer free following until you get to that.. there are multiple mechanisms in the body that can result in "cancer" .. its an end result, not the cause. The jump to "we can engineer this out" is exactly what a reader would expect from an investment-and-profit medical company. There are untold numbers of small poisons and behavioral habits that are known to increase cancer inducement in humans.. all of which could be addressed, but there is little profit in prevention. Overall, I am taking the time to write this because a rush to genetic engineering is something that might behave like cancer itself over time.
- OkayPhysicist 4y ago
  >> a rush to genetic engineering is something that might behave like cancer itself over time. Can you elaborate on this? To me, it seems perfectly reasonable that a directed and intentional process of man-made engineering could blow the random process of evolution out of the water, both in timescale and in effectiveness. For example, there's not really an evolutionary advantage to eliminating geriatric cancer: kids have been made, genes have been passed, in all likelihood multiple generations down by the time old-age related illnesses develop. Yet, we want to live longer, and live better lives during that time, so we can take the reigns and address what evolution couldn't.
  - dylan604 4y ago
    What's the quote, "in their speed to find a solution, they never slowed down to think if they should"? There are plenty of examples of humans rushing to market something they think works one way but upon a much longer study, the results are something much worse than if we had not instead. Heavy use of asbestos, heavy use of lead in fuel, paint, etc. Genetically modifying anything just sounds like the most obvious of things that should be studied for much much longer than whatever the first company looking to profit is wanting.
    - Gatsky 4y ago
      Agree, this is something that would take centuries probably. The most plausible way to do it would be including extra copies of TP53 under appropriate regulation. This has been done in mice and they seem fine. Unfortunately, it would need to be done in larger animals progressively to show safety, which would take 20 - 30 years for a full lifecourse study in primates (unfortunate because we are experimenting on primates). Even longer if their lifespan is increased. After that, we would be left with a conundrum, which is the ethics of modifying the germline of an embryo. I don't know what the solution is there. Maybe it could be justified in families with an elevated risk of cancer, or Mars colonists for whom any sort of cancer will be a death sentence. Another option would be an as yet uninvented way to edit the genome, but provide an 'Undo' function to reverse the edit, say by giving some small molecule.
wbillingsley 4y ago
I've always been curious that old dogs often get cancer, despite "old" for a dog only being the early teens as well as dogs being smaller.
- thewebcount 4y ago
  I asked a doctor about this once. He said that as any animal ages, the protective mechanisms they have eventually break down, and either work less well or stop working. In dogs, they break down sooner than in humans. For example, the ends of chromosomes have telomeres[0]. When chromosomes are copied they can’t copy the full length of the chromosome, so every copy has fewer of these telomeres. When they eventually run out of telomeres, cell division stops happening. (I don’t know whether dog chromosomes have fewer telomeres or if it’s some other mechanism, but telomeres are an example of a cellular mechanism that has a limited lifetime.) [0] https://en.wikipedia.org/wiki/Telomere https://en.wikipedia.org/wiki/Telomere
  - rich_sasha 4y ago
    What I never understood is that, for the most part, a 30-something year old male and female can create a pristine new being from their already-slightly-knackered cells. I know it breaks down somewhat with age. So... we can create pristine new life with biological clock reset at 0, but not do so for our own bodies.
    - IanCal 4y ago
      Women are born with all their eggs, which do deteriorate. The vast majority won't make it all the way through puberty even (lots will be gone by the time they're actually born). That's why there's a drop-off in fertility over time.
    - Gatsky 4y ago
      Women are born with their supply of eggs, so they are more ‘pristine’ than any other cell. Sperm are generated continuously throughout life, and there is evidence sperm quality decreases over time. Some diseases associate with increasing age of the father (autism, schizophrenia). The effect takes hold mainly after paternal age 40. Having said that, I recall there is some work showing sperm generating cells are kinda special in that they don’t develop as much mutational damage as other cells. Does make you worry though that progressive generations of older and older fathers may lead to some kind of problem. With rates of assisted fertility increasing, perhaps 16 yo boys should bank sperm for the future.
odabaxok 4y ago
> 1. Bigger animals have larger cells, so the number of cells does not scale linearly with the mass of the animal. Where is this coming from? If I google "do larger animals have larger cells", it says the opposite.
- Gatsky 4y ago
  The wikipedia article has a section on it. But just consider nerve cells that control limbs. A nerve cell consists of a neuronal body and a long axon. If you have a longer limb, you will need a longer axon, and therefore a larger neuronal body to maintain it.

by Gatsky 4y ago

mistrial9 4y ago

> we could consider engineering humans to be cancer free following until you get to that.. there are multiple mechanisms in the body that can result in "cancer" .. its an end result, not the cause. The jump to "we can engineer this out" is exactly what a reader would expect from an investment-and-profit medical company. There are untold numbers of small poisons and behavioral habits that are known to increase cancer inducement in humans.. all of which could be addressed, but there is little profit in prevention. Overall, I am taking the time to write this because a rush to genetic engineering is something that might behave like cancer itself over time.

OkayPhysicist 4y ago
>> a rush to genetic engineering is something that might behave like cancer itself over time. Can you elaborate on this? To me, it seems perfectly reasonable that a directed and intentional process of man-made engineering could blow the random process of evolution out of the water, both in timescale and in effectiveness. For example, there's not really an evolutionary advantage to eliminating geriatric cancer: kids have been made, genes have been passed, in all likelihood multiple generations down by the time old-age related illnesses develop. Yet, we want to live longer, and live better lives during that time, so we can take the reigns and address what evolution couldn't.
- dylan604 4y ago
  What's the quote, "in their speed to find a solution, they never slowed down to think if they should"? There are plenty of examples of humans rushing to market something they think works one way but upon a much longer study, the results are something much worse than if we had not instead. Heavy use of asbestos, heavy use of lead in fuel, paint, etc. Genetically modifying anything just sounds like the most obvious of things that should be studied for much much longer than whatever the first company looking to profit is wanting.
  - Gatsky 4y ago
    Agree, this is something that would take centuries probably. The most plausible way to do it would be including extra copies of TP53 under appropriate regulation. This has been done in mice and they seem fine. Unfortunately, it would need to be done in larger animals progressively to show safety, which would take 20 - 30 years for a full lifecourse study in primates (unfortunate because we are experimenting on primates). Even longer if their lifespan is increased. After that, we would be left with a conundrum, which is the ethics of modifying the germline of an embryo. I don't know what the solution is there. Maybe it could be justified in families with an elevated risk of cancer, or Mars colonists for whom any sort of cancer will be a death sentence. Another option would be an as yet uninvented way to edit the genome, but provide an 'Undo' function to reverse the edit, say by giving some small molecule.

wbillingsley 4y ago

I've always been curious that old dogs often get cancer, despite "old" for a dog only being the early teens as well as dogs being smaller.

thewebcount 4y ago
I asked a doctor about this once. He said that as any animal ages, the protective mechanisms they have eventually break down, and either work less well or stop working. In dogs, they break down sooner than in humans. For example, the ends of chromosomes have telomeres[0]. When chromosomes are copied they can’t copy the full length of the chromosome, so every copy has fewer of these telomeres. When they eventually run out of telomeres, cell division stops happening. (I don’t know whether dog chromosomes have fewer telomeres or if it’s some other mechanism, but telomeres are an example of a cellular mechanism that has a limited lifetime.) [0] https://en.wikipedia.org/wiki/Telomere https://en.wikipedia.org/wiki/Telomere
- rich_sasha 4y ago
  What I never understood is that, for the most part, a 30-something year old male and female can create a pristine new being from their already-slightly-knackered cells. I know it breaks down somewhat with age. So... we can create pristine new life with biological clock reset at 0, but not do so for our own bodies.
  - IanCal 4y ago
    Women are born with all their eggs, which do deteriorate. The vast majority won't make it all the way through puberty even (lots will be gone by the time they're actually born). That's why there's a drop-off in fertility over time.
  - Gatsky 4y ago
    Women are born with their supply of eggs, so they are more ‘pristine’ than any other cell. Sperm are generated continuously throughout life, and there is evidence sperm quality decreases over time. Some diseases associate with increasing age of the father (autism, schizophrenia). The effect takes hold mainly after paternal age 40. Having said that, I recall there is some work showing sperm generating cells are kinda special in that they don’t develop as much mutational damage as other cells. Does make you worry though that progressive generations of older and older fathers may lead to some kind of problem. With rates of assisted fertility increasing, perhaps 16 yo boys should bank sperm for the future.

odabaxok 4y ago

> 1. Bigger animals have larger cells, so the number of cells does not scale linearly with the mass of the animal. Where is this coming from? If I google "do larger animals have larger cells", it says the opposite.

Gatsky 4y ago
The wikipedia article has a section on it. But just consider nerve cells that control limbs. A nerve cell consists of a neuronal body and a long axon. If you have a longer limb, you will need a longer axon, and therefore a larger neuronal body to maintain it.