Comment by astazangasta | Hacker News Reader

Comment by astazangasta | Hacker News Reader

It's laughable that they led with the genetic cause for schizophrenia which (a) probably doesn't exist and (b) wasn't found a few months ago; they found a weak statistical association across a large number of variants that explains < 3.5% of the variability in disease susceptibility. What this demonstrates is what we've learned over and over across the past decade with association studies: yes, we're a product of our genes, and variation affects us, but no, common diseases are probably not mostly driven by genetics.

For me, the big story in genomics over the past few years is one of massive failure. We spent a lot of time and effort sequencing tumors in the hopes that the genetics would tell us something interesting and lead to cures. It did not. We now have a relatively complete cabinet of the major variants that drive tumors. Most of these variants we already knew about before we did these genomics studies (through older sequencing methods from decades prior), and most of what we learned tells us nothing new.

Genetics is at this point mostly garbage information. Why? Because we don't know what it means. We still don't understand gene expression, we don't understand signal transduction, and we can't understand the effects of mutations without painstaking characterization. All of these things mean our sudden wealth of knowledge of genetic variation tells us fuck-all about biology.

What? This is so very wrongheaded.

We learned quickly that 'cancer' is to the twentieth century 'the fevers'. We learned there are many reasons and causes for the catch-all, 'cancer'. Some we now know how to cure effectively. Some we now now how to prevent, effectively. Some we now know what to do to cure, but don't have good tools yet. And many we still do not understand. That is a significant improvement in a very short time span.

But there's a LOT more to learn than 'how to cure cancer'. We very clearly understand gene expression and signal transaction to a first order, and have bits of the second order down too. There might be more - but that doesn't make that first order inneffective or wrong. There's lots you can do with a first order understanding - see what Newtonian physics did for the world - it was correct only to the first order. The idea that we know 'fuck-all' about biology because of dna sequencing is just ridiculous. The ability to read and write dna is fueling one of the fastest growing segments of human progress today.

We didn't learn any of those things because of genomics. The major cancer therapies of today were developed before short read sequencing was even a thing; cancer researchers been saying for decades that cancer is "not one disease". In fact the genomics efforts were largely intended to overturn that wisdom by using genetic lesions to unify disparate cancer types (to little avail). About the only really interesting thing we learned from these recent efforts is that tumors are a lot more genetically heterogeneous than we previously appreciated, which just expands the problem space.

The proof in the pudding is this: you can get your exome sequenced today and report hundreds of tumor variants, but there is a bare handful of variants that will result in a change in your treatment, and most of those lesions were well-studied before genomics took off.

>We very clearly understand gene expression and signal transaction to a first order, and have bits of the second order down too. There might be more - but that doesn't make that first order inneffective or wrong.

Yes, in fact, our first order understanding IS ineffective. This is what I study every day, so perhaps I'm too close to this, but we literally do not understand the effect of most (99.9%) of genetic variants on gene expression. Sure, there's lots you can do with a first order understanding, but materially, what happens when you sequence a tumor (or a germline, for that matter), is that researchers get a list of mutations, stare at it mystified for a while, and then shrug and move on, because there's really nothing you can do to understand what these things mean.

Yes, this stuff is the way of the future, and it's important to do it for our greater knowledge and understanding in the future. But we're far, far away from this point right now.

I think your point is accurate, but jaded. Much as the above posters point out, there was no sudden 'click' where an individual discovered something and made genomics possible. And to the extent that's what we mean by 'genome sequencing', then you are correct - the shotgun approach coupled with big-data hasn't been very useful yet. However, if the message is more one of genetics at large, and how the ability to read/write DNA has affected our research, our discoveries, our therapeutics, and will affect our lives in the near-future, then your tone seems entirely too myopic. Nearly every drug you see on TV commercials today is a monoclonal antibody - which cannot have been made but for the ability to read and write DNA. Sure, it doesn't require the ability to read an entire animals' DNA at once (do the full genome sequences yet actually read every base in your genome even?). But it is a very real and very finite milestone on that exact same path. You are correct, genomic ≠ genetic, but in so far as they are similar (mostly), our understanding of genetics really has been a powerful driver in the past two to three decades.

Of course I recognize the potential of this technology; I wouldn't be in this field otherwise. And I probably am jaded, because I think people are constantly overemphasizing and overplaying our understanding of things in order to sound sexy and attract funding.

I think there's probably a fifteen-year lag in this stuff being useful. The insights we're having now are because of the sequencing of the human genome; the work we're doing now will pay off in another decade and a half when we've figured out how to deal with gene expression.

>do the full genome sequences yet actually read every base in your genome even?

Read, sequence: yes. Align: no.

I'm a bit surprised by your reaction. You do know we use genomics in clinical labs all the time, right? We can find drug-targetable mutations in tumors, we can direct patient care in rare (and some common-ish) diseases from germline mutations. Now, with liquid biopsy we can actually track tumor progress through treatment and identify resistance mutations that pop up. Before long, we'll be able to do cancer screenings from blood! None of that would be possible without cheap, scalable NGS sequencing tech.

Tumor sequencing is a HUGE boon to cancer treatment and research. Patients lives have been drastically improved by targeted treatment.

Targeted therapies were not developed as a result of genomics. Erlotinib was approved in 2005. We've had Sanger sequencing assays for EGFR, BRAF etc for years, and they're still standard of care. We can identify resistance mutations, but we often don't know what to do with this information. Your patient becomes resistant, you identify the causative variants, you watch your patient progress and die.

Sure, genomics gives us a comprehensive way to sequence, but my point is that it did not yield the sudden, vast sweep of insights that we expected it would.

IMO, it's a bit like geneticists walked into the human genome expecting a simple SQL database, and discovered the thing was littered with pl/sql functions, and that some of the functions actually double as data, when shifted over a byte or two. It's no surprise then that it's taking longer to understand the genome, and nor surprising why differential genomics is so useful.

Whether this was the best use of scientific resources, I donno.

This hysteria exist mainly because most people are led to believes "genes" are something that they are not.

They are not "blueprints" much less some sort of engineering document.

More realistically, they are a simple list of materials (in this case a listing of proteins).

They only describe the materials that make up a structure, not what that structure is nor how it functions.

Its the equivalent of someone saying: 14,234 tons of steel, 23,000 tons of concrete, 8000 tons of glass...etc. Now, what does it make? Why does it make it?

While this analogy is most likely not understood by people who don't understand gene expression, I still like it.

I think of genes as the initial configuration in Conway's game of life. Small initial (genetic) variations can cause large differences after some generations. Some don't matter at all and just die out. But no matter what is the end result, it's not a blue print or a description, it just _is_, and the result flows from it using some basic rules.

So what mechanism carries the information of how the body functions from generation to generation if not genes?

Transgenerational epigenetic inheritance ?

https://en.wikipedia.org/wiki/Epigenetics#Transgenerational

Epigenetics may influence gene expression, but as your link says others are skeptical that it constitutes an independent information vector. Epigenetic activities may themselves be encoded in genes.

Epigenetics as a concept can also be abused into a sort of neo-Lamarckism.

>Epigenetic activities may themselves be encoded in genes.

But good luck growing a healthy organism without its epigenetic landscape properly initialized

Has it been verified experimentally that it's not possible?

Physics. More specifically, 'conditions'. More specifically, the environment in which the ingredients are produced determines how the ingredients assemble. The analogy to the ingredients list is a decent one, but it is also a tad misleading. You generally do require knowledge of the environment to figure out how the parts will assemble, but many of the parts do work in many different environments and can be considered whole and separable objects rather than ingredients. But trying to separate evolution/life from its environment is the first mistake a student makes when studying evolution. As a grandparent stated, if the genes are the starting positions in Conway's Game of Life, the laws of physics are the rules of the game, and the physical conditions (temperature, pH, gravity, time, etc.) are the topology and specifics of the board you'll be playing on. Then you just hit play and certain concepts self-assemble - the flier, the block, the boat, etc. Some can then be used as objects in themselves, some can be used structurally, some can be used to build/destroy structure - that is life.

If the laws of physics are universal (fingers crossed), then this factor gets canceled out. Obviously organisms which evolved under our physical regime can only function properly within our physical regime. But this doesn't add any information as to why one set of genes manifests itself differently than another set of genes, since the physical laws are the same.

>If the laws of physics are universal (fingers crossed), then this factor gets canceled out

This is beside the point, as parent already explained what he meant in his first 2 sentences: "Physics. More specifically, 'conditions'".

So, yes, the laws of physics might be universal, but gravity is X here and N on the moon, pressure is Y here and M under the sea, temperature, etc...

"Genes" as protein coding regions is a common shorthand, but there's another, broader definition of "gene" as "a locus in the genome that bears some responsibility for a trait". For instance, the ability to consume lactose post infancy is a trait driven by a mutation not in a protein coding region, but could reasonably called a "gene for lactase persistence". In general, we don't have good bottom-up ways of understanding which regions of the genome are regulatory, much less what that regulation is doing.

So according to one definition, it's even worse than your 14,234 tons of steel example: it's closer to "steel is a mixture of iron and carbon and trace amounts of other dopants, glass is silicon dioxide, concrete is ..." Without even listing the amounts. But by another definition, the genes are, if not a blueprint, at the very least a recipe and ingredient list. "Butter, flour, water, sugar, apples, cinnamon, cloves. Cut 125g butter into flour; if too coarse, continue cutting. Add water to ice. Add water from ice into flour..."

The information is clearly there—we have a long, unbroken history of offspring being very similar to their parents, despite having started with only a single, undifferentiated cell. But with the new tools available to us, we're starting to have a hope of understanding it, even if we're using more brute force than we'd like.

> More realistically, they are a simple list of materials (in this case a listing of proteins).

> Its the equivalent of someone saying: 14,234 tons of steel..

I feel like that's taking things a bit too far in the other direction. With our current understanding, it's like saying:

14,234 tons of steel that's capable of self-assembling (e.g., collagen), 23,000 tons of concrete that automatically folds into a specific structure (~everything other than disordered proteins).

That's not to say that we fully understand how proteins fold/function... but it's a bit more than a static block of steel.

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