Enjoy that vacation and leave this screen be until you get back. But when you have time I’ll look forward to getting your balancing view to that of the upstart Ball. 
From the article that @MarkD quoted:
There is nothing indicating that “ENCODE was basically right”. We are still at the point where we can point to regions of DNA that are transcribed into RNA but have no additional evidence for function. For the bulk of these RNA transcripts, they are very low in number and are almost immediately broken down by the cell. The DNA in these regions are also accumulating mutations at a rate consistent with neutral drift which is not what we would expect to see from functional DNA.
Being transcribed is not the same as being functional. We don’t expect non-functional DNA to be chemically inert, and the same applies to the RNA transcribed from that DNA. The enzymes responsible for transcribing RNA are not capable of knowing which stretches of DNA are functional, so it isn’t a surprise that non-specific interactions will produce what is essentially junk RNA.
If by “ENCODE was basically right” means 80% of the human genome produces functional RNA transcripts, then the majority of the molecular biology community disagrees (at least from my estimation). Transcription alone is a not evidence of function.
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Thanks for the clarification. No doubt it is all part of the intracellular soup, but that doesn’t make it functional, except in the most rudimentary sense of taking up space and wandering around. Sort of like some people I know.
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Heh, so true.
People often criticize the use of “junk” to describe DNA/RNA, but I think it’s a pretty good description. Our everyday experience with junk makes it a decent analogy. We all have a garage, closet, or drawer somewhere in our house that contains our accumulation of junk over the years, and genomes are no different (at least the genomes of complex eukaryotes).
What interests me more is why there is junk DNA. The simple answer is because there can be junk. That is, there is nothing stopping it from accumulating in the genomes of species with large cells and small populations. This is further driven home by the species with very little junk DNA (e.g. bacteria). In larger cells the majority of their energy is spent making proteins and maintaining homeostasis. Smaller effective population sizes means you need larger and larger differences in relative fitness in order for natural selection to differentiate between genotypes. It is only in small cells with large populations that small increases in junk DNA can be seen by natural selection. For eukaryotes like humans, natural selection is only able to see junk DNA that is highly expressed as RNA or RNA that is translated into protein. Those cost the most energy so can be affected by natural selection.
There’s a really great paper on this very topic:
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Being now possessed of a computer again…
The skepticism results from the preponderance of the evidence, some of which @T_aquaticus has already mentioned. The near-outrage stems from the way the ENCODE people (or at least some of them) handled the concept of ‘functional’. In their studies, they used an extremely broad definition: if a stretch of DNA was biochemically active, it was functional. Now in an ordinary sense of ‘functional’, being biochemically active is a prerequisite for being functional but is far from guaranteeing it. (For example, introns in genes were counted as functional, even though in most cases their DNA is transcribed into RNA and the RNA is immediately excised and thrown away – the specific sequence of bases doesn’t matter at all.) But in their public comments, ENCODE spokesmen made it sound as if they had shown that most of the genome actually did something useful, hyping their results and distorting their scientific meaning.
As for subsequent evidence for function for all of those RNA transcripts, the claims of huge numbers of long, functional noncoding RNAs are highly controversial. Here is a good recent review of the subject: Genome-Wide Analysis of Human Long Noncoding RNAs: A Provocative Review - PubMed
Set against the patchy evidence for functionality are the reasons that biologists came to regard much DNA as junk in the first place: lack of conservation across species, accumulation of mutations within species at a rate consistent with neutral evolution, sometimes large differences in genome size between very similar species, and obvious sources for much of the sequence that are not intrinsically adaptive (e.g. ~45% of the human genome consists of remnants of transposons, which are selfish genetic elements that insert themselves into the genome without regard for functional consequences). ENCODE itself concluded that evidence at the time suggested that ~10% of the human genome was functional in a conventional sense.
There is also considerable fuzziness to any definition of ‘functional’. There can be genetic elements that affect phenotype without truly serving a function. For example, a series of mutations (e.g. including insertion of transposons) might each slightly decrease expression of some gene, each one causing too small a change to be excluded by purifying selection, but resulting in the end in a suboptimal expression level – low enough that another mutation that adds an enhancer to the region to increase expression is now selectively favored and is therefore incorporated. So you can end up with a whole set of sequence fragments that each contribute to generating the optimal expression level, and each of which is now under some selective pressure to be preserved, but which collectively have no good reason for being there – they exist to offset each other.
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I wonder if Michael Levin was part of that effort. Ball quotes him as saying:
Levin says, “so we made what we call Picasso tadpoles. By manipulating the electrical signals, we made tadpoles where everything was in the wrong place. It was totally messed up, like Mr. Potato Head.” And yet from this abstract rearrangement of tadpole features, normal frogs emerged. “During metamorphosis, the organs take unusual paths that they don’t normally take, until they settle in the right place for a normal frog face,” Levin says. It’s as if the developing organism has a target design, a global plan, that it can achieve from any starting configuration. This is far different from the view that cells are “following orders” each step of the way. “There’s some way the system is storing a large-scale map of what it’s supposed to build,” Levin says.
Kindle location 4318
I believe he is saying that there are other functions genes can serve for the organism than blueprinting development and other ways it can accomplish it too. I’m still trying to wrap my head around it but I don’t understand a lot to begin with as you can tell. Pretty heady stuff.
… the bioelectrical signal could override the message seeping up from the genes and keep normal morphogenesis on track in the embryo. Or rather, you might say, the membrane voltage conveys information that is at least as important for the cell as are the activities of genes.
Kindle location 4324
I’m still unclear what connection either of them have with ENCODE but they seem pretty chummy in this video. Is Michael Levin any more in favor with mainstream biology than Ball?
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Skimming through some of his work, it looks like he is focused on membrane potential as an important part of development. Membrane potential is most often talked about in relation to nerves where there is a difference in charge across a membrane created by pumping certain ions out from the cell.
Levin seems to be a “player” in the developmental biology world, but I haven’t really heard enough about him to say one way or the other. Also, developmental biology is not in my wheelhouse so I will leave it to those scientists to render their judgments. At face value, Levin seems very capable at promoting his ideas. How well those ideas have panned out is a bigger question.
I will say that his website for his lab group sets off a few alarm bells.
All of human biology connects with ENCODE at some level. I would assume Levin is studying frog embryos as a model for understanding development in mammals and humans, so he would ultimately be interested in the gene expression and transcription factor data within the ENCODE database. If Levin is also one of the “lots of the human genome is functional” supporters, then that might be why he is chummy with some of those scientists.
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Thanks for that. I confess both Ball and Levin interest me most for the philosophical implications of their work. Both talk about what essentially cognition and agency are and at what level do they come into play. It’s exciting to think of every living cell as having both in a minimal way and how their ability to interact with neighbors to influence their environments make possible the tissues and organs which metanoans require and that somehow underwrite our own cognition and agency. Very speculative of course but we know cognition, agency and consciousness exist even though we can’t easily define them or say how they work. Looking at simpler creatures offers the hope of being able to see things more clearly.
It reminds me of reading The Dancing Wu Li Masters a few decades ago. If I hadn’t gone into biology I would have gone into physics, so it has always intrigued me. That book is by no means a good scientific reference for physics, but it is still a fun read if you like a non-serious mix of philosophy and science. It’s a bit like trying to learn history through a Hollywood movie.
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I remember that book and probably bought it. Don’t think I got much out of it though.
The discussion brought to mind a fascinating, and according to Robert Wolff, “in some ways the most underappreciated passage in the Transcendental Aesthetic.” He begins talking about it at the 53:20 mark
In summary:
“We cannot judge in regard to the intuition of other thinking beings whether they are bound by the same conditions as those which limit our intuition and which for us are universally valid.” Kant
Kant will consider the possibility of other non-divine beings for who Euclidean geometry is not valid.
Wolff asks, “Is it possible that our forms of intuition are culturally encoded?” That some human beings have one system of intuition and other human beings have another system.
Pill bugs aren’t insects!
They’re crusty-acians.
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I’ve read that book nine times and I’m always fascinated by the Watchmakers, who are but aren’t “regular” Moties; since they breed true they’re effectively a different species.
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I think the only class which doesn’t “breed true” are the mediators which are “mules,” a sterile cross between the masters and engineers. Most survive the cycle because some are kept by those who want the advantages they provide in the future (including the Watchmakers). However this doesn’t explain the type adapted to post-nuclear cities and the book doesn’t explain where they come from. They are only used as evidence that the Moties are long adapted to post war conditions.
I think the choices of individual cells – thinking of single-celled critters – would be like those of robots that can be told “put the red block on the blue one” in an environment filled with objects, and the robot proceeds to find that red block and put it in place. I watched a demonstration of this where initially the robot didn’t even know what a block was at the start but through simple feedback learned to differentiate between block, sphere, pyramid, and cylinder. The environment was made slowly more difficult, ending with the space having two levels, one eight inches higher than the other, with the red block on one level and the blue on the other – and the robot not capable of making that step up. Along with everyone else I gasped when the robot, having located the two blocks, proceeded to use other objects to make a crude ramp then use it to put red black on blue.
If a robot with bare rudimentary knowledge of spatial relationships can problem solve on that level, does it have free will? No one told it how to do anything, it just tried different things and learned via feedback. To anyone watching it was like seeing a child figure things out such as putting LEGO bricks together; to the robotics team it was a triumph of a learning algorithm. To the first group, the robot appeared to have free will; to the second not so much.
That reminded me of an article I read where a team of lawyers was working with some programmers to teach software how to write legal briefs. That software also had a learning algorithm and over time (I forget how long) it got as good at writing legal briefs as a lawyer just out of law school. That was over a decade ago; now, with things like ChatGPT software is writing not just briefs but motions, and framing out legal arguments for courtrooms, and is reportedly good enough that the job of legal assistant is doomed, probably along with junior partners at law firms.
So does that mean the software has free will? or maybe that legal assistants and junior partners don’t?
But given the above robot and software examples, what theory of agency will be able to distinguish between life and computers?
I’ve known two sets of identical twins. In both cases, within a week of spending time with them I could tell them apart. What was intriguing about that was that they had friends who’d known them for years but still couldn’t tell them apart without some clue such as clothing. One set was when I was student teaching; they deliberately dressed identically to try to throw me off, but I still knew which was which. They were frustrated because I couldn’t explain how I knew which was which; I just knew.
So did my mind have some sort of built-in algorithm that most people lack? I certainly hadn’t studied them closely and figured out some little thing, so whatever was going on wasn’t at a conscious level.
And mannerisms! The two I mentioned just above brushed their hair back, scratched their noses, stretched, and more, to the point that they seemed like robots with identical movements programmed in. They also not just finished each other’s sentences but switched back and forth when speaking, clause by clause.
When I was taking computer science courses there was a saying: the great thing about computers is that they do exactly what you tell them, and the greatest failing of computers is that they do exactly what you tell them.
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- The theory that when a lawful subpoena requiring a human’s appearance in a specific courtroom on a specific date, a human being will show up and a robot and software will not.
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I wonder why you think that. I can’t imagine anything living as robotic. I believe life is miraculous all the way down.
I don’t believe they can. Problems can be solved by way of devices but the solver is the one who programs the algorithms. AI isn’t artificial or any other kind of intelligence. It is only algorithmic invention. It takes a human being to decide if any of the inventions are of value.
As you can tell I don’t share the enthusiasm for AI.