A door into RNA world

[N.B.: This post is a little on the technical side, if you're not a biology type.  Trust me, the work is worth it, because what these people have discovered is stupendous.]

I had the experience yesterday of stumbling on an article published in Nature this week that, from the title, seemed like something that could only interest biochemistry geeks.

Then I started reading it, and I had to pick my jaw up off the floor.

Before I tell you about the paper, a little background.

Most laypeople know that genes are basically stretches of DNA, and that DNA is a double helix made of chains of smaller molecules called nitrogenous bases, of which there are four -- adenine, thymine, guanine, and cytosine.  (A, T, G, and C for short.)  Because the bases always pair the same way (A to T, C to G), it allows for DNA to replicate itself.

So far, so good.  But how do you get from a gene to a trait?  It took a long time to figure this out, and there's still work being done on how genes switch on and off during development.  But a simplified explanation goes like this:

The first step is that one gene (a piece of DNA) is copied into a similar, but not identical, chemical called RNA.  (This is called transcription.)  RNA is a single helix, so only one side of the DNA gene is copied; the other side only exists so the DNA can be replicated.  Then the RNA goes to a cellular structure called a ribosome, where the base sequence is read in threes (a group of three is a codon), and each trio instructs the ribosome to bring in a specific amino acid.  The amino acids dictated by the codon sequence are linked together into a protein, and those proteins directly generate the trait.  (This is called translation.)  Every trait is basically produced this way, whether it's something simple like skin color, or the interaction between the thousands of genes and proteins that it takes to generate a functioning human heart.

Okay, gene > RNA > protein > trait.  The sequence is so ubiquitous that it's been nicknamed The Central Dogma of Molecular Genetics.

[Image licensed under the Creative Commons  , Pre-mRNA-1ysv-tubes, CC BY-SA 3.0]

But here's the problem.  When life first began, how did the process get started?

The problem isn't the building blocks; given the conditions that we're virtually certain existed on the early Earth, all of the pieces -- the bases, the sugars that make up the backbone of both DNA and RNA, the amino acids -- form spontaneously and abundantly.  They will even link up to form chains on their own.  It's likely that any Earthlike, water-containing planet has plenty of all the biochemical bits and pieces.

But how do you get from a particular RNA to a particular protein?  Remember, it's the sequence of bases in RNA that determines the sequence of amino acids in the protein, but to read the RNA sequence and assemble those amino acids requires a lot of cellular machinery -- first and foremost the ribosome.

Which is itself made of RNA.

So it seems like the first life had to pull itself up by its own bootlaces.  Put succinctly, to do transcription and translation, you need to have the mechanisms of transcription and translation already in place.

Or at least, that's what I thought until I read this paper.

Enter the team led by Felix Müller of Ludwig-Maximilians-Universität in Munich, Germany, and their paper "A Prebiotically Plausible Scenario of an RNA-Peptide World."  Here's how the paper begins, with a couple of parenthetical notes added by me:

A central commonality of all cellular life is the translational process, in which ribosomal RNA catalyses peptide [i.e. protein] formation with the help of transfer RNAs, which function as amino acid carrying adapter molecules.  Comparative genomics suggests that ribosomal translation is one of the oldest evolutionary processes, which dates back to the hypothetical RNA world [the theory that the earliest self-replicating genetic molecules were RNA, not DNA, which is generally accepted in the scientific world].  The questions of how and when RNA learned to instruct peptide synthesis is one of the grand unsolved challenges in prebiotic evolutionary research.

The immense complexity of ribosomal translation demands a stepwise evolutionary process.  From the perspective of the RNA world, at some point RNA must have gained the ability to instruct and catalyse the synthesis of, initially, just small peptides.  This initiated the transition from a pure RNA world into an RNA–peptide world.  In this RNA–peptide world, both molecular species could have co-evolved to gain increasing ‘translation’ and ‘replication’ efficiency...

We found that non-canonical vestige nucleosides [i.e. unusual bases which are still part of some structures made of RNA, but aren't on the list of the four standard bases], which are key components of contemporary RNAs, are able to equip RNA with the ability to self-decorate with peptides.  This creates chimeric structures, in which both chemical entities can co-evolve in a covalently connected form, generating gradually more and more sophisticated and complex RNA–peptide structures...  We... found that peptides can simultaneously grow at multiple sites on RNA on the basis of rules determined by sequence complementarity, which is the indispensable requirement for efficient peptide growth.

Which is way more dignified than what I'd have written, which is, "Holy shit, we just figured out how gene expression evolved!"

In my AP Biology classes, I ended the unit on evolution with a list of some of the questions that evolutionary theory had not yet solved, and the origins of gene expression and protein synthesis topped the list.  It looks like that one might now be checked off -- which, if my assessment is correct, should put Müller and his team in contention for this year's Nobel Prize in chemistry.

I find it so fascinating that there are still some of the Big Questions out there, and that scientists are actually making inroads into answering them.  Good science doesn't just say "it's a mystery" and forthwith stop thinking.  We're gradually chipping away at problems that were thought to be intractable -- in this case, giving us insight into how life began on Earth four billion years ago.

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The recipe for life

Back in my teaching days, I was all too aware of how hard it was to generate any kind of enthusiasm for the details of biology in a bunch of teenagers.  But there were a few guaranteed oh-wow moments -- and one that I always introduced by saying, "If this doesn't blow your mind, you're not paying attention."

What I was referring to was the Miller-Urey experiment.  This phenomenal piece of research was an attempt to see if it was possible to create organic compounds abiotically -- with clear implications for the origins of life.  Back in the early twentieth century, when people started to consider seriously the possibility that life started on Earth without the intervention of a deity, the obvious question was, "How?"  So they created apparatus to take collections of inorganic compounds surmised to be abundant on the early Earth, subject them to various energy sources, and waited to see what happened.

What happened was that they basically created smog and dirty water.  No organic compounds.  In 1922, Soviet biochemist Alexander Oparin suggested that the problem might be that they were starting with the assumption that the Earth's atmosphere hadn't changed much -- and looking at (then) new information about the atmosphere of Jupiter, he suggested that perhaps, the early Earth's atmosphere had no free oxygen.  In chemistry terms, it was a reducing atmosphere.  Oxygen, after all, is a highly reactive substance, good at tearing apart organic molecules.  (There's decent evidence that the pathways of aerobic cellular respiration originally evolved as a way of detoxifying oxygen, and only secondarily gained a use at increasing the efficiency of releasing the energy in food molecules.)

It wasn't until thirty years later that anyone tested Oparin's hunch.  Stanley Miller and Harold Urey, of the University of Chicago, created an apparatus made of sealed, interconnected glass globes, and filled them with their best guess at the gases present in the atmosphere of the early Earth -- carbon monoxide, methane, hydrogen sulfide, sulfur dioxide, water vapor, various nitrogen oxides, hydrogen cyanide (HCN), and so on.  No free (diatomic) oxygen.  They then introduced an energy source -- essentially, artificial lightning -- and sat back to wait.

No one expected fast results.  After all, the Earth had millions of years to generate enough organic compounds to (presumably) self-assemble into the earliest cells.  No one was more shocked than Miller and Urey when they came in the next day to find that the water in their apparatus had turned blood red.  Three days later, it was black, like crude oil.  At that point, they couldn't contain their curiosity, and opened it up to see what was there.

All twenty amino acids, plus several amino acids not typically found in living things on Earth.  Simple sugars.  Fatty acids.  Glycerol.  DNA and RNA nucleotides.  Basically, all the building blocks it takes to make a living organism.

In three days.

A scale model of the Miller-Urey apparatus, made for me by my son, who is a professional scientific glassblower

This glop, now nicknamed the "primordial soup," is thought to have filled the early oceans.  Imagine it -- you're standing on the shore of the Precambrian sea (wearing a breathing apparatus, of course).  On land is absolutely nothing alive -- a continent full of nothing but rock and sand.  In front of you is an ocean that appears to be composed of thick, dark oil.

It'd be hard to convince yourself this was actually Earth.

Since then, scientists have re-run the experiment hundreds of times, checking to see if perhaps Miller and Urey had just happened by luck on the exact right recipe, but it turns out this experiment is remarkably insensitive to initial conditions.  As long as you have three things -- (1) the right inorganic building blocks, (2) a source of energy, and (3) no free oxygen -- you can make as much of this rather unappealing soup as you want.

So, it turns out, generating biochemicals is a piece of cake.  And a piece of research at Friedrich Schiller University and the Max Planck Institute have shown that it's even easier than that -- the reactions that create amino acids can happen out in space.

"Water plays an important role in the conventional way in which peptides are created," said Serge Krasnokutski, who co-authored the paper.  "Our quantum chemical calculations have now shown that the amino acid glycine can be formed through a chemical precursor – called an amino ketene – combining with a water molecule.  Put simply: in this case, water must be added for the first reaction step, and water must be removed for the second...  [So] instead of taking the chemical detour in which amino acids are formed, we wanted to find out whether amino ketene molecules could not be formed instead and combine directly to form peptides.  And we did this under the conditions that prevail in cosmic molecular clouds, that is to say on dust particles in a vacuum, where the corresponding chemicals are present in abundance: carbon, ammonia, and carbon monoxide."

The more we look into this, the simpler it seems to be to generate the chemicals of life -- further elucidating how the first organisms formed on Earth, and (even more excitingly) suggesting that life might be common in the cosmos.  In fact, it may not even take an Earth-like planet to be a home for life; as long as a planet is in the "Goldilocks zone" (the distance from its parent star where water can exist in liquid form), getting from there to an organic-compound-rich environment may not be much of a hurdle.

That's still a long way from intelligent life, of course; chances are, the planets with extraterrestrial life mostly have much simpler organisms.  But how exciting is that?  Setting foot on a planet covered with life -- none of which has any common ancestry with terrestrial organisms.

I can think of very little that would be more thrilling than that.

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People made fun of Donald Rumsfeld for his statement that there are "known unknowns" -- things we know we don't know -- but a far larger number of "unknown unknowns," which are all the things we aren't even aware that we don't know.

While he certainly could have phrased it a little more clearly, and understand that I'm not in any way defending Donald Rumsfeld's other actions and statements, he certainly was right in this case.  It's profoundly humbling to find out how much we don't know, even about subjects about which we consider ourselves experts.  One of the most important things we need to do is to keep in mind not only that we might have things wrong, and that additional evidence may completely overturn what we thought we knew -- and more, that there are some things so far out of our ken that we may not even know they exist.

These ideas -- the perimeter of human knowledge, and the importance of being able to learn, relearn, change directions, and accept new information -- are the topic of psychologist Adam Grant's book Think Again: The Power of Knowing What You Don't Know.  In it, he explores not only how we are all riding around with blinders on, but how to take steps toward removing them, starting with not surrounding yourself with an echo chamber of like-minded people who might not even recognize that they have things wrong.  We should hold our own beliefs up to the light of scrutiny.  As Grant puts it, we should approach issues like scientists looking for the truth, not like a campaigning politician trying to convince an audience.

It's a book that challenges us to move past our stance of "clearly I'm right about this" to the more reasoned approach of "let me see if the evidence supports this."  In this era of media spin, fake news, and propaganda, it's a critical message -- and Think Again should be on everyone's to-read list.

[Note: if you purchase this book using the image/link below, part of the proceeds goes to support Skeptophilia!]

The walk of life

It's remarkably difficult to decide exactly what we mean when we say something is alive.

As a biologist, this is kind of embarrassing.  After all, "biology" means "the study of life."  So in a very real sense, we're studying something when we're not even sure what it is.  Oh, sure, there are some clear-cut examples; a dog is alive, a rock is not.  But amazingly enough, when you try to pinpoint what the dog is doing that the rock is not, you get into some shaky ground -- and rules that are rife with exceptions.

How about "capable of reproducing?"  You can't just say "reproduces," because a good many organisms don't reproduce because of choice or circumstance.  And let's even throw out the timeworn exceptions of the hybrid, infertile mules and ligers as being genetic anomalies.  But what about worker ants?  Worker ants are females that had the development of functional reproductive anatomy suppressed, so they are completely infertile; but they're not genetic accidents like infertile hybrids are.  They are not even theoretically capable of reproducing, but I doubt seriously anyone would argue that they're not alive.

Then, there's "limited life span."  Living things die, usually after a length of time characteristic of the particular species.  However, the bristlecone pine (Pinus longaeva) doesn't seem to have an upper bound on its life span.  Most plants, even most trees, age out after a while -- birch trees live thirty to forty years, silver maples eighty or ninety, red oaks two hundred, white oaks as much as eight hundred -- bristlecone pines don't do that.  Unless they meet with misfortune, they just keep on living.  A bristlecone in the Inyo National Forest of California is 4,851 years old.  To put that into perspective, when the Great Pyramid at Giza was built, this tree was already three hundred years old.

And it isn't just plants.  There's a jellyfish, Turritopsis dohrnii, that is effectively immortal -- when it reaches senescence, it begins to despecialize its cells, returning to the polyp (juvenile) stage, then redifferentiating.  There seems to be no limit to the number of times it can do this -- putting the Time Lords with their twelve regeneration cycles to considerable shame.

And don't get me started on viruses, which are an exception to the majority of the usually-accepted characteristics of life.

The upshot is that the whole topic is way more controversial than you'd think.  Even such seemingly-obvious ones as "composed of one or more cells" and "encodes genetic information as DNA or RNA" may be looking at things from an Earth-bound perspective; life on other planets might well compartmentalize their metabolic processes and store their genetic information in entirely different ways, and still be recognizably "alive."

There's one characteristic, though, that very few people whose opinions count will argue over; living things are subject to evolution by natural selection.  (Okay, the creationists will argue like hell about it, but they conspicuously fail on the "opinions counting" qualification.)  Clearly living things evolve, and it's hard to imagine a non-living thing that would do so.  This, then, would make "evolution by natural selection" not only a necessary condition for being alive, but a sufficient one.

Which would settle once and for all the questions of whether viruses are alive.  They clearly evolve, which is why one flu shot doesn't make you immune for life.

[Image licensed under the Creative Commons Myworkforwiki, Major Evolutionary Transitions digital, CC BY-SA 4.0]

Well, as I am wont to do, I've been leading you down the garden path.  Because if you have been nodding your head and saying, "Okay, that makes sense" to what I've written above...

... scientists in a research lab in Germany have just created life.

Christian Mayer, a chemist at the Center for Nanointegration, and Ulrich Schreiber, a geologist at the University of Duisberg-Essen, have long been of the opinion that life on Earth began underground, not in shallow tide pools (the more common hypothesis).  The heat and pressure in deep crevices in the Earth create conditions that would lead to the formation of vesicles -- water-filled bubbles surrounded by a lipid-bilayer membrane.  These are thought to be the earliest cells, eventually trapping bits of RNA and leading to the first true life-forms.

So Mayer and Schreiber decided to recreate these deep crevices.  They allowed the temperature in lab apparatus simulating deep-Earth characteristics to fluctuate between 40 and 80 C, and the pressure between 60 and 80 bar.  Sure enough, under those conditions, a "primordial soup" forms vesicles readily.  Like soap bubbles, they are created and destroyed rapidly, some lasting longer than others.

But unlike soap bubbles, these vesicles evolve.

For full impact, here's the relevant quote from the press release:

In their laboratory experiment, they regularly changed the pressure in the system at 20-minute intervals, thereby changing the quality of the solvent, as it also occurs in nature through tidal forces and geysers.  In the process, the vesicles were periodically destroyed and re-formed.  Thus, a total of 1,500 generations of vesicles were created and disintegrated again within two weeks. 

The researchers discovered that an increasing number of vesicles survived the generation change.  Analyses showed that these vesicles had embedded specific sequences of 10 to 12 amino acids from the pool of possible peptides into their membrane in a cluster-like manner.  Further tests, specifically carried out with one of these peptides, revealed three effects on the vesicles in question: They became thermally more stable, smaller and hence more resistant and – most importantly – the permeability of their membrane was considerably increased.

Put simply, the vesicles underwent natural selection and evolved to increase their stability and permeability.  The embedded peptides they mention are the first approach to the transmembrane channel proteins that every cell has, allowing it to transport materials across the membrane as needed.

"As we have simulated in time-lapse, functions could have been created billions of years ago that made such vesicles stable enough to come to the surface from the depths, for example with the flow of tectonic fluids or during geyser eruptions," said study co-author Ulrich Schreiber.  "Subsequently, a first metabolism with concentration gradients as an energy source could have developed.  If the ability to self-replicate is eventually acquired, then even from a biological point of view an inanimate component slowly becomes a living organism, a first cell."

So there you are.  Mayer and Schreiber, being cautious scientists, are not saying they've created life, but the implication is there -- and even the most hesitant amongst us (not you, creationists) would have to admit that whatever you want to call it, this represents a huge step toward generating something that is unequivocally alive.

Which I find to be somewhere beyond mind-boggling.

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These days, I think we all are looking around for reasons to feel optimistic -- and they seem woefully rare.  This is why this week's Skeptophilia book recommendation of the week is Hans Rosling's wonderful Factfulness: Ten Reasons We're Wrong About the World--and Why Things Are Better Than You Think.  

Rosling looks at the fascinating bias we have toward pessimism.  Especially when one or two things seem seriously amiss with the world, we tend to assume everything's falling apart.  He gives us the statistics on questions that many of us think we know the answers to -- such as:  What percentage of the world’s population lives in poverty, and has that percentage increased or decreased in the last fifty years?  How many girls in low-income countries will finish primary school this year, and once again, is the number rising or falling?  How has the number of deaths from natural disasters changed in the past century?

In each case, Rosling considers our intuitive answers, usually based on the doom-and-gloom prognostications of the media (who, after all, have an incentive to sensationalize information because it gets watchers and sells well with a lot of sponsors).  And what we find is that things are not as horrible as a lot of us might be inclined to believe.  Sure, there are some terrible things going on now, and especially in the past few months, there's a lot to be distressed about.  But Rosling's book gives you the big picture -- which, fortunately, is not as bleak as you might think.

[Note: if you purchase this book using the image/link below, part of the proceeds goes to support Skeptophilia!]

The power of "only"

Today, I ran into a story that got me thinking about how powerful a single word can be in changing the gist of a claim.

An article in Online Medical Daily entitled "'Seeds Of Life' Collected During Perseid Meteor Shower: Scientists Say Algae 'Can Only Have Come From Space'," writer John Ericson describes an unusual find on the (formerly) sterile sides of a British research balloon.

In a study described at the Instruments, Methods, and Missions for Astrobiology conference in San Diego, British biologist Chandra Wickramasinghe told attendees about a discovery, that (if true) revolutionizes what we know about the origins of life on Earth.  Wickramasinghe and his colleagues launched a balloon into the stratosphere during the annual Perseid meteor shower, and upon retrieval, found that the surface had a microscopic blob of microorganisms stuck to it.  "The entities varied from a presumptive colony of ultra-small bacteria to two unusual individual organisms - part of a diatom frustule and a 200 micron-sized particle mass interlaced with biofilm and biological filaments," Wickramasinghe said, in an interview with The Daily Mail.

Diatom frustules (skeletons)

"By our current understanding of the means by which such particles can be transferred from Earth to the stratosphere they could not - in the absence of a violent volcanic eruption occurring within a day of the sampling event - make such a journey," Wickramasinghe explained.  "If there is no mechanism by which these biological entities could be elevated from Earth to the stratosphere then it must have arrived from above the stratosphere and have been incoming to Earth...  They can only have come from space."

What Wickramasinghe is claiming is not a new idea.  Called panspermia, the speculation is that the ancestors of all terrestrial species was a microorganism (probably an extremeophile) that rode in on a meteorite or on cometary debris.  Chemist Svante Arrhenius was fond of the claim, as was astronomer Fred Hoyle; but it's not much in vogue these days, largely due to slim evidence supporting the contention.  Wickramasinghe himself is kind of a fringe figure in the minds of much of the scientific community -- not only has he championed panspermia with a single-mindedness that approaches obsession, but he also testified for the defense in a 1981 McLean vs. the Arkansas State Board of Education trial, one of many cases that considered the constitutionality of teaching creationism in public schools.  During the trial, he referred to the famous fossil of Archaeopteryx as a "hoax."

None of this wins him any points in my book.

Of course, to be fair, you have to consider a claim separate from the person making it; even complete wingnuts can land on correct ideas sometimes.  And here, we have at least some sort of hard evidence -- traces of microorganisms on a sterile balloon that had taken a trip into the stratosphere during a meteor shower.  Has Wickramasinghe been vindicated?

There's the problem here, and it revolves around the use of the word "only."  Wickramasinghe said that his algae blob "can only have come from space."  Take out the word "only," and I'm with him 100%.  The blob could have come from space.  Its presence on the balloon is certainly suggestive.  But to say that it only can have come from space requires a great deal more than that.

Stratospheric dust collection is a notoriously difficult task.  Contamination is a constant hazard, especially if you are trying to obtain a pure sample of interplanetary dust -- i.e., material that did not originate on Earth.  Terrestrial dust, made up of windblown sediments, volcanic ash, and more prosaic materials such as pollen, can reach amazing heights in the atmosphere, and travel extraordinary distances.  A recent study found that dust from the Sahara can reach stratospheric heights -- and affect weather in western North America.

So even if Wickramasinghe's group was careful -- and I am not trying to imply that they weren't -- the possibility of contamination has to be weighed into any argument about the origin of the microorganisms on the balloon.  As NASA's page on "Cosmic Dust" puts it, "Once in the stratosphere this ‘cosmic dust’ and spacecraft debris joins terrestrial particles such as volcanic ash, windborne desert dust and pollen grains."

But of course, Wickramasinghe has a dog in this race, and once you take out the word "only," you don't have much of a story left.  Debris, some containing organic compounds or even microorganisms, has been found before and been alleged to have an extraterrestrial origin.  Thus far, none of these claims has been conclusively supported, so (to be fair) we have to consider the jury to be still out on the idea of panspermia.

Now, don't get me wrong.  No one would be more delighted than me if extraterrestrial life was discovered, even if it turned out just to be single-celled organisms.  I've long suspected that we're not alone in the universe -- what I know about evolutionary biology suggests to me that life is probably plentiful out there in space.  But if you make a claim to have discovered aliens, even microscopic ones, you have to be held to a higher standard of evidence than suspicions and suggestions.  And your case isn't made more watertight simply because of a judicious use of the word "only."