Exploring Evolution Series: Self-Assembling Molecules Like These May Have Sparked Life on Earth

When his students successfully converted chemical precursors into an RNA-like molecule in the

form of a yellow gel, Nicholas Hud scribbled down the surprising recipe. Image: Nicholas Hud

Self-Assembling Molecules Like These

May Have Sparked Life on Earth

http://www.wired.com/wiredscience/2014/02/rna/

by Emily Singer, Quanta Magazine

February 20, 2014

For Nicholas Hud, a chemist at the Georgia Institute of Technology, the turning point came in July of 2012 when two of his students rushed into his office with a tiny tube of gel. The contents, which looked like a blob of lemon Jell-O, represented the fruits of a 20-year effort to construct something that looked like life from the cacophony of chemicals that were available on the early Earth.

To some biochemists, Hud’s attempts to find an evolutionary precursor to ribonucleic acid may have seemed a fool’s errand. The dominant theory to explain the origins of life — known as the RNA world hypothesis — regards ribonucleic acid as the first biological molecule. Its allure comes from the molecule’s dual nature. Unlike DNA, the molecule that provides the blueprint for all living things, RNA acts as both an information carrier and an enzyme, catalyzing reactions. That means the molecule has the potential to copy itself and to pass along its genetic code, two essential components for Darwinian evolution.

If RNA was indeed the first biological molecule, discovering how it first formed would illuminate the birth of life. The basic building blocks of RNA were available on prebiotic Earth, but chemists, including Hud, have spent years trying to assemble them into an RNA molecule with little success. About 15 years ago, Hud grew frustrated with that search and decided to explore an alternative idea: Perhaps the first biological molecule was not RNA, but a precursor that possessed similar characteristics and could more easily assemble itself from prebiotic ingredients. Perhaps RNA evolved from this more ancient molecule, just as DNA evolved from RNA.

Hud’s team started exploring this idea explicitly a decade ago. When the gel formed in 2012, after the testing of dozens of chemicals, Hud’s team knew it had made a significant advance in the chemistry of a possible proto-RNA world. After years of failed attempts, a surprisingly simple chemical recipe had produced a conglomerate of long, ribbonlike molecules whose structure and chemical components resembled those of RNA.

Hud immediately asked the students to recite the protocol they had used for the reaction, scribbling it down as they spoke. “I wanted to be sure that we would always remember how they had obtained [the end-product] by such a simple procedure,” he said. In December 2013, the results were published in the Journal of the American Chemical Society.

The chemist Nicholas Hud proposes that RNA evolved from a molecule
that  was easier to assemble on the early Earth, as illustrated in this model.Photo: Georgia Institute of Technology

“In my opinion, nothing like this has been seen before,” said Stephen Freeland, a biologist at the University of Maryland Baltimore County, who was not involved in the study. Although he isn’t certain that the chemicals Hud picked will end up being the precise components of proto-RNA, Freeland said Hud has “made conceptual progress.”

Hud isn’t the first scientist to explore an alternative chemistry for RNA. But the robustness of his reaction is unique — the molecules seem to seek one another out, reacting without a lot of chemical coaxing. Hud and others say this ease of creation is essential for reactions to have taken place in the chaotic chemical cauldron of early Earth. “Before this, people just didn’t focus on the real-world situation,” Freeland said. “We need something so robust that no matter what the situation is, it will still happen.”

Hud’s team is now testing whether its reactions will work in a messy mix of molecules more analogous to the primordial soup.

Hud’s chemistry — and the concept of proto-RNA in general — still faces hurdles. His molecule possesses a polymer-like structure of repeating units similar to nucleic acids. In RNA and DNA, the sequence of those units is essential for carrying information, allowing those molecules to store and transmit the code of life. But Hud’s molecule uses only two chemical letters, compared with RNA’s four, and the repeating units can easily come apart. That means it doesn’t have the informational content of RNA, an essential characteristic of life.

Proponents of the traditional RNA world hypothesis say that moving from an RNA precursor like Hud’s to RNA itself still represents an incredible challenge, possibly as daunting as making RNA from scratch. If these molecules were successful enough to launch the origins of life, where are they now?

“To me, the proto-RNA idea raises more questions than it answers,” said John Sutherland, a chemist at the MRC Laboratory of Molecular Biology in Cambridge, England, who nonetheless described Hud’s work as elegant and well done. “If it’s too difficult for RNA to assemble chemically, how can a primitive biology invent RNA?”

From Soup to Structure

In the modern cell, cooking up an RNA molecule is a complex process involving multiple enzymes that link a sugar (ribose) to one of four nucleobases — chemical letters that make up the genetic code and come in the flavors guanine, adenine, uracil and cytosine — and a phosphate, which provides the backbone of the structure. Another enzyme ties together repeating units of each of these three components into the long chain of RNA.

But in the pre-biotic Earth, there were no enzymes. So how could the first RNA molecules have formed? According to the RNA world hypothesis, RNA spontaneously came together through geochemical processes. Scientists studying the origins of life have spent the past 40 years trying to figure out exactly how this could have happened, analyzing the likely chemical components of early Earth and devising chemical reactions to bring them together. “The chemistry of making RNA is so difficult that it’s hard to imagine that you could have a one-pot reaction, where molecules come together and spontaneously make this complex molecule,” Hud said.

Scientists have been able to produce a few of these components without enzymes. In 2009, Sutherland and collaborators showed for the first time that they could synthesize one of the basic units of RNA from scratch. They argue RNA could have formed this way in nature, but Hud and Freeland say the precise chemical conditions and steps required for the reaction would have been unlikely to occur in the chaotic chemical cauldron of prebiotic Earth.

* * * * *

My Grandfather’s Ax

Scientists have long considered alternative chemistries for RNA, synthesizing molecules with alien components that have even found their way into biotechnology applications. Nicholas Hud, a chemist at the Georgia Institute of Technology, takes a broader approach — perhaps every component was different and each changed over time. To explain, Hud employs an ancient Greek paradox called “my grandfather’s ax”: If your father replaced the handle and you replaced the blade, the result would be an entirely new ax. “Everyone accepts that DNA comes from RNA and DNA is harder to make than RNA,” Hud said. “So if you’re willing to accept that DNA evolved from RNA, then why not that RNA is product of evolution of proto-RNA?”

* * * * *

An alternative hypothesis is that RNA as we know it has undergone substantial chemical and biological evolution. “The origins of life and the origin of the genetic code are no longer synonymous,” said Antonio Lazcano, a biologist at the National Autonomous University of Mexico in Mexico City and former president of the International Society for the Study of the Origin of Life who was not involved in Hud’s study. “You can have a significant part of the genetic code that will be the outcome of biological evolution and a largely undescribed stage of chemical evolution.”

Scientists have been examining molecules with alternative bases or sugars almost since RNA was proposed as the first biological molecule in the 1960s. But this approach creates an overwhelming set of possible permutations, as each of the three components — sugar, phosphate and base — has numerous potential replacements. “The chemical space becomes enormous,” Hud said. “It’s a really big task to find out what came first.”

Hud’s team started with the bases, looking for candidates that could form something like the traditional base pairs of RNA and DNA, in which certain bases seek each other out like lost lovers; in RNA, adenine binds only with uracil and guanine with cytosine. It’s this pairing that enables the molecules’ unique capacity to store information. Each molecule acts as a template for the next generation, creating a sort of mirror image of its predecessor.

But Hud also wanted base pairs that, unlike traditional bases, could spontaneously assemble into long polymers. “If you have a complex mixture of thousands of molecules, the chemistry relies on what reacts the fastest,” Hud said. “The molecules need to organize themselves.”

Rather than limit themselves to the four bases used in RNA, the members of Hud’s team considered a library of roughly 100 structurally similar molecules, including only those that were predicted to have existed on prebiotic Earth or in meteorites, which may have carried with them essential components of life. “We’re foolish if we don’t think about this: either why nature picked these four or what nature did before picking these four,” Freeland said.

Molecular Recipes

To try to find bases that bond like those of RNA, Hud’s team started mixing chemicals under various conditions. After several years, the researchers homed in on a few promising candidates, most notably two molecules, triaminopyrimidine (TAP) and cyanuric acid (CA). Last year, in a paper published in the Journal of the American Chemical Society, the researchers showed that a slightly modified version of triaminopyrimidine and cyanuric acid self-assemble in water, creating something that resembles traditional base pairs. However, rather than the conventional duo of base pairs, adenine and uracil or cytosine and guanine, the molecules form hexamers, or six-membered rings. The hexamers stack on top of one another, forming long, polymerlike structures. They had found a chemical pairing that spontaneously assembled into a complex, RNA-like arrangement. “We were surprised it worked so well,” Hud said.

Hud’s team set out to tackle the next problem in RNA assembly: How do bases attach to the ribose sugar? In their newest paper, published in the same journal, the researchers showed that TAP and ribose easily bond when mixed in water, creating molecules known as nucleosides. (The finding was especially encouraging because this bond has been difficult to form between sugars and traditional RNA bases.) When the researchers added the other base, CA, and heated the mixture, it formed into long polymers, about the length of genes. It’s these polymers that create the gel that excited Hud’s team.

“I think it’s an important step because it shows that the physical forces that hold genomes together today can be reproduced in the protoworld,” said Frank Schmidt, a biochemist at the University of Missouri in Columbia who was not involved in the studies. “He has shown that you can start with star stuff [chemicals originally produced by stars] and get something with some of the fundamental properties of RNA.”

The beauty of Hud’s chemistry is that the assembly doesn’t require an enzyme or a template — the molecules come together on their own.

According to the protoRNA theory, each of the components of RNA — sugar, base and
phosphate backbone — may have originally taken different forms. Image: Nicholas Hud

Big Questions

However, there are still important differences between Hud’s polymer and RNA. “These lovely properties come at the price of taking a step away from the chemistry we all know,” said Michael Yarus, a molecular biologist at the University of Colorado in Boulder who was not involved in the studies. For example, unlike RNA, each molecule in the stack is linked by a relatively weak kind of bond known as a non-covalent bond. Like a set of magnetic beads that can break apart and reconnect, the structure can separate more easily than RNA, which is more similar to beads knotted on a string. That flexible structure impairs the polymer’s potential to reliably store information in the sequence of bases, which makes up the code of life.

Other big questions include why and how these molecules could have evolved into modern RNAs, considering that it might have been easier for the precursor molecule to maintain the status quo. Proponents of the traditional RNA world view this as a giant obstacle, but Hud disagrees. CA can be converted into uracil and TAP into guanine and adenine with only a few chemical changes, he said. His team is now exploring other candidate bases capable of forming pairs and self-assembling with ribose sugars. The researchers are also looking at alternatives for the other components of RNA, the sugars and phospates, as well as how to stitch together nucleosides in a way that mimics the knotted string of RNA. Even though the final result may look quite different than RNA, Hud argues that because RNA is the superior system, natural selection will favor its creation and drive its precursor to extinction.

Even those who are not convinced of the proto-RNA world say it’s worth exploring the possibilities. “It’s important to have a lot of routes to find the one that really happened, the one that’s highly probable,” Yarus said, adding that how far Hud’s chemistry will travel along that path of probability is not yet clear.

Others are looking at an even broader set of chemical alternatives. In a paper published in November 2013, Freeland and collaborator Jim Cleaves, a chemist at the Earth-Life Science Institute in Tokyo, used computational methods to examine alternative amino acids, which are the building blocks of proteins. The team plans to do the same for the building blocks of RNA. “Hud’s list is just the tip of the iceberg,” Freeland said. “There could be tens of thousands of structures to seriously consider.”

Original story reprinted with permission from Quanta Magazine, an editorially independent division of SimonsFoundation.org whose mission is to enhance public understanding of science by covering research developments and trends in mathematics and the physical and life sciences.

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Index to past articles on "Science & Religion"

Stephen Hawking's Newest Proposal: Black Holes have no Event Horizon. Only an Apparent Horizon

An artist conception of a black hole spewing radiation all around it. Image: NASA

A Brief History of Mind-Bending Ideas About Black Holes
http://www.wired.com/wiredscience/2014/01/brief-history-of-black-holes/

by Adam Mann
January 29, 2014

Physicist Stephen Hawking made headlines recently by saying that black holes – the incredibly massive astronomical objects that made him famous – do not exist. Or they exist, but not how we think. Or something. The truth is complicated.

In fact, to really understand where Hawking and the rest of the astrophysics community are coming from, it’s important to know a little history. Just how we arrived at this complex situation is strange, involving a spate of discoveries about the properties of black holes, each solving some previous problem. But, like a hydra sprouting new heads for each one cut off, the solutions generated new difficulties, eventually leading to Hawking’s recent declaration.

The story starts in 1784, when a geologist named John Michell was thinking deeply about Isaac Newton’s theory of gravity. In Newtonian physics, a cannonball can be shot into orbit around the Earth if it surpasses a particular speed, known as the planet’s escape velocity. This speed depends on the mass and radius of the object you are trying to escape from. Michell’s insight was to imagine a body whose escape velocity was so great that it exceeded the speed of light – 300,000 kilometers per second – first measured in 1676 by the Danish astronomer Ole Romer.

Michell presented his results to other scientists, who speculated that massive “dark stars” might exist in abundance in the sky but be invisible because light can’t escape their surfaces. The French mathematician Pierre-Simon Laplace later made an independent discovery of these “dark stars” and both luminaries correctly calculated the very small radius – 6 kilometers – such an object would have if it were as massive as our sun.

After the revolutions of 20th century physics, black holes got much weirder. In 1916, a short while after Einstein published the complex equations underpinning General Relativity (which Einstein himself couldn’t entirely solve), a German astronomer named Karl Schwarzschild showed that a massive object squeezed to a single point would warp space around it so much that even light couldn’t escape. Though the cartoon version of black holes has them sucking everything up like a vacuum cleaner, light would only be unable to escape Schwarzschild’s object if it was inside a particular radius, called the Schwarzschild radius. Beyond this “event horizon,” you could safely leave the vicinity of a black hole.

Trailing above galaxy NGC 4194 is a tidal tail formed by a collision with another galaxy. The bright blue X-ray source found on the left side of the tail is a black hole. Image: X-ray: NASA/CXC/Univ of Iowa/P.Kaaret et al.; Optical: NASA/ESA/STScI/Univ of Iowa/P.Kaaret et al.

Neither Schwarzschild nor Einstein believed this object was anything other than a mathematical curiosity. It took a much better understanding of the lives of stars before black holes were taken seriously. You see, a star only works because it preserves a delicate balance between gravity, which is constantly trying to pull its mass inward, and the nuclear furnace in its belly, which exerts pressure outward. At some point a star runs out of fuel and the fusion at its core turns off. Gravity is given the upper hand, causing the star to collapse. For stars like our sun, this collapse is halted when the electrons in the star’s atoms get so close that they generate a quantum mechanical force called electron degeneracy pressure. An object held up by this pressure is called a white dwarf.

In 1930, the Indian physicist Subrahmanyan Chandrasekhar showed that, given enough mass, a star’s gravity could overcome this electron degeneracy pressure, squeezing all its protons and electrons into neutrons. Though a neutron degeneracy pressure could then hold the weight up, forming a neutron star, the physicist Robert Oppenheimer found that an even more massive object could overcome this final outward pressure, allowing gravity to win and crushing everything down to a single point. Scientists slowly accepted that these things were real objects, not just weird mathematical solutions to the equations of General Relativity. In 1967, physicist John Wheeler used the term “black hole” to describe them in a public lecture, a name that has stuck ever since.

But as researchers studied black holes, they kept finding new ways in which they were bizarre. In 1974, Stephen Hawking made his most famous discovery: black holes can emit radiation. Down at the subatomic scale, fundamental particles are constantly winking in and out of existence. (It’s freaky to think that this is happening all around you all the time but it’s true.) Hawking realized that if a particle and its antiparticle appeared just at the edge of a black hole’s event horizon something odd would happen. Typically, these two particles would annihilate one another and release their energy back to the universe. But if one of the pair got sucked into the black hole, the other would get flung outward. The expelled particle would carry a bit of the black hole’s energy away, slowly sapping its strength. Given enough time, black holes would evaporate.

This introduced a dilemma: What exactly happens to that particle falling into the black hole? According to the laws of quantum mechanics, information about that particle cannot be destroyed. But once a particle has slipped beyond the event horizon, nothing about it, including its quantum mechanical information, can be recovered. Or at least, that’s what Hawking argued for more than 30 years, even going so far as to make a famous bet with physicist John Preskill in 1997 that the intense gravity of the black hole somehow overpowers the laws of quantum mechanics. But in 2004, Hawking had to concede that he was wrong. The work of other scientists, particularly string theorist Donald Marolf and physicist Juan Maldacena, showed incontrovertibly that there was no way to destroy quantum information and that it was actually leaking out of the black hole.

Despite the fact that everyone agreed on this conclusion, no one had any idea of exactly how it was happening. The result generated yet another intractable problem. The particle and antiparticle responsible for this whole mess were quantum mechanically entangled, which means that their properties are forever linked. Theoretical physicist Joseph Polchinski, working with Marolf and others, showed in 2012 that, in order for everything else known about black holes to be true, this quantum entanglement would have to be severed. Such a process is possible but violent. Disentangling the twins would generate a huge amount of energy right at the black hole’s event horizon. This energy would form a wall of blazing fire around the black hole, incinerating anything that came near.

Yes, we’re getting to the bit about Hawking’s recent proposal. Just hold on. Nothing about black holes is quick and easy.

The searing firewall solution has yet to be fully resolved in the physics community. Some believe it, some don’t. But even for those inclined toward the idea, it creates, you guessed it, another major problem. According to Einstein’s relativity, an astronaut falling into a black hole shouldn’t notice anything particularly different about the universe when s/he passes the event horizon. Getting incinerated certainly counts as “something peculiar going on here.” Scientists are faced with a choice: give up on Einstein and acknowledge that firewalls exist or give up on quantum mechanics and realize that information gets destroyed in a black hole.

A fanciful image of what the heart of a black hole might look like. Of course, new theories could change this view. Image: NASA/JPL-Caltech

In an attempt to thread the needle between the options, Hawking recently proposed to do away with something else: the event horizon. He instead suggests that physicists consider a much more nebulous term called the “apparent horizon” around a black hole. The apparent horizon works a lot like an event horizon, in that light beams inside of it can’t escape. They get stuck in a holding pattern, moving as fast as they can to stay in the same place, like the Red Queen in Alice in Wonderland. In this way, light and other information can get sort of “stored” in an apparent horizon but eventually find its way out.

The apparent horizon and the event horizon don’t entirely overlap. 1) Because a black hole can grow (by sucking in extra mass), its event horizon may move outward past its apparent horizon. 2) Or, by releasing Hawking radiation, a black hole can diminish, shrinking its event horizon inside of its apparent horizon. The entire concept is pretty strange, even to physicists, and seems to depend on the way that you decide to slice up space-time in your equations. In his latest paper, Hawking is saying that the apparent horizon is the only real thing, allowing scientists to ignore the event horizon and the firewall/Einstein problems arising there.

Using an apparent horizon actually solves one other problem, namely how information can escape from a black hole. Because the apparent horizon’s trap is only temporary, radiation can leave the black hole and carry information, albeit in a very scrambled and chaotic form.

So does that mean that black holes’ problems are done away with? Absolutely not! Firstly, it will take some time for the physics community to digest exactly what Hawking is suggesting. Already, some scientists are for it while others aren’t so sure. The one thing that can basically be guaranteed at this point is that physicists will eventually find some other mind-bending property of black holes that seems to contradict everything we thought before.

- - -

Adam is a Wired Science staff writer. He lives in Oakland, CA,
near a lake and enjoys space, physics, and other sciency things.

Man's Ancient Past: Neanderthal Genes Helped Modern Humans Adapt to the Cold

Image by erix! via Flickr

"Interestingly, while earlier studies have estimated that 1 to 4 percent of a modern,

non-African human’s DNA has Neanderthal origins, authors of the Science paper

found that about 20 percent of Neanderthal genes live on in modern humans.

The researchers believe additional research based on a larger sample size may

reveal that our extinct relatives contributed a much greater share to our genome

than previously thought."

Neanderthal Genes Helped Modern Humans Adapt to Cold

http://blogs.discovermagazine.com/d-brief/2014/01/29/neanderthal-genes-helped-modern-humans-adapt-to-cold/#.Uu7q5lAo7qBBy 

by Gemma Tarlach

January 29, 2014

You’ve heard that Neanderthal DNA lives on in the genes of many modern humans — now there’s evidence that it helped our early ancestors adapt to life beyond the tropics and subtropics of Africa.

As gene sequencing becomes increasingly sophisticated, scientists have been able to prove that early modern humans traveling out of Africa to Europe and Asia interbred with Neanderthals already established in those regions. As a result, most non-African humans today have at least some Neanderthal genes.

But, using new techniques to zero in on traces of Neanderthal DNA in modern humans, researchers found the genes were not distributed evenly.

No Balls About It

Neanderthal-origin genes are concentrated in areas of the modern human genome that regulate the appearance of skin and hair. This finding, researchers say, suggests the genes were beneficial to modern humans by giving them characteristics that helped them adapt to colder climates (like thicker body hair, for example).

Even more unexpected, scientists discovered certain areas of the modern human genome had no Neanderthal DNA. In particular, genes on the X chromosome and those concerning the testes had no Neanderthal origin. Researchers believe these segments of Neanderthal DNA in a male hybrid must have reduced his fertility and thus were not passed on to later generations.

Neanderthal DNA Today

To determine Neanderthal DNA distribution in the modern human genome, authors of today’s paper, published in Nature, used a method comparing known Neanderthal genetic patterns with samples from more than 1,000 modern humans to find archaic genetic material from our long-lost relatives that has survived in our species’ genome.

A separate paper, published today in Science, compared the Neanderthal genome with the genes of more than 600 modern humans and reached similar conclusions.

Interestingly, while earlier studies have estimated that 1 to 4 percent of a modern, non-African human’s DNA has Neanderthal origins, authors of the Science paper found that about 20 percent of Neanderthal genes live on in modern humans. The researchers believe additional research based on a larger sample size may reveal that our extinct relatives contributed a much greater share to our genome than previously thought.

Image by erix! via Flickr