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Saturday, September 17, 2011

Lab Times Screws Up the Discussion of Junk DNA

 
Lab Times is a magazine that reports on news for life scientists in Europe. Their current issue (Sept. 14, 2011) has an "analysis" called Past, present and future Everything you ever wanted to know about the non-coding stretches of DNA. The author is Frederick Gruber who appears to be a science writer drawing on information supplied by various researchers.

You know the article is going to be misleading as soon as you read the opening paragraph.
When the first draft of the human genome finally became available, there were many surprises, one of them being the ridiculously large amount of DNA that did not code for proteins – or anything at all. It seemed like the genome was just a huge chaotic mess sprinkled with tiny nuggets!
The reason this is misleading is because it totally misrepresents the history of the human genome. It's been four decades since we first became aware of the fact that only 1-2% of the human genome encoded proteins. This was hardly a surprise—in fact it was one of the principle arguments against sequencing the human genome. (What was the point of wasting all that money on DNA sequences that were mostly junk?)

One of the unfortunate characteristics of the junk DNA deniers is that they are completely unaware of the historical arguments in favor of junk DNA (e.g. False History and the Number of Genes, Genetic Load, Neutral Theory, and Junk DNA). Everyone who understood the problem was quite happy to find verification when the first draft of the human genome was published. It's exactly what the knowledgeable experts predicted.

The article raises the standard question that seems to have only recently occurred to some researchers; namely, what is all that DNA doing? It's mostly junk—at least that's the conclusion reached by many scientists back in the 1970s and most of what we've discovered since then has supported that view.

The article points out that the term "junk DNA" was coined by Susumu Ohno back in 1972 and he identified pseudogenes as prime examples. The article goes on to say,
Today, the term ‘junk DNA’ is no longer en vogue among many genome experts. They rather prefer to talk about ‘noncoding DNA’. And this certainly includes much more than just pseudogenes, which actually represent less than 1% of the noncoding DNA. The remaining 99% are made of everything else, for which no involvement in any protein-coding function has been found so far including, for example, introns, repeated sequences, interspersed elements, telomers, transposons…
Theme
Genomes
& Junk DNA
This is nonsense on many levels. "Noncoding DNA" is the part of the genome (about 98%) that does not encode protein. We've known for decades that some noncoding DNA is functional; therefore, it can't be junk DNA. Examples of functional noncoding DNA include: genes that encode various RNAs, regulatory sequences, some parts of introns, 5′ leader sequences, 3′ trailer sequences, centromeres, telomeres, scaffold attachment regions (SARS), origins of replication, and recombination hot spots.

There has never, ever, been a time when a substantial number of knowledgeable experts thought that all noncoding DNA was junk and they certainly don't think so today. We know for a fact that junk DNA exists (e.g. pseudogenes) so it would be very silly to abandon the term. What we don't know for certain is how much of our genome is junk. It's extremely likely that more than half is junk in spite of what science journalists (and some unknowledgeable scientists) might think.

It's true that there are some "experts" who think that most of our DNA is functional. Some of them will put in an appearance in the comments to this posting. Naturally, those "experts" will avoid the term "junk DNA" because they reject the concept. The Lab Times article is misleading because it doesn't mention that there is a substantial number of genome experts who believe that most of our genome is junk. It may even be a majority.
In the last decades, considerable research has been carried out showing indeed some – mostly regulatory – functions for a couple of these non-coding elements. For most of the ‘junk’, however, we still have not the slightest idea why it is there, why it is maintained over time or what it is doing.
It's worth noting that the existence of functional nonoding DNA dates back to the early 1960s so it's not a new phenomenon by any stretch of the imagination. It's also worth noting that substantial parts of our genome do not have any known function and that's why they are called "junk." It's not correct to say that "... we still have not the slightest idea why it is there ..." since neutral evolution and random genetic drift are perfectly adequate explanations. This is the kind of statement that can only come from someone who doesn't understand evolution.

As usual, the discussion often turns to transposable elements (TEs).
In fact, functional TEs within their sequence actually code for the enzymes needed to cut and paste themselves anywhere in the genome. However, the picture is even more ambivalent: In recent years, researchers have added a considerable amount of evidence indicating that TEs might not at all be completely ‘useless’. Thus, the question, whether still to assign TEs to ‘junk DNA’, has become ever more pressing. In the meantime, many would clearly say ‘no’.
Keep in mind that almost 50% of our genome is composed of degenerate (nonfunctional) transposons and viral DNA. It's true that there are some examples of transposons that have acquired a function. At latest count this amounts to about 0.1% of the genome and that leaves a lot of explaining for the junk DNA deniers. This issue is discussed in my review of The Myth of Junk DNA by Jonathan Wells [Junk & Jonathan: Part 9—Chapter 6]. You don't discredit the existence of junk DNA by finding a few unique and exceptional sequences. That's no way to make a scientific argument.
At the population level, TEs apparently also play important roles. By jumping around the genome at a much higher rate than any known mutation rate, they create a great deal of nucleotide diversity, which, in turn, is the raw material of evolution. Therefore, these TEs may well contribute to adaptation of species to new environments and even speciation.
First let's get the facts correct. Every new human zygote contains about 130 new mutations not found in the parents [Mutation Rates]. On the other hand, new transposon insertion occur at the rate of one every 20 zygotes [Transposon Insertions in the Human Genome]. By my calculations, standard errors of DNA replication create diversity at more than 2000 times the rate of transposons.

It is true that over the course of several hundred million years of evolution in a variety of well-studied species (humans, mice, Drosophila, yeast, C. elegans, Arabidopsis etc.) we have detected a few dozen examples of transposon insertions that have led to beneficial effects. It's also true that in those same species there have likely been millions of insertions that turned out to be lethal. Anyone who thinks that the existence of a few active transposons in a genome could be selected because they provide a future benefit to the species just hasn't thought hard enough. (Besides, this "explanation" doesn't explain the existence of huge amounts of defective transposon sequences.)
In conclusion, a great deal of the DNA previously described as junk DNA can be ascribed well-established functions today – there is hard evidence for it, at least. However, there are lots and lots of DNA stretches that still don’t seem to be of any function at all.

Only time will tell if these sequences are, indeed, true junk or whether we are still too blind to see the real meaning of the “Dark Matter of the Genome”.
It is simply not true that a "great deal" of what used to be called junk DNA has now been shown to have a "well-established function." The only way that could become a true statement is if "great deal" is taken to mean less than 1%.

I think the real underlying problem here is that most scientists (and science writers) see evolution entirely in terms of natural selection and adaptation. This means that the existence of massive amounts of junk DNA in our genome is a "problem" because it conflicts with their view of evolution. To them, there is no explanation for the existence of junk DNA because the ideas of neutral mutations and random genetic drift are just not on their radar. They see junk DNA as a "mystery" and they continue to look for, and invent, adaptationist explanations in order to solve the mystery.



26 comments :

Schenck said...

"Keep in mind that almost 50% of our genome is composed of degenerate (nonfunctional) transposons and viral DNA."
You've said this and things like it many times, and each time it completely blows my mind. I know that it makes sense, and that I should've known about it for a long time now, but it still seems absolutely stunning.


Also, to clarify, you often talk about 'non-coding DNA', am I wrong, or is this synonymous with 'DNA that doesn't produce proteins' or 'non-proteinmaking DNA' (because it seems like calling it non-proteinmaking DNA really drives the point home and I wonder why its not used, besides being an ugly term perhaps).

Atheistoclast said...

Schneck:

Non-coding DNA refers to seqeuences outside of the reading frames of genes that represent protein sequences. It also can refer to RNA genes that don't use a code as such.

Some non-coding DNA is absolutely essential to regulate both transcription and translation as well as alternative splicing. Some is also necessary to facilitate DNA repair and replication, as well as to prevent degradation.

Larry refes to the fact that 40-50% of the genome is made up of (retro)transposons that are inactive and deemed to be parasitical. However, we do know that many retrotransposons are active, or can be reactivated, and when they do insert they donate important cis-regulatory sequences to promoters that affect transcription.

If their sequences were junk, they would always be deleterious or useless. But the fact that they are often found to be useful undermines Larry's argument. Sure, most retrotransposons currently do nothing - but that is a good thing as we don't want them inserting all over the place all at once. They represent an important evolutionary reservoir of regulation for future adaptations.

The Other Jim said...

Atheistoclast said...

If their sequences were junk, they would always be deleterious or useless.


All of the evidence on mutation accumulation and ability-to-delete within these regions does support the "useless" stance, does it not?

"Deleterious" is not something associated with junk DNA by anyone.

Atheistoclast said...

Other Jim:

Well, truly "junk DNA" is a waste of space and is deleterious in that it incurs an unnecessary metabolic cost on the cell in order to reproduce it. It may also interfere with other molecular processes. Professor Moran has done some extensive calculations and has found a small but still significant energy cost.

My main gripe with Larry,whom I think is being a little too entrenched and inflexible, is that Alu sequences, for example, appear to contain binding sites for transcription factors should they be inserted in cis-regulatory regions. Here is a paper on the subject:

Alu elements contain many binding sites for transcription factors and may play a role in regulation of developmental processes

So it appears that Alu sequences, which make up 10% of the genome, are not random sequences of junk DNA but those which contain important regulatory motifs. Larry's point is over whether they are active or inactive - if most are defective than they can't do anything useful. But when they do insert themselves into promoter regions upstream of the transcriptional start site, they do confer adaptive functions and benefits. So they represent a potential reservoir for evolutionary change.

I'll keep my junk thank you very much.

David Winter said...

"They represent an important evolutionary reservoir of regulation for future adaptations."

What beneficent ancestor's we've had. carrying around all that DNA just so it will be of use in the future!

The Other Jim said...

Quoting Atheistoclast;

Well, truly "junk DNA" is a waste of space and is deleterious in that it incurs an unnecessary metabolic cost on the cell in order to reproduce it.


This is a typical response, but is clearly not though through. Replication is a miniscule metabolic cost for a cell. The estimate for an actively dividing bacterial cell is only 2% (Lane & Martin (2010) Nature 467, 929–934). Note this is for the time frame where DNA is actually being replicated. Most cells in a multicellular are not replicating at any given time outside of embryognesis/ early development, so what is the actual cost of the extra DNA?

Second, The only variable that scales with genome size over a broad context is the inverse relationship with the effective population size. (Lynch & Connerly (2003) Science 302(5649):1401-4; Lynch et al. (2011) Annual Review of Genomics and Human Genetics Vol. 12: 347-366).

So the argument is that the cost of excess DNA is low, and the organisms with huge quantities of junk DNA have tiny effective populations sizes. Random genetic drift is a very good explaination of the accumulation of excess DNA.

Please defend your position with some actual data, and not though undefended claims that contradict the literature. "It must be" doesn't cut it.

The Other Jim said...

@ Atheistoclast

Regarding the Alu paper - already covered to death on this blog

http://sandwalk.blogspot.com/2011/02/new-way-of-regulating-human-genes.html
http://sandwalk.blogspot.com/2011/05/whats-in-your-genome.html

and other blogs...
http://sfmatheson.blogspot.com/2011/05/alu-need-to-know-about-parasitic-dna.html

You are suggesting that we are carrying around potentially lethal, mutagenic elements in our genome "just in case"? Any yet you worry about extra metabolic cost of extra bases? I cannot understand this logic at all.

For every "positive" description of and Alu, there are 2-3 negatives. In 2008 a review pointed out there were (in 2007-2008) 65 known disease insertions (http://www.sciencedirect.com/science/article/pii/S0092867408011793) . We know from Drosophila that most mobile element insertions are lethal gene knockouts, and only a small percentage are viable mutants. SO we never see all of the negative effects of these things and are just reporting the postives, and ignoring the "pretty bad" cases. In order to publish in a sexy journal, authors understate the negatives in their papers, while ID / creationists just ignore it to avoid complicating their cute little story by not bringing up the down-side.

The alternate perspective is that the vast majority are inactive (so neutral or nearly-neutral junk) but mobilization keeps occurring at some small rate. Many of these rare-event mobilizations are lethal, so never observed. A subset are deleterious (ex. the human patients mentioned above). And a even more rare number have a neutral or beneficial function.

Just like in TV's "MacGyver", the bomb left to kill you can, under the correct circumstances, be put to good use. But the case-by-case reality is more like Saturday Night Live's "MacGruber". We end with a dead hero and just move on.

Anonymous said...

@Atheistoclast

Alu sequences, for example, appear to contain binding sites for transcription factors

[...]

So it appears that Alu sequences, which make up 10% of the genome, are not random sequences of junk DNA but those which contain important regulatory motifs.


Junk /= 'Random'.

Alu sequences are rogue derivatives of a 'legitimate' sequence: 7SL RNA. They are SINEs, selfish genetic elements that transpose around the genome utilising both the host machinery and enzymatic assistance from another selfish element, LINEs.

In order to do anything at all, they have to be transcribed. So it is no real surprise that they bind transcription factors. However, this binding is not likely to be to the benefit of the host, as many diseases are associated with Alu. Successful Alu elements - those that can colonise 10% of a genome, say - will be those that incorporate the means to spread within themselves - such as transcription factor binding sites.

And of course their grubby non-random fingerprints form powerful evidence for the reality and the pattern of common descent among the primates.

Atheistoclast said...

Well,let's get something straight:

The insertion of random sequences of DNA in transcriptional regulatory regions will not have any beneficial effect under any circumstances.

Yet numerous Alu elements are found conserved in promoters and enhancers of genes, suggesting that these Alu elements function as carriers of cis-regulatory elements. The evo-devo crowd are becoming increasingly interested in them.

Sure, they can also cause disease...but so can the overexpression of functional genes.
On an evolutionary level, our species is better of with Alu sequences than without them - this may not be true for individuals.

If Larry had his way, he would create synthetic genomes based on about 10% of what we currently have. I think this is a recipe for disaster.

Anonymous said...

Well,let's get something straight:

The insertion of random sequences of DNA in transcriptional regulatory regions will not have any beneficial effect under any circumstances.


The Alu elements themselves contain the transcription binding sites. This is necessary for the mechanism of transposition - if you don't get transcribed, you don't transpose. Transposons aren't a collection of handy switches that can be delivered at a moment's notice to someplace that might benefit from a little transcription - they promote their own transcription, and jump, along with everything that got transcribed, including the transcription binding sites.

It is entirely possible that they may cause a beneficial change in transcription at their insertion site. But they have TF binding because there is selection for effective transposition at the level of the transposon, not because there is a genome wide need to maintain a herd of these mobile switches.

Sure, they can also cause disease...but so can the overexpression of functional genes.
On an evolutionary level, our species is better of with Alu sequences than without them - this may not be true for individuals.


I doubt the species is any better off with Alu than it is with imperfect error detection and repair, or recombinational slippage (caused, in part, by transposons). It's just another kind of mutagenesis, and the same spectrum of benefit, neutrality and detriment will arise. The fact that opportunistic benefit can arise from 'undesirable' imperfections is the very hallmark of evolution. But this is not the same as saying that the reason for these imperfections is the generation of evolutionary novelty.

If Larry had his way, he would create synthetic genomes based on about 10% of what we currently have. I think this is a recipe for disaster.

I had not realised he was a mad scientist. I shall be more cautious.

Atheistoclast said...

Alan Miller says:

Transposons aren't a collection of handy switches that can be delivered at a moment's notice to someplace that might benefit from a little transcription - they promote their own transcription, and jump, along with everything that got transcribed, including the transcription binding sites.

I never claimed they were unselfish and not opportunistic. But their insertions in promoter regions do represent changes that single-nucleotide mutations are unlikely to achieve.

Hundreds of research papers do show that Alu elements both contribute to adaptation and also to disease just as gene duplication does. Therefore, they serve two purposes in creating genomic flexibility, and also in keeping reproductive fitness down. I know that sounds callous, but disease does keep population levels under control.

I advise you to read this review:

TE-mediated tinkering of cis-regulatory networks

Larry is missing the bigger picture because he is not thinking on an evolutionary timescale - only in terms of immediate benefits.

Atheistoclast said...

Here is also another great paper on Alu inserts in non-coding intron sequences and how this can affect alternative splicing. In this way, they add to the diversity of the protein repertoire and have influenced primate evolution:

Intronic Alus Influence Alternative Splicing

So who are the real "deniers", Dr. Moran? How long can keep this up?

Anonymous said...

@Atheistoclast,

I think you missed the point about mutagenesis. Creationist/ID types routinely dismiss mutation as a creative force because they perceive them as a Bad Thing. But they like transposon-mediated mutagenesis because it gives a putative function to swathes of DNA that their Designer would not just allow to accumulate ad hoc ... would he?

So you get to have your cake and eat it. Mutations Bad, Transposons Good. But the arguments about mutation and transposon domestication are pretty interchangeable. In both instances we have a 'random' process that generates a continuum of results, from the seriously deleterious through neutral to the genuinely beneficial.

I don't deny that some transposons have proved of benefit, any more than I would argue that all mutations are deleterious. They are a genuine evolutionary force. But to argue that transposons are there in order to drive evolution is precisely equivalent to arguing that mutations are. To be maintained for a 'purpose', including future-proofing, requires that the genetic basis of doing it gives more reproductive success than not doing it. Unless, of course, one believes that it all derives from a mysterious "someone"'s purpose, in which case anything and everything is just tickety-boo.

ID-ers don't like 'random' processes. But here they are, bigging-up this hugely random process of cut/copy-and-paste of sequence to be reinserted Christ-knows-where. Or maybe his dad does.

Atheistoclast said...

Allan,

Some creationists do consider mutations as all-bad (as a consequence of original sin and the Fall) but others,like myself see them as being able to switch off certain genes when it is necessary.

I regard mutations and insertions as serving two purposes in the grand scheme of things:

1) Keeping fitness levels down through disease and so on and so preventing overpopulation.

2) Allowing for flexibility/versatility in response to environmental pressures.

Individuals may suffer from having transposable elements insert themselves in some places and cause disease but, as a species, we benefit from their presence because they can rewire gene regulatory networks, and achieve some of the things I have been describing, to facilitate adaptation.

The beauty of this is that it requires no intervention. It is a form a dynamic self-regulation and fine-tuning which the most intelligently designed system are capable. But creationists also endorse another random process: genetic recombination as a way of achieving diversity. The reason for this is that recombination tends to not destroy genetic information as mutations can do.

The Other Jim said...

@ Atheistoclast,

I think you need to re-read
"Intronic Alus Influence Alternative Splicing". Every point you make in your post is prefaced by a "could" in the discussion of the paper, and is not actually supported by their results.

And the whole paper rides on the wave of the "rampant alternative-splicing is real, and not just errors" view, that I do not support. See;
-Nucleic Acids Res. 2009 37(14): 4873–4886. doi:10.1093/nar/gkp471
-PLoS Genet 2010 6(12): e1001236. doi:10.1371/journal.pgen.1001236

In light of the observation that mice have more alt-splicing in advanced disease state (PLoS Genet 2009 5(12): e1000773. doi:10.1371/journal.pgen.1000773)
how to be interpret human alt-splicing, which is defined in derived cell lines (cancer cells or immortalized cells)?

Anonymous said...

Well I am no expert and my degree in Biological Sciences was way back in 1997, but I consider Junk dna to have a function. Think of the plastic wrap you get from the Post Office to protect your fragile articles you wish to send via the postal service: Bubble Wrap. DNA is fragile, and can be "knocked about" and damaged. The Junk dna surrounds and protects the important coding dna from this damage. As for DNA viruses or RNA viruses that need to be translated to DNA to do their pathogenic work, maybe part of removing pathogenic viruses is to incorporate their rendered harmless form into the genome.

The Other Jim said...

@ Ponto,

The problems with this hypothesis are laid out and discussed over at "Does junk DNA protect against mutation?"

http://www.genomicron.evolverzone.com/2009/12/does-junk-dna-protect-against-mutation/

Additionally, the other issue is that mutation rates are always per base. So if you have 10x the number of bp's in your DNA, you will get 10x the number of mutations per replication cycle. Exogenous damage, etc is covered at the blog post above.

Anonymous said...

Atheistoclast

The beauty of this is that it requires no intervention.

Ummm ... That's the beauty of the Intelligent Design of a self-modifying system? That it does away with the need for a Designer? Ingenious! Since you seem to agree that random mutation and recombination (to both of which phenomena transposition contributes) are capable of generating all evolutionary novelty unaided, I wonder why you feel the need to interpose a magic being at any point in the process?

The Other Jim said...

@Allen Miller,

Nice catch. You just made my day!

Atheistoclast said...

@The Other Jim

LOL. Maybe you are realizing that most papers on evolution are based on speculation!

However, the current mood in the community is that TEs are important in adaptation. The author of the paper below is a complete idiot - he has written some really crap stuff - but he may be partly right on this one:

Transposable element insertions have strongly affected human evolution

You may be interested in this creationist take on ncDNA:

More nails in the coffin of ‘junk DNA’

Enjoy.

The Other Jim said...

LOL. Maybe you are realizing that most papers on evolution are based on speculation!

You really didn't read the paper, did you. It was a capital G Genomics paper.

The Other Jim said...

I was trying to keep this discussion to the science, but that last comment is quite ridiculous.

You quote a paper as evidence of you position, then when that paper is contested, you claim it is "only speculation"?

And you wonder why we have a hard time taking you seriously?

"The community" you are quoting is the genomics community, where misconceptions about evolution are as common as the ones spouted by the ID crowd. Not the evolution community.

Anonymous said...

However, the current mood in the community is that TEs are important in adaptation.

Not really - adaptation is the process whereby populations become enriched in beneficial alleles. Transposons are one of numerous mutational sources that can result in beneficial alleles, but they don't drive adaptation - this requires filtration of the scattergun results of the mutational process. These same mutagenic processes offer up alleles to neutral evolution (where the change has no effect on fitness) and purifying selection (where it is detrimental).

From a single 'seed' transposable sequence, copy number will increase over time. In the case of Alu sequences, for example, we have over a million copies. Now, if you threw a million sequences over a wall at an invisible genome, you could not help but have some land in coding or regulatory sequence. You could not help but have some fraction of those cause a change that proved to be of benefit. What of the rest - the misses?

Is that beneficial fraction of a fraction a sufficient explanation for the existence of every single one of those 1.1 million copies of Alu?

Perhaps you would say these are the price we pay for hosting an occasionally useful mutagen. But these misses, individually, surely serve no purpose - which is to say, they are junk. How many, do you think? 900,000? A million? 2?

Anonymous said...

@Atheistoclast.

You may be interested in this creationist take on ncDNA:

More nails in the coffin of ‘junk DNA’

Enjoy.


"It may well be that, due to harmful mutations (the consequence of sin and our living in a fallen world), some DNA is genuinely junk"

Hilarious! :0) Another child bollixed up by the sins of the father; sorry kids. (males are, of course, precisely 5.14 times more sinful than the average female - even those bastard squirrel monkeys).

W. Benson said...

Larry.
In an earlier Sandwalk posting (June 15 2010 – “False History and the Number of Genes”) you cite the population genetics estimates of gene number of King and Jukes (1969) and Ohno (1972) in the range of 30,000 – 40,000. I checked the Ohno reference and find he cited an earlier estimate of Hermann J. Muller made in 1967 and did not propose one himself. Muller may thus be the first to estimate gene number based on solid theory. The fact is interesting because he (along with Fisher, Haldane, etc.) has a long history of insightful ideas that later turned out correct. Muller was a founding member and important contributor to Thomas H. Morgan’s fly lab at Columbia in the 1910s (when Muller was an undergraduate) and later on, like Morgan, won a Nobel Prize for his own work.
The idea that the size of gene sets was optimized by natural selection seems to have been ‘in the air’ in the mid 1960s. In 1966 naturalist (as was Mr. Darwin) George C. Williams in his classic book “Adaptation and Natural Selection” suggested that there should be an “optimum” amount of genetic material “determined by the amount of information that can be maintained by selection in the face of randomizing processes.” (p. 41). He goes on to propose (p.42) that “all [higher] organisms . . . may have much the same amounts of information in their nuclei.” If I correctly understand Williams, animals like Drosophila may have fewer genes because they have higher mutation rates. Has anyone published on this?
Thanks again for the stimulating series of posts.

Psi Wavefunction said...

@Atheistoclast,
I'd pick a fight with you, but then again you demonstrated your profound ignorance elsewhere by callously (and needlessly) insulting an expert on the field with a childish ad hom. Just pointing it out that you're useless to argue with. I mean, if a well-respected academy member is a poor scientist by your haughty standards, then what can his mere lowly lab tech say to you?

So just a suggestion: don't go around insulting on the internet random people you don't know, and then perhaps, just maybe, you might be taken seriously from time to time. Otherwise, you're just a notorious troll.



Moving right along, nothing to see here, folks ;-)
--
Failure to admit the existence of crap in genomes is just a reflection of a *very poor* grasp of basic, fundamental evolutionary theory. Which can be fixed through learning, but some of us are apparently resistant to *any* mutation in the way they think already, and are in an intellectual dead end...