Expanding the genetic alphabet

| 19 Comments

By Gert Korthof.

“It is a very, very hard problem. Getting all the pieces to work means re-engineering 3.5 billion years of evolution. It’s so ambitious.” These are the words of a scientist 14 years ago [1]. He was talking about the project of inventing new bases to include in DNA and let the new DNA function in a living cell. Now an important milestone has been reached towards that goal. Scientists have succeeded in adding a new base pair, d5SICS (call it X) and dNaM (call it Y), to the DNA of the bacterium E. coli and let it replicate its DNA [2]. Furthermore, the growth rate of the bacterium was not significantly slowed down, and the DNA-repair system did not remove the new bases. These results give us hope for realistic answers to the so far speculative questions as to why evolution settled on only two base pairs in DNA. Could there be superior bases and superior DNA?

Plasmid_modified_from_wiki.jpg

Plasmid, modified from Wikipedia. The yellow dot is the new base pair.

The researchers included the new base pair in a plasmid and introduced it in to the bacterium E. coli (the yellow dot in the illustration is the new base pair). The plasmid replicated including the new base pair. This is a significant result, because there are many requirements for bases in DNA in general.

For example, any base pair must enable DNA to form a regular double helix with fixed dimensions over long distances; a base must attach properly to the DNA-backbone; any base in a pair must pair exclusively to its partner and not to bases of other pairs; any base must not pair with itself; the base pairing must be strong enough to be stable, but not too strong to make the process of strand separation (required for replication) too difficult; etc.

Once new bases are developed, many new possibilities are opened. For example, consider the effect on the coding potential of the genetic code. How many new amino acids could the bacterium produce? Let’s see. We are not replacing any of the existing bases. So, the DNA of the modified bacterium has now six different bases: A,T,C,G,X,Y and three base pairs: AT, CG, XY. Any position of its DNA can be a A,T,C,G,X,Y. Three bases in a row code an amino acid. There are 20 natural amino acids. Instead of the standard 4 ח 4 × 4 = 64, there are now 6 × 6 ח 6 = 216 different triplets or codons. If we subtract the 3 triplets of the standard 3 stop codons - which do not code for an amino acid - we are left with 61 in the old and no less than 213 different triplets available for coding amino acids in the new bacterium.

That is, theoretically. Life on earth uses 61 triplets to code for 20 amino acids. That is a redundant coding system. On average there are about 3 codons per amino acid. Theoretically, such a coding system could code for 61 amino acids. But evolution decided otherwise. If we leave intact the redundant coding system for the standard 20 amino acids, the modified bacterium theoretically could code for 216 –’ 64 (including stop codons) = 152 extra amino acids. A huge gain! Proteins can be imagined with properties not possible with the standard code.

At the moment it is too early to say anything sensible about the performance of the new bases. First, the bases need to code for an amino acid, and the transcription and translation system must be working. And it would be nice to observe the new bases in the bacterial chromosomal DNA.

It would also be nice to observe the behavior of the new bases in eukaryotic chromosomes (plants and animals). Even if it turned out that the overall performance of alternative bases is inferior to the natural bases in DNA, that would be valuable information. The question whether the 4 universal bases in DNA are uniquely fit for coding the genetic information of life on earth isn’t pure speculation any more. It can now be attacked experimentally.

Science has also a short News feature about the research [4].

Notes 1. Robert F. Service (2000), Creation’s Seventh Day, Science, Volume 289, issue of 14 Jul 2000, pp. 232-235.

2. Ross Thyer, Jared Ellefson (2014), Synthetic biology: New letters for life’s alphabet, Nature, News and Views, 15 May 2014 (online 7 May 2014) (not free).

3. Denis A. Malyshev et al. (2014), A semi-synthetic organism with an expanded genetic alphabet, Nature, 15 May 2014 (online 7 May 2014) (this is the original research article).

4. Robert F. Service (2014) Designer Microbes Expand Life’s Genetic Alphabet, Science, News & Analysis, 9 May 2014 (free).

19 Comments

Well, if we find that there are bases that are superior to the ones used in biological systems, then I guess life is not very intelligently designed. In fact, these guys could have done a better job than the supposedly intelligent designer. Good to know.

I don’t see why a base that pairs only with itself wouldn’t work.

Wouldn’t you also need a whole new suite of polymerase, m- and t- RNA’s to make it actually do something?

Variations of the four bases have many functions in living systems, e. g., ATP, ADP, GTP, etc. So, they may have been coopted from other modalities, particularly if the Metabolism First theory is correct. It would be interesting to see if the two new bases can be made to perform in other than genetic processes.

This comment has been moved to The Bathroom Wall.

Jon Fleming said:

I don’t see why a base that pairs only with itself wouldn’t work.

Good remark. As long as two identical paired bases fit in the double helix, and the base does not pair with any other, it could work just fine. One could even imagine a very economical coding scheme with only 3 bases X,Y,Z and the pairs XX, YY, ZZ. The coding potential on the basis of a triplet codon would be 3 x 3 x 3 = 27 and allowing for 1 to 3 stop codons it would still be enough to code for 24 - 26 amino acids (with very low redundancy)… The researchers didn’t use bases pairing with itself, neither did nature. But Why? (gert korthof)

Perhaps Robert would like to tell us how much junk there is in the human genome. Perhaps not. Perhaps he should STFU about things he knows nothing about and couldn’t begin to understand if he tried. Fortunately, that was his last comment on this thread, regardless.

Certainly even Robert can see that if scientists can design a new kind of life, fundamentally superior to the kind found today, that will mean at least that the supposedly intelligent designer was extremely limited, if not incompetent. This new kind of life could be less prone to copying errors, produce a wider variety of proteins, have more redundancy, be more efficient, less susceptible to infestation, more adaptable and overall just plain better that the old kind. After all, it’s not too surprising that humans might eventually do better than the kind of life produced by random chance and selection. A little forethought and planning could go a long way to avoiding some of the problems currently found in the human genome. And of course, it would be obvious that such tinkering had gone on, as opposed to what is observed in the current human genome.

https://me.yahoo.com/a/MS5uiot7uZ_4[…]3UhltA#8ff99 said:

Jon Fleming said:

I don’t see why a base that pairs only with itself wouldn’t work.

Good remark. As long as two identical paired bases fit in the double helix, and the base does not pair with any other, it could work just fine. One could even imagine a very economical coding scheme with only 3 bases X,Y,Z and the pairs XX, YY, ZZ. The coding potential on the basis of a triplet codon would be 3 x 3 x 3 = 27 and allowing for 1 to 3 stop codons it would still be enough to code for 24 - 26 amino acids (with very low redundancy)… The researchers didn’t use bases pairing with itself, neither did nature. But Why? (gert korthof)

These are really fascinating fundamental questions. I have a couple as well. Since this is the internet, I’ll bother to clarify in advance that I am an interested pro-science commenter, not a science denier playing games.

1) What are the concentrations of d5SICS (call it X) and dNaM (call it Y) in the natural environment, compared to the four standard bases?

These novel bases represent the result of careful chemical synthesis, with the goal of generating a novel base pair that would allow replication. But if standard bases or precursors to standard bases were present in the environment in appreciable amounts, and other hypothetically equally good bases just weren’t there, or were at massively lower concentration, that alone might explain why abiogenesis resulted in the use of the four standard bases for DNA. In other words, there may be a large number of “hypothetically just as good” bases that exist at the level of abstraction - that could be synthesized - but if they weren’t around, that explains why they were never used.

2) What would happen if a cell tried to transcribe a sequence of DNA, containing d5SICS (call it X) and dNaM, into some kind of RNA? Would transcription stop when the novel base was encountered? Would the sequence be transcribed with a deletion where the novel base would have been? Would a “best fit” standard RNA base be inserted as a pair mate for the novel base? Some stochastic combination of these or other possible events? I suppose you could also ask these questions about DNA replication, if the only novel bases were in the template DNA, and none available in solution for synthesis of the growing strand.

harold said:

These novel bases represent the result of careful chemical synthesis, with the goal of generating a novel base pair that would allow replication. But if standard bases or precursors to standard bases were present in the environment in appreciable amounts, and other hypothetically equally good bases just weren’t there, or were at massively lower concentration, that alone might explain why abiogenesis resulted in the use of the four standard bases for DNA. In other words, there may be a large number of “hypothetically just as good” bases that exist at the level of abstraction - that could be synthesized - but if they weren’t around, that explains why they were never used.

Well that would be a constraint of natural evolution, but not of intelligent design. Therefore, this type of research could falsify intelligent design once and for all. Then all you would be left with would be unintelligent design and that won’t get you very far.

DS said:

harold said:

These novel bases represent the result of careful chemical synthesis, with the goal of generating a novel base pair that would allow replication. But if standard bases or precursors to standard bases were present in the environment in appreciable amounts, and other hypothetically equally good bases just weren’t there, or were at massively lower concentration, that alone might explain why abiogenesis resulted in the use of the four standard bases for DNA. In other words, there may be a large number of “hypothetically just as good” bases that exist at the level of abstraction - that could be synthesized - but if they weren’t around, that explains why they were never used.

Well that would be a constraint of natural evolution, but not of intelligent design. Therefore, this type of research could falsify intelligent design once and for all. Then all you would be left with would be unintelligent design and that won’t get you very far.

Glad to read that, the same thought had entered my mind before I read your comment. Which goes to prove that you don’t need to know all that much about biology & evolution to understand a few things, if you want to understand.

Rolf said:

Glad to read that, the same thought had entered my mind before I read your comment. Which goes to prove that you don’t need to know all that much about biology & evolution to understand a few things, if you want to understand.

SIr, you are truly a gentleman and a scholar. All great minds … as they say.

DS said: [emphasis added]

Certainly even Robert can see that if scientists can design a new kind of life, fundamentally superior to the kind found today, that will mean at least that the supposedly intelligent designer was extremely limited, if not incompetent. This new kind of life could be less prone to copying errors, produce a wider variety of proteins, have more redundancy, be more efficient, less susceptible to infestation, more adaptable and overall just plain better that the old kind. After all, it’s not too surprising that humans might eventually do better than the kind of life produced by random chance and selection. A little forethought and planning could go a long way to avoiding some of the problems currently found in the human genome. And of course, it would be obvious that such tinkering had gone on, as opposed to what is observed in the current human genome.

And that is the problem with the “grey goo”. If we can create “life” that is “better” than “the old kind” of life, the theory of evolution would suggest that “the old kind of life” doesn’t stand much of a chance of surviving. That would include us.

How much “forethought and planning” would be required to avoid unintended consequences?

No, I’m not trying to be an “alarmist”. I’m not opposed to GMO foods, for example. But if you produce a kind of life that has all the characteristics that DS identifies, and against which “the old kind” of life has no defense, or is simply unable to compete effectively, then what ultimate outcome does that suggest to you?

Yeah, it’s a really cool engineering project, but it also has some really serious downsides.

Absolutely. It’s a very powerful technology. It could make humans virtually invincible. Or it could spell the end for all life as we know it. It just depends on how you choose to use the technology. Same thing with genetic engineering. If you are going to play god, you better get it right.

But the point is, that if a barley scientifically literate species of hairless apes can design a form of life far superior to that which we see on earth today, it pretty much spells the end for any intelligent design nonsense.

I guess you should make that “barely literate”.

barley scientifically literate species of hairless apes

I thought you were referring to the greatest scientific field of them all, Brewing Science.

No, I’m not trying to be an “alarmist”. I’m not opposed to GMO foods, for example. But if you produce a kind of life that has all the characteristics that DS identifies, and against which “the old kind” of life has no defense, or is simply unable to compete effectively, then what ultimate outcome does that suggest to you?

I’m going to go right ahead and not worry about this at all. I prioritize my worries. Right now, I’ve got this one ranked well below

As far as GMO foods, I’m so eccentric, I actually take a “nuanced” view.

I’m strongly in FAVOR of the concept of applying contemporary genetic technology to agriculture. It’s potentially a great way to maximize food yields in a sustainable way.

However, that does not mean that I am in favor of all commercial applications of GMO. For example, a common application is to make crops resistant to herbicide, so that vast amounts of herbicide can be used to kill weeds. By a truly amazing coincidence that no-one would ever guess in advance, the companies that market this approach also make the herbicide. I’m not “against” pesticides and herbicides, of course, but it’s generally more sustainable to seek strategies that minimize, rather than maximize, their use.

I thought you were referring to the greatest scientific field of them all, Brewing Science.

Somebody should write an essay about how the science of Brewing contributed to the evolution of mankind from flocks of hunter-gatherers to advanced multi-billion civilization over just a few thousand years.

I understand Noah didn’t have grain to spare so he had to do with the next best thing.

sez ds: “…this type of research could falsify intelligent design once and for all.” Optimist. You know very well that the ‘theory’ of Intelligent Design, being a wholly-owned subsidiary of good old Creationism, cannot and will not be affected by anything as plebeian as mere scientific falsification. ID will go away only when ID-pushers decide there’s no more point in pushing ID… and given the fact that Young-Earth Creationism is still a very real thing, I wouldn’t hold out much hope for that outcome.

xubist said:

sez ds: “…this type of research could falsify intelligent design once and for all.” Optimist. You know very well that the ‘theory’ of Intelligent Design, being a wholly-owned subsidiary of good old Creationism, cannot and will not be affected by anything as plebeian as mere scientific falsification. ID will go away only when ID-pushers decide there’s no more point in pushing ID… and given the fact that Young-Earth Creationism is still a very real thing, I wouldn’t hold out much hope for that outcome.

Sure. But we will still have one more reason to laugh at them.

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This page contains a single entry by Matt Young published on May 15, 2014 11:09 AM.

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