> DNA not only contains the most basic information, but all the information.
This is simply false. I don't understand why you would make this claim. You mention counterexamples below (e.g. PTMs). As you know, DNA dictates whether a protein can be expressed or not, but not whether it is expressed in any particular cell, how much is expressed, or whether and how much is activated or otherwise modified over time. And, of course, it can't contain environmental factors, such as the gut microbiome from the OP.
> Isolating a single protein, looking at its expression, and assaying activity is not only the bane of every biochemists existence, it takes a significant amount of time and would have to be done for every single enzyme that we want to look at.
I worked for a few years in a lab doing quantitative protein expression, including certain PTMs, that can compare multiple states (e.g with and without a drug, or in different tissues) across a large section of the proteome. This was not particularly new 10 years ago, but it is a lot of work, and sensitivity, specificity, and practicality is still improving rapidly.
> Why would I want a snapshot of something when I need to predict drug-gene interaction before I give someone a drug?
Because there are cases (probably the majority) where drug-gene interaction is insufficient.
I'm certainly not trying to argue that there aren't significant examples where the gene existence is sufficient. It sounds like that will continue to be an essential part of diagnosis and treatment. It is not surprising that current state of the art stops at these straightforward gene-based analyses, but it is surprising that you think it will be sufficient going forward and don't think the nuance of real protein expression will be useful. There is so much room between measuring "gene-existence" and measuring "intelligence". Adding pharmacoproteomics to your list of "ways 21st century medicine will be awesome" is a pretty gentle request!
If DNA doesn't code for everything then you deserve the Nobel prize because there isn't any other mechanism for how cells derive structure and function from that is known outside of this conversation. What else codes for PTM, ubiquitination, and basal level expression.
>DNA dictates whether a protein can be expressed or not, but not whether it is expressed in any particular cell, how much is expressed, or whether and how much is activated or otherwise modified over time.
It does determine whether it is expressed and how much is expressed. The difference between being a heterzygote and homozygote for certain proteins literally determines whether one will have fully protein expression or half. When a gene is doubled in the genome its expression is usually doubled as well.
>Because there are cases (probably the majority) where drug-gene interaction is insufficient.
80-90% of drugs are metabolized by CYP2D6, CYP2C19, CYP2C9, CYP3A4 and CYP3A5 to which we are starting to isolate polymorphisms in the general public. This isn't that difficult to do the genotyping, but what's limited right now is correlating polymorphism to what the side effect of drug is; this is going to be purely a time and data collection issue. I'm curious what your examples would be, because the majority of cases I've been apart of it's a simple base pair substitution that cause deleterious effects.
This is simply false. I don't understand why you would make this claim. You mention counterexamples below (e.g. PTMs). As you know, DNA dictates whether a protein can be expressed or not, but not whether it is expressed in any particular cell, how much is expressed, or whether and how much is activated or otherwise modified over time. And, of course, it can't contain environmental factors, such as the gut microbiome from the OP.
> Isolating a single protein, looking at its expression, and assaying activity is not only the bane of every biochemists existence, it takes a significant amount of time and would have to be done for every single enzyme that we want to look at.
I worked for a few years in a lab doing quantitative protein expression, including certain PTMs, that can compare multiple states (e.g with and without a drug, or in different tissues) across a large section of the proteome. This was not particularly new 10 years ago, but it is a lot of work, and sensitivity, specificity, and practicality is still improving rapidly.
> Why would I want a snapshot of something when I need to predict drug-gene interaction before I give someone a drug?
Because there are cases (probably the majority) where drug-gene interaction is insufficient.
I'm certainly not trying to argue that there aren't significant examples where the gene existence is sufficient. It sounds like that will continue to be an essential part of diagnosis and treatment. It is not surprising that current state of the art stops at these straightforward gene-based analyses, but it is surprising that you think it will be sufficient going forward and don't think the nuance of real protein expression will be useful. There is so much room between measuring "gene-existence" and measuring "intelligence". Adding pharmacoproteomics to your list of "ways 21st century medicine will be awesome" is a pretty gentle request!