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Not to take away from these findings, but in general, individual genetics can radically change the way many drugs work, and even doctors seem blissfully unaware

Not to take away from these findings, but in general, individual genetics can radically change the way many drugs work, and even doctors seem blissfully unaware of this. Caffeine, for example, has a different elimination half-life based on your genetics. There are also genetic polymorphisms in adenosine and dopamine receptors that can change its effects: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242593/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242593/. Another obvious example is how some people can't process alcohol. If you think about this for a minute, it sheds some light into how primitive medical research is. We generally assess the effectiveness of a drug based on how it affects one metric on average for a large group of people. It could well be that a drug is helpful to some and detrimental to others based on genetics, microbiome, etc. It follows that we are very likely to be giving people drugs that are harmful to them, and rejecting drugs in medical studies that could be helpful to some but are unhelpful to most.

Medicalidiot 7y ago
These are all salient points and I would like to comment as someone who has experience in medicine. We are truly on the precipice of so many breakthroughs in the medical field. Cancer is going to be a chronic condition soon. HIV will likely be gone in our lifetime. Congenital diseases will be eradicated very soon. What's going to also happen that mainstream media has failed to grasp the gravity of is pharmacogenomics/pharmacogenetics. Essentially what we are going to do the second you enter the ED/PCP/PreOP is sequence your DNA. Then we will tailor your drug regime based on your phenotype (What traits/characteristics you have expressed). This kind of thing was just imaginary, but last year I listened to one of the world's leading pediatric pharmacogenomicists that had a half dozens cases he shared; one of them was having a 16 y/o female that presented with depression that was not ameliorated with first line SSRI. Upon sequencing her genome they realized that her phenotype was incompatible with this SSRI, switched her and upon 4 week followup her symptoms were significantly reduced. The 20th century was the century of physics, the 21st will be the century of biology.
- tachyonbeam 7y ago
  > The 20th century was the century of physics I'd argue that the 20th century was the beginning of the information age, and if you'd like to roll that under physics, then I would respond that computers are as much physics as medicine/biotech is.
- jmilloy 7y ago
  Isn't your DNA largely insufficient for determining phenotype, particularly locally as in the case of cancerous cells? It takes a tremendous amount of chemical and software processing to capture a snapshot of quantitative protein expression, and even more to measure, say, phospho-regulated protein expression, but that is what is really needed for diagnosis and tailored treatment. You may be right about the "precipice", but I feel like you are over-selling pharmacogenomics.
  - Medicalidiot 7y ago
    Definitely for certain things like intelligence, but many disease processes will be one gene coding one deleterious enzyme. For example Hyper-IgE syndrome will be a STAT3 mutation, Cystic Fibrosis is going to be a change typically at 508 to F(amino acid phenylalanine) on the CFTR gene, and Menkes disease, with its kinky hair, is going to have a mutation with ATP7A. These phenotypes are easy to recognize because the symptoms precipitate so significantly that most individuals die prematurely and because we've isolated them time and time again in the same diseased individuals. My point here is that isolating a phenotype from a genotype is pretty easy for a significant amount of polymorphisms. Now what makes drug metabolism easy to understand is that it will typically be one gene that codes for one enzyme (I'm overly simplifying this here, it's way more complicated and we don't fully understand gene expression). It will also usually be one enzyme that is going to break down a certain drug (I'm also oversimplifying this). Let's look at ethanol; it's broken down by alcohol dehydrogenase to acetaldehyde, the thing that gives you the hang over. Certain populations, Asian and Native Americans namely, have a different alcohol dehydrogenase enzyme than other populations and thus have a common effect; colloquially termed Asian flush. This variability in how an enzyme breaks down a drug is part of the reason why some people will have certain effects whereas other people won't (overly simplified, again). Pharmacogenomics is actually one of the more easy phenotypes to delineate versus other, more nebulous, things.
amelius 7y ago
> It follows that we are very likely to be giving people drugs that are harmful to them Yes, or the wrong dosages.
mkagenius 7y ago
> Caffeine, for example, has a different elimination half-life based on your genetics. I don't really feel woken up by coffee, could that be related? Nothing helps more than being hydrated (after 8 hours of no water) and ample sleep time.
- tachyonbeam 7y ago
  AFAIK some people also have a different variant of the adenosine receptor that makes it so caffeine doesn't bind to it in the same way. I recall seeing a study about this pass by, you might be able to find it with some googling. There's also a question of tolerance of course. If you drink coffee every day, then after a while you build tolerance and the effect becomes much milder. In order to assess whether coffee is effective you would need to take a break for a week. I know that when I have no tolerance, a strong cup of coffee has a very strong effect, I feel an instant mood lift and become much more active, I want to spend energy.
- a_random_name 7y ago
  It's also possible that your brain is impacted by caffeine differently. I have adhd and caffeine can make me feel sleepy sometimes.
mft_ 7y ago
Most doctors are probably intellectually aware of the concept/possibility... but powerless to influence anything because a) we don't have usable genetic information available on people, and b) we don't routinely have information on the impact of different genetics on drugs.
GordonS 7y ago
I totally agree with this, as I (unfortunately) have a lot of experience in taking pharmaceuticals and having adverse side effect. But while academia is coming to the conclusion that genetics (and often enzyne activity as a direct result) play a huge role in drug response, it will be decades before we see any real change as a result. I can understand to some degree, but sometimes the pace of change in medicine is truely maddening.
- tachyonbeam 7y ago
  I think the huge amount of regulation and barriers in the field are largely to blame. You can't really have pharma startups the way you can have tech startups. You couldn't just start a company tomorrow and start incrementally prototyping a drug by testing it on people (or even animals) with lots of genetic testing... Even though I'm sure a lot of people (eg: cancer patients) would gladly volunteer.

Medicalidiot 7y ago

These are all salient points and I would like to comment as someone who has experience in medicine. We are truly on the precipice of so many breakthroughs in the medical field. Cancer is going to be a chronic condition soon. HIV will likely be gone in our lifetime. Congenital diseases will be eradicated very soon. What's going to also happen that mainstream media has failed to grasp the gravity of is pharmacogenomics/pharmacogenetics. Essentially what we are going to do the second you enter the ED/PCP/PreOP is sequence your DNA. Then we will tailor your drug regime based on your phenotype (What traits/characteristics you have expressed). This kind of thing was just imaginary, but last year I listened to one of the world's leading pediatric pharmacogenomicists that had a half dozens cases he shared; one of them was having a 16 y/o female that presented with depression that was not ameliorated with first line SSRI. Upon sequencing her genome they realized that her phenotype was incompatible with this SSRI, switched her and upon 4 week followup her symptoms were significantly reduced. The 20th century was the century of physics, the 21st will be the century of biology.

tachyonbeam 7y ago
> The 20th century was the century of physics I'd argue that the 20th century was the beginning of the information age, and if you'd like to roll that under physics, then I would respond that computers are as much physics as medicine/biotech is.
jmilloy 7y ago
Isn't your DNA largely insufficient for determining phenotype, particularly locally as in the case of cancerous cells? It takes a tremendous amount of chemical and software processing to capture a snapshot of quantitative protein expression, and even more to measure, say, phospho-regulated protein expression, but that is what is really needed for diagnosis and tailored treatment. You may be right about the "precipice", but I feel like you are over-selling pharmacogenomics.
- Medicalidiot 7y ago
  Definitely for certain things like intelligence, but many disease processes will be one gene coding one deleterious enzyme. For example Hyper-IgE syndrome will be a STAT3 mutation, Cystic Fibrosis is going to be a change typically at 508 to F(amino acid phenylalanine) on the CFTR gene, and Menkes disease, with its kinky hair, is going to have a mutation with ATP7A. These phenotypes are easy to recognize because the symptoms precipitate so significantly that most individuals die prematurely and because we've isolated them time and time again in the same diseased individuals. My point here is that isolating a phenotype from a genotype is pretty easy for a significant amount of polymorphisms. Now what makes drug metabolism easy to understand is that it will typically be one gene that codes for one enzyme (I'm overly simplifying this here, it's way more complicated and we don't fully understand gene expression). It will also usually be one enzyme that is going to break down a certain drug (I'm also oversimplifying this). Let's look at ethanol; it's broken down by alcohol dehydrogenase to acetaldehyde, the thing that gives you the hang over. Certain populations, Asian and Native Americans namely, have a different alcohol dehydrogenase enzyme than other populations and thus have a common effect; colloquially termed Asian flush. This variability in how an enzyme breaks down a drug is part of the reason why some people will have certain effects whereas other people won't (overly simplified, again). Pharmacogenomics is actually one of the more easy phenotypes to delineate versus other, more nebulous, things.

amelius 7y ago

> It follows that we are very likely to be giving people drugs that are harmful to them Yes, or the wrong dosages.

mkagenius 7y ago

> Caffeine, for example, has a different elimination half-life based on your genetics. I don't really feel woken up by coffee, could that be related? Nothing helps more than being hydrated (after 8 hours of no water) and ample sleep time.

tachyonbeam 7y ago
AFAIK some people also have a different variant of the adenosine receptor that makes it so caffeine doesn't bind to it in the same way. I recall seeing a study about this pass by, you might be able to find it with some googling. There's also a question of tolerance of course. If you drink coffee every day, then after a while you build tolerance and the effect becomes much milder. In order to assess whether coffee is effective you would need to take a break for a week. I know that when I have no tolerance, a strong cup of coffee has a very strong effect, I feel an instant mood lift and become much more active, I want to spend energy.
a_random_name 7y ago
It's also possible that your brain is impacted by caffeine differently. I have adhd and caffeine can make me feel sleepy sometimes.

mft_ 7y ago

Most doctors are probably intellectually aware of the concept/possibility... but powerless to influence anything because a) we don't have usable genetic information available on people, and b) we don't routinely have information on the impact of different genetics on drugs.

GordonS 7y ago

I totally agree with this, as I (unfortunately) have a lot of experience in taking pharmaceuticals and having adverse side effect. But while academia is coming to the conclusion that genetics (and often enzyne activity as a direct result) play a huge role in drug response, it will be decades before we see any real change as a result. I can understand to some degree, but sometimes the pace of change in medicine is truely maddening.

tachyonbeam 7y ago
I think the huge amount of regulation and barriers in the field are largely to blame. You can't really have pharma startups the way you can have tech startups. You couldn't just start a company tomorrow and start incrementally prototyping a drug by testing it on people (or even animals) with lots of genetic testing... Even though I'm sure a lot of people (eg: cancer patients) would gladly volunteer.