Biology

New Twist Found in the Story of Life’s Start

All life on Earth is made of molecules that twist in the same direction. New research reveals that this may not always have been so.

Chirality

Brendan Monroe for Quanta Magazine

The mirror-image asymmetry of life is one of the biggest mysteries in biology.

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For 30 years, Gerald Joyce has been trying to create life. As a graduate student in the 1980s, he studied how the first RNA molecules — chemical cousins to DNA that can both store and transmit genetic information — might have assembled themselves out of simpler units, a process that many scientists believe led to the first living things.

Unfortunately, he had a problem. At a chemical level, a deep bias permeates all of biology. The molecules that make up DNA and other nucleic acids such as RNA have an inherent “handedness.” These molecules can exist in two mirror image forms, but only the right-handed version is found in living organisms. Handedness serves an essential function in living beings; many of the chemical reactions that drive our cells only work with molecules of the correct handedness. But the pre-biological building blocks of life didn’t exhibit such an overwhelming bias. Some were left-handed and some right. So how did right-handed RNA emerge from a mix of molecules?

Joyce was able to build RNA out of right-handed building blocks, as others had done before him. But when he added in left-handed molecules, mimicking the conditions on the early Earth, everything came to a halt. “Our paper said if you have [both] forms in the same place at the same time, you can’t even get started,” Joyce said.

His findings, published in Nature in 1984, suggested that in order for life to emerge, something first had to crack the symmetry between left-handed and right-handed molecules, an event biochemists call “breaking the mirror.” Since then, scientists have largely focused their search for the origin of life’s handedness in the prebiotic worlds of physics and chemistry, not biology.

Olena Shmahalo / Quanta Magazine

Many molecules come in mirror-image forms, known as left-handed and right-handed. A chemical process will create both forms of a given molecule, but a biological process will produce just one.

Three decades later, Joyce’s latest research has shown that perhaps life came first after all. Joyce, now at the Scripps Research Institute in La Jolla, Calif., and Jonathan Sczepanski, a postdoctoral researcher, created an RNA enzyme — a substance that copies RNA — that can function in a soup of left- and right-handed building blocks, providing a potential mechanism for how some of the first biological molecules might have evolved in a symmetrical world. The new experiment, published in the November 20 issue of Nature, is reinvigorating the discussion over how life first arose. “They have really opened up a new realm of possible roads,” said Niles Lehman, a biochemist at Portland State University in Oregon who wasn’t involved in the study.

Even more intriguing, Joyce and Sczepanski’s enzyme works differently from other RNA-copying molecules, a discovery that may have profound implications for how life originated. The enzyme is much more efficient and flexible than other RNA-based enzymes developed to date, and it may provide the key to Joyce’s ultimate goal — making life from scratch.

A Crack in the Mirror

Louis Pasteur, the famous 19th-century French chemist, was the first to describe chemical handedness, or “chirality.” He was puzzled by the fact that crystals derived from the dregs of wine twisted light in a specific direction, but the same crystal synthesized in the lab did not. Examining the crystals under a microscope, he discovered that the synthetic chemical came in two mirror-image forms, which canceled out the polarizing effect. The crystal derived from wine had only one.

Scientists later discovered that this bias encompasses the entire living world. Synthetic chemical processes will generate both left- and right-handed molecules. But when nature makes a molecule, the product is either left- or right-handed. For example, all amino acids that are used to make proteins twist light to the left.

Indeed, chirality is an essential component of biochemistry. “It provides a form of molecular recognition,” said Donna Blackmond, a chemical engineer at Scripps and a colleague of Joyce’s. The chirality of a molecule affects how it interacts with other components of the cell. Molecular locks can only be opened with a key of the correct handedness.

Some scientists look to the heavens to explain how this biological bias first arose. Some meteorites show a slight predominance of left-handed amino acids, the building blocks of proteins, suggesting that the influence came from outer space. An alternative cosmic origin story proposes that circularly polarized light coming from a supernova triggered a bias. In addition, radioactive decays produce electrons that are slightly more likely to be left-handed. Such electrons raining down on Earth’s surface might have changed its early chemistry.

Yet most biologists and chemists are skeptical of these astrophysical theories. The bias they create is just too minute. The theories create “a beautiful union between life and nonlife,” said Marcelo Gleiser, a theoretical physicist at Dartmouth College. “But the problem is that those interactions are very weak and short-range.” According to Joyce, the effect of these physical forces would be lost in the noise of chemical reactions. “Such a small asymmetry in the universe is not enough to move the needle,” he said.

Biochemists have tended to favor an alternative proposal, that a chance occurrence of prebiotic chemistry triggered an initial disequilibrium. Perhaps a slight excess of right-handed nucleotides was trapped and amplified in a shallow pool or some other prebiotic test tube. Eventually the bias reached a tipping point, breaking the chemical mirror and setting the stage for the emergence of life. Blackmond has done extensive work showing how to transform a small asymmetry to a nearly complete one using purely physical and chemical means.

Shaking Both Hands

When Joyce entered the field 30 years ago, researchers were already trying to test some of the astrophysical theories. But Joyce was skeptical. “I thought, why are you trying so hard to find a universal explanation when it’s probably chance?” he said.

Courtesy of The Scripps Research Institute.

Gerald Joyce (right), a biochemist at the Scripps Research Institute, and postdoc Jonathan Sczepanski created an RNA enzyme that can replicate in an entirely new way.

Around the same time, scientists were trying to figure out how the building blocks of life — amino acids and nucleic acids — could have spontaneously formed into more complex molecules such as proteins, DNA and RNA. Joyce thought that this assembly process might generate a crack in the mirror. A reaction that selectively plucked right-handed building blocks from the primordial soup would quickly start to create only right-handed molecules, just as a machine that selects only red or only blue Legos from a mixed box would create single-colored towers.

Such a process would simultaneously solve two problems in the origins of life: It would create complex biological molecules while breaking the mirror. Joyce’s experiment in the 1980s set out to test that idea, but its failure called into question how right-handed RNA molecules could form from the ingredients of the primordial soup. “It was a mess,” Joyce said. “The left-handed building block poisons the growing chain.”

The findings were particularly problematic for the nascent “RNA world” theory, which proposed that life began with an RNA molecule capable of replicating itself. RNA is the best candidate for the first biological molecule because it shares characteristics of both DNA and proteins. Like DNA, it carries information in its sequence of bases. And like an enzyme, it can catalyze chemical reactions. (RNA enzymes are known as ribozymes.)

But if a ribozyme that copies RNA can’t function in a chemically symmetrical world, how could RNA-based life have emerged? “It’s kind of a showstopper,” said Peter Unrau, a biochemist at Simon Fraser University in Canada. In the decades since Joyce’s 1984 experiment, scientists have proposed myriad ways around the problem, from physical and chemical theories to RNA precursors that lack chirality.

Given the known limitations, Joyce began to focus on creating a simple ribozyme that could copy RNA when only right-handed blocks were around. His group had some success, but none that fulfilled the requirements of the RNA world theory.

So last year, Joyce and Sczepanski decided to start from scratch. They unleashed a pool of random right-handed RNA molecules and let them react in a test tube with left-handed building blocks. They hoped that within that random pool of RNA molecules was a ribozyme capable of stringing the building blocks together. They then isolated the best candidates — ribozymes that could copy RNA of the opposite handedness — replicated them, and subjected the new pool to the same trial over and over again.

In just a few short months, they had a surprisingly effective ribozyme. The right-handed version binds to a left-handed RNA template and produces a left-handed copy. The left-handed copy can then go on to produce a right-handed version. “It’s amazing what they did,” said John Chaput, a biochemist at Arizona State University in Tempe. “It really does get to the heart of the question of the origins of chirality and provides some solid evidence to move things forward.”

Perhaps even more exciting is how well the enzyme works. Other ribozymes created to date are too finicky to have spawned life; they replicate only certain RNA sequences, like soil that will grow potatoes but not carrots or peas. But Joyce’s ribozyme could produce a range of sequences — including its own. And it’s still getting better. The ribozyme in the paper emerged after just 16 rounds of evolution, a shockingly short run for this kind of experiment. Further rounds of evolution have already boosted its abilities, though these findings are not yet published. “The beautiful thing is that this is still a young enzyme,” Lehman said. “There’s lots of room for improvement.”

The new ribozyme nearly fulfills the most basic properties of life — the ability to replicate and to evolve.

The reason the new ribozyme works so well lies in the unusual way it operates. A regular ribozyme binds to its target according to its sequence of letters, like two sides of a zipper coming together. Sometimes it works too well, and the targets get stuck. This kind of binding only works with two molecules of the same handedness, which means Joyce’s ribozyme can’t bind this way.

Instead, it binds based on the molecule’s shape rather than its sequence, an approach that turns out to be much more flexible. “They found something completely novel,” Lehman said. “It goes to show there’s a lot out there we don’t know.”

Scientists now have an enzyme that doesn’t need a chiral world. Researchers, including Joyce himself, are still trying to understand the implications. The findings open the possibility that chirality emerged after life first evolved. “Maybe we didn’t need to break symmetry,” said Blackmond.

Jack Szostak, a biochemist at Harvard University and one of Joyce’s collaborators, is excited by the findings, particularly because the ribozyme is so much more flexible than earlier versions. But, he said, “I am skeptical that life began in this way.” Szostak argues that this scenario would require both left-handed and right-handed RNA enzymes to have emerged at the same time and in the same place, which would be highly unlikely.

Right-Handed Reign

If chirality emerged sometime after the origins of life, the question remains: Why did right-handed RNA win? Left- and right-handed molecules have chemically identical properties, so there’s no obvious reason for one to triumph.

David Kaplan, Petr Stepanek and Ryan Griffin for Quanta Magazine; music by Kai Engel

Video: How Did Life Begin on Earth?
David Kaplan explores the leading theories for the origin of life on our planet.

Joyce and others suspect it’s simply chance. Say a ribozyme capable of transforming a pool of mixed nucleic acids into left- and right-handed RNAs appeared on the early Earth. It would produce two distinct groups, lefties and righties, which in turn might have functioned like competing populations. “If the right hand stumbles on useful mutations and runs away with the game, then the other side of the mirror can go dark,” Joyce said. For example, the right-handed group of RNAs might have developed some kind of competitive advantage, such as producing proteins, eventually overtaking the left-handed group and generating the bias we see today.

There is only one way to truly determine whether one hand is superior: Build life forms that twist in each direction and evaluate them side by side. George Church and collaborators at Harvard are aiming to do just that. If they can make mirror versions of all the cells’ parts, they can construct synthetic cells and compare otherwise identical left- and right-handed versions of life.

To create mirror-image RNAs, Church and his collaborators first need to make mirror enzymes capable of stitching together mirror building blocks. Michael Kay’s team at the University of Utah has almost finished developing a method for chemically synthesizing an ordinary version of one such enzyme. Once completed, the two teams will apply the same approach to make a mirror enzyme capable of assembling mirror RNAs. Church and others are also building tools to detect mirror life, which could prove important when searching for signs of life on other planets.

Joyce remains interested in making life from scratch. Everything else, including the chirality problem, is just a hurdle toward that larger prize, he said.

The new ribozyme may provide the best shot yet. It nearly fulfills the most basic properties of life — the ability to replicate and to evolve. “They went so far as to show the mirror image can copy itself,” Chaput said. “That gets very close to replication.” The next step will be to make that happen iteratively. “If you look in the mirror, make a copy, then put yourself in the mirror, and make a copy of the person in the mirror, then you have replication,” Chaput said.

That iterative process opens the possibility for evolution, as mistakes made during copying will allow the molecule to evolve new traits. “The real key to all of it has been setting up a system in the lab capable of evolution on its own,” Unrau said. “Jerry is close.”

Editor’s Note: Donna Blackmond, Gerald Joyce and Jack Szostak receive funding from the Simons Foundation as Simons Investigators.

This article was reprinted on ScientificAmerican.com.

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  • Interesting.

    Here are three facts:

    (1) Life happened only once on earth. (We know this because life is all alike at the molecular level, so it’s almost certain that all life has a single common ancestor.)

    (2) Our best scientists in the 21st century are unable to create life.

    (3) The evidence for life away from earth amounts to exactly zip.

    And, paradoxically, some so-called scientists contend that life — this thing we can’t create when our best scientists try, and happened only once on the most favorable environment we know of, and for which we have no evidence elsewhere — happens all the time virtually everywhere.

    This contention that life is everywhere sounds not like science, but faith.

  • I would reword your facts to say:
    1. Life happened X times on Earth, where X=>1.
    2. Most scientists of the 21st Century may not have even been born, and what they will be able to achieve is currently unknown.
    3. Discovering life elsewhere in a 13 billion year old universe containing trillions of distant stars and planets has not been accomplished in our first 50 years of trying to find it.

    The contention that life is everywhere is not faith, it is a hypothesis based on multiple threads of evidence gathered to date. Many avenues exist to obtain more evidence which would further support this hypothesis, perhaps even confirming it within our lifetime in our own solar system.

    Faith is what one is reduced to relying upon when the scientific method is unable to generate a deeper level of understanding on a topic. Biology is a LONG way from relying on faith.

  • Taking the solar system, the sun, and many other variables in conjunction with the Kepler data. Dr. Laird Close of the University of Arizona has come up with statistical data that shows there may only be three planets in the galaxy capable of intelligent life. If true, it’s sad.

  • Very interesting article. I’m intrested though in knowing if synthetically produced vitamins are enantiomorphs , if so is there a difference in how our system reacts to the mirror image of the default?

  • Glenn:

    1) Life may have happened more than once. Similar processes could lead to similar distinct emergences;

    2) Scientists may be able to create life in the 22nd Century, or 23rd. Myopic to think otherwise;

    3) Evidence for life elsewhere is absent, but we’ve only just started. It’s akin to scooping a glass in ocean water and then presuming there’s no life in the ocean. We searched a tiny portion of sky within a 100-lightyear bubble. Absence of evidence isn’t evidence of absence;

    Saying life is everywhere isn’t faith, it’s statistics. Hundreds of billions of stars just in this galaxy means an insane amount of solar systems, not to mention the several hundred billion galaxies each with billions of stars. To think we’re special is arrogant.

  • Even if only a (comparatively) tiny number of planets in our galaxy were suitable for the development of “intelligent life” (a fairly subjective label), that hardly rules out the possibility that there are many more with some form of life. On the minus side, the odds that we will be able to observe or detect other life, given the size of our universe, are not wonderful…

  • Glenn, the reason these beliefs are not faith is because they are not believed unquestionably.

    Most, but not all, scientists believe that life is elsewhere in the universe. That is based on the best data we have, and is the prevailing scientific hypothesis and theory. However not one of these scientists have “faith” in this belief, only a certain degree of confidence.

  • Also Glenn: your point three is broken, we’ve found precursors several times despite rather inhospitable conditions (and I quote from the article: “Some meteorites show a slight predominance of left-handed amino acids, the building blocks of proteins”).

  • Fascinating implications hampered by a tedious article.

    The article’s expository sections waffle between many “left-” and “right-handed” references. Even the most dedicated reader is left struggling for clarity. A diagram, or an editor, would have helped immensely.

    “Organic” DNA and RNA are both right-handed.

    “Pre-biological building blocks” were both RH / LH.

    Researchers could “create” right-handed RNA successfully, as others had done.

    [Replicate from RNA + aminos? RNA “emerges” from aminos?]

    Researchers tried mixing in left-handed “molecules” — aminos? RNA? Not specified.

    Researchers could not replicate either left- or right-handed RNA in a mixed LH / RH environement.

    New concept: “RNA enzyme”, copies RNA. New RNA enzyme “functions” in a mixed LH / RH environment.

    Amino acids, used to make proteins, are all left-handed.

    [Wait, what?!]

    Space rocks and cosmic rays are lefties, too.

    Most are skeptical that these explain the biological bias.

    [Huh? If RNA is RH why woudld LH space rocks cause the bias?]

    Biochemists propose random local phenomena giving rise to RH dominance.

    [Whew! At least we’re back to RH again. But is this really any different from space rocks? How about a space rock landing in a tide pool?]

    30 years ago, scientists were learning how amino and nucleic acids form more complex molecules: proteins, DNA, RNA.

    [LH amino -> RH RNA … unexplained to the reader]

    Joyce thought a RH-selective reaction “would quickly start to create only right-handed molecules” [no kidding?] and that magically explains both the emergence of increased molecular complexity and switch in chirality.

    So Joyce’s experiment 30 years ago tests “that idea.”

    [The experiment does not test the idea that a right-favoring reaction makes right-handed products.]

    And the expieriment was a “failure”.

    [The experiment was supposed to replicate left-handed molecules!]

    Experiment’s failure makes it unclear how we got from primordial LH / RH basic molecules, to modern, complex RH molecules.

    Let’s try to work in an RH-only model. We have some, but not complete, success.

    [How is this work different from the 80’s research presented earler? Is this referring to that same work?]

    Now let’s try to work with LH “building blocks” [aminos?] and RH-RNA, and breed the best results.

    Success! Right-handed RNA can bind to a left-handed “RNA template.” [Huh? is that an amino acid?]

    And it “produces a left-handed copy.” The left-handed “copy” can produce a right-handed “version.”

    [It sounds like this intermediate molecule cannot possibly be an exact copy if it a produces different result.]

    [This intermediate molecule is the most important part of this research, but our poor reader must slosh through puddles of digital ink to uncover it.]

    [Does the “right-handed version” go on to produce only right-handed molecules?]

    [Could we create a ribozome that only ever produces left-handed molecules? Could we eventually synthesize a completely parallel set of complex organic lifeforms formed from only left-handed molecules?]

    [Did we ever actually learn where the increase in molecular complexity came from?]

  • @Dave:

    “It’s akin to scooping a glass in ocean water and then presuming there’s no life in the ocean.”

    You’d get plenty of life in a glass of ocean water.

    Our search for life in space is more like shooting a harpoon into the ocean. We don’t know if mermaids exist, we have never harpooned one, and we don’t have any reliable records of one swimming up to our boat.

  • @Ken:
    I like that analogy. Someone who insists that there is extraterrestrial life (before we have proof) is relying on faith, whereas a scientist should hypothesize the possibilities, but recognize the lack of evidence as well.

  • I found this article extremely interesting.

    It brought to mind something else I find extremely interesting regarding the earth and it may indeed relate to life as we know it as well.

    That is the electrical conductivity of air at sea level is 1000v/mm , yet when the air pressure increases the voltage required increases (or the resistance increases) , and yet when the air pressure decreases the voltage required also increases (or the resistance increases).

    I think the fact that we live on the apex of the lowest possible resistance in air for electricity is an astounding fact, and the abundance of life on Earth is very likely related to this fact.

    The “Goldi Locks” zone that we think of, is in my opinion, much more complex than simply enough air and water, and discovering other planets which exist on the same apex of resistance that Earth has is no easy task either 8-).

  • Is it possible that this situation could be analogous to matter/antimatter creation in the early universe, with matter eventually dominating?
    Perhaps the building blocks of life originally were present in both mirror image versions which subsequently combined via some mechanism, the product being non-viable; an initial slight excess of the RH version then continuing alone.

  • @Bernhard:

    That really is a fascinating physics stat! I, too, have always wondered what was so special about the ingredients of our particular primordial soup.

    I wanted to learn a little more about this curiosity, and I seemed to find some easy verification of your number here: [ http://hypertextbook.com/facts/2000/AliceHong.shtml ] — and of course some interesting notes and numbers unearthed at Wikipedia: [ http://en.wikipedia.org/wiki/Paschen%27s_law ].

    I didn’t see much specific mention of air temperature affecting conductivity, so I assume the numbers are based on STP. There is plenty of variance of temperatures found at 1ATM of pressure, but I cannot tell you from these equations how dramatic an effect that range would have on conductivity.

    The image of the Paschen curves in the Wikipedia entry seems to illustrate the “apex” of conductivity quite well. Too bad about that Y-axis, though – instead of showing us as emerging improbably from the apogee of an energetic curve, though, we seem to slip out from the nadir of a depression of least resistance.

  • @Glen, Please keep your psycho babble to yourself. Thanks! The items you’ve listed are not facts, all but one of them are false statements you’re using to discredit the power and genius of modern day science. “So-called scientists???” What else would you call them? They are scientists whether you agree with their research or not. What evidence do you have for creationism, other than your feelings and beliefs in a being that’s as magical as Santa Claus?

  • Can anyone please define what is life?

    The general symptom of life appears to be locomotion and consciousness. Motion requires energy, which appears to be one (that which moves matter), but reveals itself differently through interaction with various objects. Consciousness also is the uniform content “I know…..”, though the object of knowledge vary. Thus, we can visualize it as a sea where the objects are like fish, coral, sea weed, etc., which appear, disappear and reappear in different combinations of chemicals in the natural process due to changing nature of entropy.

  • Is it possible that the earth's magnetic field could have influenced the 'handedness' of molecules billions of years ago?
    Is this likely?
    I'm an interested member of the public,not a scientist.

  • Yes, in my opinion, is very likely that magnetic field to modulate this process.
    Physical, chemical and biological systems may respond not only at high-energy stimulus but also to complex stimulus.
    Member of the public.

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