Grand Unification Theory (in Physic not Physics)

[-SB-]

Hi chaps,
I'm going to keep this short and sweet.
After 30 years of doing what you guys do and surfing from radioactive sequencing through into the world of nanopore and passing through countless academic groups, biotech and pharmaceutical corporations using the same ultra-high throughput techniques (from FRET to PHRED) - I think that a single, simple answer is about to emerge.

From a strict perspective of health (the diseases of Western living)

There are 2 metabolic biochemical states (in effect 'FED' (high GI carb + protein or the Ins/IGF-1 promoting state) and 'FASTED' states (recapitulated through a certain profile of low GI veggie and certain types of oil)).

1. These 2 biochemical states drive 2 mutually exclusive genetic networks.
2. The 'FED' network gives rise to growth (and internal damage through consequence of increased energy (ROS etc) expenditure).
3. The 'FASTED' network gives rise to internal house-keeping procedures.
4. The 'FASTED' state is (naturally) essential for health.
5. The 'FASTED' state can't be recapitulated in 'FED' state as they're fundamentally mutually exclusive like binary 1 and 0.
6. In the absence of awareness of these 2 genetic networks, ALL drug discovery programs (clinical trials) (testing people in the 'FED' not 'FASTED' state are off).
7. --- example --- Imagine if TNFa (the current #1 selling drug is anti-TNFa) is essential for infectious disease clearance, tumour surveillance in 'FASTED' state ie is essential for health in the 'FASTED' state and we introduce an inhibitor for it - we're destroying our own capacity to 'clean' ourselves.

The two heavyweight champions of the world - NGS and biologics appear to have an issue with one another - much like NGS and CRISPR in the last heavyweight belt unification bout - thanks to one of Allan B's latest papers where NGS emerged supreme. Am wondering whether PacBio's lovely long reads will topple Illumina ... ... it's all happening, isn't it ?

[-SB-]

Apologies - can't edit the post above.

I've sent this basic idea to the 2 human longevity organizations (Craig V's (boo!) and Valter L's (yay!)) in San Diego and San Francisco as they've the sequencing rigs to prove it all.
I however am unemployed since Friday and so unable to prove any of it.

All as stated in The Book of Simpsons.

http://www.youtube.com/watch?v=qqrCoyVK80I

Try '50 years old' (give or take a few days) and I made £72.40 per week for 6 months on Job seeker's allowance which to be fair is considerably :-) over (by a factor of 3) the $600 annual salary quoted by Bart for phds.

One may therefore conclude that the starving scientist inadvertently stumbles across the solution to health through novel (at least in this day and age) metabolic state acquired.
The experimentalist never leaves the laboratory.

[-SB-]

Brenner questioned the ability of computational approaches to derive functional knowledge from genomic sequence alone--a "hideously difficult task," he said--because some problems are simply "not soluble or computable." The future, according to Brenner, requires going back to the bench. Old-fashioned data on the biochemistry of the cell would then be used to flesh out ... ...

Just found that ^^ on the link that I've posted on my Introduction.

Sydney is a little :-) special and Sydney is correct.

We just needed to think about the problem (what Simpson's Bart might consider sitting in deep thought on a park bench) NOT generate phenomenally large (phenomenally difficult to organise) amounts of data.

I suppose it's only right that since Cambridge gave over the #1 biologic via CAT and the #1 NGS technique via Solexa ... ... that Cambers should provide the correct answer ... ... third time lucky ... ... John M and David B. won't mind - they're both jolly decent chaps.

Yay!!

[luc]

I am not working in this field, but to me these ideas have some charm. I am curious about any supporting data.

Hi chaps,
I'm going to keep this short and sweet.
After 30 years of doing what you guys do and surfing from radioactive sequencing through into the world of nanopore and passing through countless academic groups, biotech and pharmaceutical corporations using the same ultra-high throughput techniques (from FRET to PHRED) - I think that a single, simple answer is about to emerge.

From a strict perspective of health (the diseases of Western living)

There are 2 metabolic biochemical states (in effect 'FED' (high GI carb + protein or the Ins/IGF-1 promoting state) and 'FASTED' states (recapitulated through a certain profile of low GI veggie and certain types of oil)).

1. These 2 biochemical states drive 2 mutually exclusive genetic networks.
2. The 'FED' network gives rise to growth (and internal damage through consequence of increased energy (ROS etc) expenditure).
3. The 'FASTED' network gives rise to internal house-keeping procedures.
4. The 'FASTED' state is (naturally) essential for health.
5. The 'FASTED' state can't be recapitulated in 'FED' state as they're fundamentally mutually exclusive like binary 1 and 0.
6. In the absence of awareness of these 2 genetic networks, ALL drug discovery programs (clinical trials) (testing people in the 'FED' not 'FASTED' state are off).
7. --- example --- Imagine if TNFa (the current #1 selling drug is anti-TNFa) is essential for infectious disease clearance, tumour surveillance in 'FASTED' state ie is essential for health in the 'FASTED' state and we introduce an inhibitor for it - we're destroying our own capacity to 'clean' ourselves.

The two heavyweight champions of the world - NGS and biologics appear to have an issue with one another - much like NGS and CRISPR in the last heavyweight belt unification bout - thanks to one of Allan B's latest papers where NGS emerged supreme. Am wondering whether PacBio's lovely long reads will topple Illumina ... ... it's all happening, isn't it ?

[-SB-]

I am not working in this field, but to me these ideas have some charm. I am curious about any supporting data.

Just a quick post to make the point.

Here's the

old fashioned biochemistry of the cell ... ...

http://www.addforums.com/forums/showthread.php?t=192741

[-SB-]

And a hastily prepared presentation of the molecular cell biology involved.

Thought I'd take all of Cambridge's own Horizon Discovery's CRISPr pathways to illustrate.

[-SB-]

Really though is it any surprise to anybody here that the basis to the diseases of Western living are caused by Western living ?

Our 2 major Oxbridge genomics centres - the WTCHG, WTSI when we started them up in the early 90s were based at least originally upon solving the common complex disorders.

About making a difference to human health.

We somehow though (some place between the 9 million eukaryote sequencing project and 37 trillion cell atlas ... ... anybody ????) lost our way.

Big data does that to you.

[-SB-]

Been trying to work out what's wrong with 'omics for the longest time.

Turns out that it's not 'ology.

The problem being that we've traded in scientific quality for technical quantity - and unsurprisingly - all that is then accomplished is big data in big data warehouses housing e-tumbleweeds.

http://www.addforums.com/forums/showpost.php?p=88461&postcount=19

When first it explicitly dawned on me back in 2004.

There’s a desperate sense to the genetic studies I’ve seen. The problem is that the statistical view has a compelling nature, and the dangers aren’t obvious. But the result is bad science, in my not so humble opinion.

What we are increasingly doing, in this modern world of studies that reanalyze and reinterpret data from other studies, is giving up on the scientific idea of actually explaining the mechanisms at work in some process of nature.

Now - the basic idea in this thread could have been worked up (at least sufficiently) in yeast without any molecular dissection required.
I'm pretty sure the basic idea could have come from an experiment in a garage ie impact of nutrients on yeast longevity ... ... which makes the idea of today's mega-medical laboratory complexes look ridiculous.

This sort of paper.

https://onlinelibrary.wiley.com/doi/full/10.1002/yea.1354

Peter Piper Published a Paper of Perfect Pertinence ?

Many species, including the Drosophila and nematode (Caenorhabditis elegans) models of ageing, rapidly readjust their survival–fecundity balance in response to environmental signals. Yeast also switches rapidly between a non‐reproductive state (G0 arrest, low metabolic activity and high stress resistance), when starved for nutrients, and a state of rapid proliferation when nutrients are available.

2 metabolic states -> 2 biochemical pathways -> 2 genetic programs

Without the 'FASTED' state the internal components of the cell in the 'FED' state acquire and retain damage ... ... and before you know it - all Hell (diseases of Western living) breaks loose.

[luc]

Thanks for the links!

[-SB-]

Thanks for the links!

:-)

A zillion other links if you like.

It's what happens when you're bored out of your skull in the usual lab meeting watching people infer the Universe from failed Western blots.

When we started all of this - we had thought that disease genes 'd fall out of the genome. Didn't happen. And because where 'if all you have is a hammer ... ... ...' meets 'the definition of insanity is doing the same thing over and over and ... ... ...' - this sort of 'science' happens - I think it was announced yesterday.

https://www.genomicsengland.co.uk/matt-hancock-announces-5-million-genomes-within-five-years/

Ironically, the genomics revolution was sold as the silver bullet towards identifying targets for intervention - it has (instead!) identified just how very complicated human beings are.
The complexity is impressive - however we need not focus on the complexity - simply the existence of 2 tracks - cellular damage accumulation and cellular damage clearance.

The science of assessing health improvement rather than microscopic analysis of the disease state; if we focus on health improvement - then the disease state never will arise.

The solution to disease arises through making the connection between biochemistry and genetics through metabolic profile arising as a consequence of lifestyle (essentially quantity and quality of food, exercise and moral/social functioning) choices.

[-SB-]

Ruby on autophagy.

https://www.bbc.co.uk/news/health-44005092

- the idea in this thread is of such great importance.

The interest which lead to NGS emerging is based around the money it was hoped would be made through diagnostics and therapeutics.
Pharma dreaming of blockbusters to power their exec's lavish lifestyles.

The idea put forwards in this thread squarely rejects the idea of both Dx and Rx and suggests that lifestyle change is absolutely required for human health ... ... that is - that we've 2 mutually exclusive Systems Networks ... ... therefore only natural and not artificial intervention can work to switch us from one into the other.

This idea (ie need to have a very large number of susceptibility loci) was the basis to the statistical model of the quantitative trait exactly 100 years ago.

An infinite (large) number of loci each contributing either a positive (+1) or a negative (-1) effect on a quantitative trait. Arrange all loci randomly to Hardy Weinberg Equilibrium and a quantitative trait results. So ... ... an infinite (large) number of loci giving rise to quantitative variation in any given trait.

Fisher’s article (1918)[1] and its easier to understand summary [2] are landmark papers that founded the field of quantitative genetics, or in modern parlance, complex trait genetics.
[Their purpose] to derive the theory of the resemblance between relatives due to their genetic covariance at 1, 2 and many loci

https://academic.oup.com/ije/advance...dyx129/3977804

Happy 100th birthday pretty much today (early October 1918).

http://www.indiana.edu/~curtweb/L567...Fisher1918.pdf

A very big deal - perhaps the most important publication in genetics ? alongside Galton's & Mendel's publications both from 1868.

Oh my ... ... Happy 150 years of age to these papers also !

The idea in this thread vindicates Fisher at least in the sense that the complex trait arises through whole genome-wide distribution; there're no key loci - and the solution to the problem (of disease) - arises through embracing the existence of 2 system-wide networks and living one's life accordingly.

Lots of articles on accessing autophagy/apoptosis on the internet.
eg https://greatist.com/live/autophagy-fasting-exercise

Is there an easier way ?
Nah. But there’s a lot money to be made if researchers can distill the benefits of autophagy into a pill, so you can be sure they’re trying.

If we strengthen physiological resilience - we never actually acquire disease - hence diagnostics/therapeutics are no longer required.

As the research proposal above suggests - we can reinvent NGS as a measure of how frightfully healthy we are ... ... which'd be nice to know.
At least to validate interventions - is 15 mins HIIT (FASTed state) as good as an hour run (FASTed state) ?
But as far as disease research - well - we have the solution to disease now.

What we needed was the realization that we absolutely need to make lifestyle changes ... that the combination of detection / therapeutic can not work - such that we'd make the necessary changes to make disease a thing of the past.

Bye bye disease hello ever increasing health - as measured by NGS.

[-SB-]

And the 2018 Nobel prize in chemistry goes to ... ... ...

--- example --- Imagine if TNFa (the current #1 selling drug is anti-TNFa) is essential for infectious disease clearance, tumour surveillance in 'FASTED' state ie is essential for health in the 'FASTED' state and we introduce an inhibitor for it - we're destroying our own capacity to 'clean' ourselves.

ooopsy !

Bicycle (4) Therapeutics

We recently identified physical exercise as a newly defined inducer of autophagy in vivo.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463459/

NF-κB Activation Represses Tumor Necrosis Factor-α-induced Autophagy

http://www.jbc.org/content/281/41/30373

[-SB-]

That particular moment when one realises that other people do know.

Oxford University waiting in the wings.

So far, abnormal autophagy has been reported to have association with the pathogenesis of coronary artery disease, neurodegenerative diseases, Type II diabetes, cancer and ageing.

The basis to human health is really ever so simple.

2 networks - mutually exclusive - FED and FASTED.

FASTED clears the damage set in FED state.

[-SB-]

... ... Continuing ... ...

The Importance of (NGS in) longevity research

https://www.longecity.org/forum/topic/102584-importance-of-longevity-research-powerpoint/

[mysentimentsexactly]

Great post I would like to thank you.