Michael Marshall

BBC Earth: The secret of how life on Earth began

6/11/2021

(Credit: Equinox Graphics Ltd)

This story was originally published on the BBC Earth website on 31 October 2016. Sadly the BBC Earth website has been deleted, so the original version of this story is now only available via the Wayback Machine.

I have reproduced it here - with notes highlighting passages I would now write differently.

Many of the photos were licensed and are not included. However, I have included the videos and stills produced by Equinox Graphics, with the permission of the company's founder Jon Heras.

A complete living cell (Credit: Equinox Graphics Ltd)

How did life begin? There can hardly be a bigger question. For much of human history, almost everyone believed some version of "the gods did it". Any other explanation was inconceivable.

That is no longer true. Over the last century, a few scientists have tried to figure out how the first life might have sprung up. They have even tried to recreate this Genesis moment in their labs: to create brand-new life from scratch.

So far nobody has managed it, but we have come a long way. Today, many of the scientists studying the origin of life are confident that they are on the right track – and they have the experiments to back up their confidence.

This is the story of our quest to discover our ultimate origin. It is a story of obsession, struggle and brilliant creativity, which encompasses some of the greatest discoveries of modern science. The endeavour to understand life's beginnings has sent men and women to the furthest corners of our planet. Some of the scientists involved have been bedevilled as monsters, while others had to do their work under the heel of brutal totalitarian governments.

This is the story of the birth of life on Earth.

Life is old. The dinosaurs are perhaps the most famous extinct creatures, and they had their beginnings 250 million years ago. But life dates back much further.

The oldest known fossils are around 3.5 billion years old, 14 times the age of the oldest dinosaurs. But the fossil record may stretch back still further. For instance, in August 2016 researchers found what appear to be fossilised microbes dating back 3.7 billion years.

The Earth itself is not much older, having formed 4.5 billion years ago.

If we assume that life formed on Earth – which seems reasonable, given that we have not yet found it anywhere else – then it must have done so in the billion years between Earth coming into being and the preservation of the oldest known fossils.

As well as narrowing down when life began, we can make an educated guess at what it was.

Since the 19th Century, biologists have known that all living things are made of "cells": tiny bags of living matter that come in different shapes and sizes. Cells were first discovered in the 17th Century, when the first modern microscopes were invented, but it took well over a century for anyone to realise that they were the basis of all life.

You might not think you look much like a catfish or a Tyrannosaurus rex, but a microscope will reveal that you are all made of pretty similar kinds of cells. So are plants and fungi.

But by far the most numerous forms of life are microorganisms, each of which is made up of just one cell. Bacteria are the most famous group, and they are found everywhere on Earth.

In April 2016, scientists presented an updated version of the "tree of life": a kind of family tree for every living species. Almost all of the branches are bacteria. What's more, the shape of the tree suggests that a bacterium was the common ancestor of all life. In other words, every living thing – including you – is ultimately descended from a bacterium.

This means we can define the problem of the origin of life more precisely. Using only the materials and conditions found on the Earth over 3.5 billion years ago, we have to make a cell.

Well, how hard can it be?

Illustration of part of a DNA molecule (Credit: Equinox Graphics Ltd)

DNA is one of the core molecules of life (Credit: Equinox Graphics Ltd)

Chapter 1. The first experiments

For most of history, it was not really considered necessary to ask how life began, because the answer seemed obvious.

Before the 1800s, most people believed in "vitalism". This is the intuitive idea that living things were endowed with a special, magical property that made them different from inanimate objects.

Vitalism was often bound up with cherished religious beliefs. The Bible says that God used "the breath of life" to animate the first humans, and the immortal soul is a form of vitalism.

There is just one problem. Vitalism is plain wrong.

By the early 1800s, scientists had discovered several substances that seemed to be unique to life. One such chemical was urea, which is found in urine and was isolated in 1799.

This was still, just, compatible with vitalism. Only living things seemed to be able to make these chemicals, so perhaps they were infused with life energy and that was what made them special.

But in 1828, the German chemist Friedrich Wöhler found a way to make urea from a common chemical called ammonium cyanate, which had no obvious connection with living things. Others followed in his footsteps, and it was soon clear that the chemicals of life can all be made from simpler chemicals that have nothing to do with life.

This was the end of vitalism as a scientific concept. But people found it profoundly hard to let go of the idea. For many, saying that there is nothing "special" about the chemicals of life seemed to rob life of its magic, to reduce us to mere machines. It also, of course, contradicted the Bible.

[If I was to write this piece again today, I would handle this section differently. The idea that Wöhler "disproved" vitalism is sometimes known as the Wöhler myth and is historically dubious. But I didn't know that at the time. The account in The Genesis Quest is rather more nuanced.]

Even scientists have struggled to shed vitalism. As late as 1913, the English biochemist Benjamin Moore was fervently pushing a theory of "biotic energy", which was essentially vitalism under a different name. The idea had a strong emotional hold.

Today the idea clings on in unexpected places. For example, there are plenty of science-fiction stories in which a person's "life energy" can be boosted or drained away. Think of the "regeneration energy" used by the Time Lords in Doctor Who, which can even be topped up if it runs low. This feels futuristic, but it is a deeply old-fashioned idea.

Still, after 1828 scientists had legitimate reasons to look for a deity-free explanation for how the first life formed. But they did not. It seems like an obvious subject to explore, but in fact the mystery of life's origin was ignored for decades. Perhaps everyone was still too emotionally attached to vitalism to take the next step.

Instead, the big biological breakthrough of the 19th Century was the theory of evolution, as developed by Charles Darwin and others.

Darwin's theory, set out in On the Origin of Species in 1859, explained how the vast diversity of life could all have arisen from a single common ancestor. Instead of each of the different species being created individually by God, they were all descended from a primordial organism that lived millions of years ago: the last universal common ancestor.

This idea proved immensely controversial, again because it contradicted the Bible. Darwin and his ideas came under ferocious attack, particularly from outraged Christians.

The theory of evolution said nothing about how that first organism came into being.

Darwin knew that it was a profound question, but – perhaps wary of starting yet another fight with the Church – he only seems to have discussed the issue in a letter written in 1871. His excitable language reveals that he knew the deep significance of the question:

"But if (& oh what a big if) we could conceive in some warm little pond with all sorts of ammonia & phosphoric salts,—light, heat, electricity &c present, that a protein compound was chemically formed, ready to undergo still more complex changes..."

In other words, what if there was once a small body of water, filled with simple organic compounds and bathed in sunlight. Some of those compounds might combine to form a life-like substance such as a protein, which could then start evolving and becoming more complex.

It was a sketchy idea. But it would become the basis of the first hypothesis for how life began.

This idea emerged from an unexpected place. You might think that this daring piece of free thinking would have been developed in a democratic country with a tradition of free speech: perhaps the United States. But in fact the first hypothesis for the origin of life was invented in a savagely totalitarian country, where free thinking was stamped out: the USSR.

In Stalin's Russia, everything was under the control of the state. That included people's ideas, even on subjects – like biology – that seem unrelated to Communist politics.

Most famously, Stalin effectively banned scientists from studying conventional genetics. Instead he imposed the ideas of a farm worker named Trofim Lysenko, which he thought were more in line with Communist ideology. Scientists working on genetics were forced to publicly support Lysenko's ideas, or risk ending up in a labour camp.

It was in this repressive environment that Alexander Oparin carried out his research into biochemistry. He was able to keep working because he was a loyal Communist: he supported Lysenko's ideas and even received the Order of Lenin, the highest decoration that could be bestowed on someone living in the USSR.

In 1924, Oparin published his book The Origin of Life. In it he set out a vision for the birth of life that was startlingly similar to Darwin's warm little pond.

Oparin imagined what Earth was like when it was newly formed. The surface was searingly hot, as rocks from space plunged down onto it and impacted. It was a mess of semi-molten rocks, containing a huge range of chemicals – including many based on carbon.

Eventually the Earth cooled enough for water vapour to condense into liquid water, and the first rain fell. Before long Earth had oceans, which were hot and rich in carbon-based chemicals. Now two things could happen.

First, the various chemicals could react with each other to form lots of new compounds, some of which would be more complex. Oparin supposed that the molecules central to life, like sugars and amino acids, could all have formed in Earth's waters.

Second, some of the chemicals began to form microscopic structures. Many organic chemicals do not dissolve in water: for example, oil forms a layer on top of water. But when some of these chemicals contact water they form spherical globules called "coacervates", which can be up to 0.01cm (0.004 inches) across.

If you watch coacervates under a microscope, they behave unnervingly like living cells. They grow and change shape, and sometimes divide into two. They can also take in chemicals from the surrounding water, so life-like chemicals can become concentrated inside them. Oparin proposed that coacervates were the ancestors of modern cells.

Five years later in 1929, the English biologist J. B. S. Haldane independently proposed some very similar ideas in a short article published in the Rationalist Annual.

Haldane had already made enormous contributions to evolutionary theory, helping to integrate Darwin's ideas with the emerging science of genetics.

He was also a larger-than-life character. On one occasion, he suffered a perforated eardrum thanks to some experiments with decompression chambers, but later wrote that: "the drum generally heals up; and if a hole remains in it, although one is somewhat deaf, one can blow tobacco smoke out of the ear in question, which is a social accomplishment."

Just like Oparin, Haldane outlined how organic chemicals could build up in water, "[until] the primitive oceans reached the consistency of hot dilute soup". This set the stage for "the first living or half-living things" to form, and for each one to become enclosed in "an oily film".

It is telling that of all the biologists in the world, it was Oparin and Haldane who proposed this. The idea that living organisms formed by purely chemical means, without a god or even a "life force", was radical. Like Darwin's theory of evolution before it, it flew in the face of Christianity.

That suited the USSR just fine. The Soviet regime was officially atheist, and its leaders were eager to support materialistic explanations for profound phenomena like life. Haldane was also an atheist, and a devoted communist to boot.

"At that time, to accept or not accept this idea depended essentially on personalities: whether they were religious or whether they supported left or communist ideas," says origin-of-life expert Armen Mulkidjanian of the University of Osnabrück in Germany. "In the Soviet Union they were accepted happily because they didn't need God. In the western world, if you look for people who were thinking in this direction, they all were lefties, communists and so on."

The idea that life formed in a primordial soup of organic chemicals became known as the Oparin-Haldane hypothesis. It was neat and compelling, but there was one problem. There was no experimental evidence to back it up. This would not arrive for almost a quarter of a century.

By the time Harold Urey became interested in the origin of life, he had already won the 1934 Nobel Prize in Chemistry and helped to build the atomic bomb. During World War Two Urey worked on the Manhattan Project, collecting the unstable uranium-235 needed for the bomb's core. After the war he fought to keep nuclear technology in civilian control.

He also became interested in the chemistry of outer space, particularly what went on when the Solar System was first forming. One day he gave a lecture and pointed out that there was probably no oxygen in Earth's atmosphere when it first formed. This would have offered the ideal conditions for Oparin and Haldane's primordial soup to form: the fragile chemicals would have been destroyed by contact with oxygen.

A doctoral student named Stanley Miller was in the audience, and later approached Urey with a proposal: could they test this idea? Urey was sceptical, but Miller talked him into it.

So in 1952, Miller began the most famous experiment on the origin of life ever attempted.

The set-up was simple. Miller connected a series of glass flasks and circulated four chemicals that he suspected were present on the early Earth: boiling water, hydrogen gas, ammonia and methane. He subjected the gases to repeated electric shocks, to simulate the lightning strikes that would have been a common occurrence on Earth so long ago.

Miller found that "the water in the flask became noticeably pink after the first day, and by the end of the week the solution was deep red and turbid". Clearly, a mix of chemicals had formed.

When Miller analysed the mixture he found that it contained two amino acids: glycine and alanine. Amino acids are often described as the building blocks of life. They are used to form the proteins that control most biochemical processes in our bodies. Miller had made two of life's most important components, from scratch.

The results were published in the prestigious journal Science in 1953. Urey, in a selfless act unusual among senior scientists, had his name taken off the paper, giving Miller sole credit. Despite this, the study is often known as the "Miller-Urey experiment".

"The strength of Miller-Urey is to show that you can go from a simple atmosphere and produce lots of biological molecules," says John Sutherland of the Laboratory of Molecular Biology in Cambridge, UK.

The details turned out to be wrong, since later studies showed that the early Earth's atmosphere had a different mix of gases. But that is almost beside the point.

"It was massively iconic, stimulated the public's imagination and continues to be cited extensively," says Sutherland.

In the wake of Miller's experiment, other scientists began finding ways to make simple biological molecules from scratch. A solution to the mystery of the origin of life seemed close.

But then it became clear that life was more complicated than anyone had thought. Living cells, it turned out, were not just bags of chemicals: they were intricate little machines. Suddenly, making one from scratch began to look like a much bigger challenge than scientists had anticipated.

Illustration of the intricate machinery of a cell membrane (Credit: Equinox Graphics Ltd)

The machinery inside cells is unbelievably intricate (Credit: Equinox Graphics Ltd)

Chapter 2. The great polarisation

By the early 1950s, scientists had moved away from the long-standing assumption that life was a gift from the gods. They had instead begun to explore the possibility that life formed spontaneously and naturally on the early Earth – and thanks to Stanley Miller's iconic experiment, they even had some practical support for the idea.

While Miller was trying to make the stuff of life from scratch, other scientists were figuring out what genes were made of.

By this time, many biological molecules were known. These included sugars, fats, proteins – and nucleic acids such as "deoxyribonucleic acid", or DNA for short.

Today we take it for granted that DNA carries our genes, but this actually came as a shock to 1950s biologists. Proteins are more complex, so scientists thought they were the genes.

That idea was disproved in 1952 by Alfred Hershey and Martha Chase of the Carnegie Institution of Washington. They studied simple viruses that only contain DNA and protein, and which have to infect bacteria in order to reproduce. They found that it was the viral DNA that entered the bacteria: the proteins stayed outside. Clearly, DNA was the genetic material. [Oof. The Hershey-Chase experiment wasn't as definitive as this, and earlier experiments by Oswald Avery were arguably better controlled.]

Hershey and Chase's findings triggered a frantic race to figure out the structure of DNA, and thus how it worked. The following year, the problem was cracked by Francis Crick and James Watson of the University of Cambridge, UK – with a lot of under-acknowledged help from their colleague Rosalind Franklin.

Theirs was one of the greatest scientific discoveries of the 20th Century. It also reshaped the search for the origin of life, by revealing the incredible intricacy that is hidden inside living cells.

Illustration of a DNA molecule, showing the double helix structure (Credit: Equinox Graphics Ltd)

DNA is at the heart of almost every living thing (Credit: Equinox Graphics Ltd)

Crick and Watson realised that DNA is a double helix, like a ladder that has been twisted into a spiral. The two "poles" of the ladder are each built from molecules called nucleotides.

This structure explained how cells copy their DNA. In other words, it revealed how parents make copies of their genes and pass them on to their children.

The key point is that the double helix can be "unzipped". This exposes the genetic code – made up of sequences of the genetic bases A, T, C and G – that is normally locked away inside the DNA ladder’s "rungs". Each strand is then used as a template to recreate a copy of the other.

Using this mechanism, genes have been passed down from parent to child since the beginning of life. Your genes ultimately come from an ancestral bacterium – and at every step they were copied using the mechanism Crick and Watson discovered.

Crick and Watson set out their findings in a 1953 paper in Nature. Over the next few years, biochemists raced to figure out exactly what information DNA carries, and how that information is used in living cells. The innermost secrets of life were being exposed for the first time.

It turned out that DNA only has one job. Your DNA tells your cells how to make proteins: molecules that perform a host of essential tasks. Without proteins you could not digest your food, your heart would stop and you could not breathe.

But the process of using DNA to make proteins proved to be staggeringly intricate. That was a big problem for anyone trying to explain the origin of life, because it is hard to imagine how something so complex could ever have got started.

Each protein is essentially a long chain of amino acids, strung together in a specific order. The sequence of the amino acids determines the three-dimensional shape of the protein, and thus what it does.

That information is encoded in the sequence of the DNA's bases. So when a cell needs to make a particular protein, it reads the relevant gene in the DNA to get the sequence of amino acids.

But there is a twist. DNA is precious, so cells prefer to keep it bundled away safely. For this reason, they copy the information from DNA onto short molecules of another substance called RNA (ribonucleic acid). If DNA is a library book, RNA is a scrap of paper with a key passage scribbled onto it. RNA is similar to DNA, except that it only has one strand.

Finally, the process of converting the information in that RNA strand into a protein takes place in an enormously elaborate molecule called a "ribosome".

This process is going on in every living cell, even the simplest bacteria. It is as essential to life as eating and breathing. Any explanation for the origin of life must show how this complex trinity – DNA, RNA and ribosome protein – came into existence and started working.

Suddenly, Oparin and Haldane's ideas looked naively simple, while Miller's experiment, which only produced a few of the amino acids used to build proteins, looked amateurish. Far from taking us most of the way to creating life, his seminal study was clearly just the first step on a long road."DNA makes RNA makes protein, all in this lipid-encapsulated bag of chemicals," says John Sutherland. "You look at that and it's just 'wow, that's too complicated'. How are we going to find organic chemistry that will make all that in one go?"

The first person to really tackle this head-on was a British chemist named Leslie Orgel. He was one of the first to see Crick and Watson's model of DNA, and would later help Nasa with their Viking programme, which sent robotic landers to Mars.

Orgel set out to simplify the problem. Writing in 1968, and supported by Crick, he suggested that the first life did not have proteins or DNA. Instead, it was made almost entirely of RNA. For this to work, these primordial RNA molecules must have been particularly versatile. For one thing, they must have been able to build copies of themselves, presumably using the same base-pairing mechanism as DNA.

The idea that life began with RNA would prove enormously influential. But it also triggered a scientific turf war that has lasted until the present day.

By suggesting that life began with RNA and little else, Orgel was proposing that one crucial aspect of life – its ability to reproduce itself – appeared before all the others. In a sense, he was not just suggesting how life was first assembled: he was saying something about what life is.

Many biologists would agree with Orgel's "replication first" idea. In Darwin's theory of evolution, the ability to create offspring is absolutely central: the only way an organism can "win" is to leave behind lots of children.

But there are other features of life that seem equally essential. The most obvious is metabolism: the ability to extract energy from your surroundings and use it to keep yourself alive. For many biologists, metabolism must have been the original defining feature of life, with replication emerging later.

So from the 1960s onwards, scientists studying the origin of life split into camps.

"The basic polarisation was metabolism-first versus genetics-first," says Sutherland.

Meanwhile, a third group maintained that the first thing to appear was a container for the key molecules, to keep them from floating off. "Compartmentalisation must have come first, because there's no point doing metabolism unless you're compartmentalised," says Sutherland. In other words, there needed to be a cell – as Oparin and Haldane had emphasised a few decades earlier – perhaps enclosed by a membrane of simple fats and lipids.

All three ideas acquired adherents and have survived to the present day. Scientists have become passionately committed to their pet ideas, sometimes blindly so.

As a result, scientific meetings on the origin of life have often been fractious affairs, and journalists covering the subject are regularly told by a scientist in one camp that the ideas emerging from the other camps are stupid or worse.

Thanks to Orgel, the idea that life began with RNA and genetics got off to an early head start. Then came the 1980s, and a startling discovery that seemed to pretty much confirm it.

Illustration of molecules of RNA (ribonucleic acid) (Credit: Equinox Graphics Ltd)

RNA could be the key to life's beginning (Credit: Equinox Graphics Ltd)

Chapter 3. Search for the first replicator

After the 1960s, the scientists on the quest to understand life's origins split into three groups. Some were convinced that life began with the formation of primitive versions of biological cells. Others thought the key first step was a metabolic system, and yet others focused on the importance of genetics and replication. This last group began trying to figure out what that first replicator might have looked like – with a focus on the idea that it was made of RNA.

As early as the 1960s, scientists had reason to think RNA was the source of all life.
Specifically, RNA can do something that DNA cannot. It is a single-stranded molecule, so unlike stiff, double-stranded DNA it can fold itself into a range of different shapes.

RNA's origami-like folding looked rather similar to the way proteins behave. Proteins are also basically long strands – made of amino acids rather than nucleotides – and this allows them to construct elaborate structures.

This is the key to proteins' most amazing ability. Some of them can speed up, or "catalyse", chemical reactions. These proteins are known as enzymes.

Many enzymes are found in your guts, where they break up the complex molecules from your food into simple ones like sugars that your cells can use. You could not live without enzymes.

Leslie Orgel and Francis Crick had a suspicion. If RNA could fold like a protein, maybe it could form enzymes. If that were true, RNA could have been the original – and highly versatile – living molecule, storing information as DNA does now and catalysing reactions as some proteins do.

It was a neat idea, but there would be no proof for over a decade.

Thomas Cech was born and raised in Iowa. As a child he was fascinated by rocks and minerals. By the time he was in junior high school he was visiting the local university and knocking on geologists' doors, asking to see models of mineral structures.

But he eventually wound up becoming a biochemist, focusing on RNA.

In the early 1980s, Cech and his colleagues at the University of Colorado Boulder were studying a single-celled organism called Tetrahymena thermophila. Part of its cellular machinery includes strands of RNA. Cech found that one particular section of the RNA sometimes detached from the rest, as if something had cut it out with scissors.

When the team removed all the enzymes and other molecules that might be acting as molecular scissors, the RNA kept doing it. They had discovered the first RNA enzyme: a short piece of RNA that was able to cut itself out of the larger strand it was part of.

Cech published the results in 1982. The following year, another group found a second RNA enzyme – or "ribozyme", as it was dubbed.

Finding two RNA enzymes in quick succession suggested that there were plenty more out there. Now the notion that life began with RNA was looking promising.

It would be Walter Gilbert of Harvard University in Cambridge, Massachusetts who gave the idea a name. A physicist who had become fascinated by molecular biology, Gilbert would also be one of the early advocates of sequencing the human genome.

Writing in Nature in 1986, Gilbert proposed that life began in the "RNA World".

The first stage of evolution, Gilbert argued, consisted of "RNA molecules performing the catalytic activities necessary to assemble themselves from a nucleotide soup". By cutting and pasting different bits of RNA together, the RNA molecules could create ever more useful sequences. Eventually they found a way to make proteins and protein enzymes, which proved so useful that they largely supplanted the RNA versions and gave rise to life as we recognise it today.

The RNA World is an elegant way to make complex life from scratch. Instead of having to rely on the simultaneous formation of dozens of biological molecules from the primordial soup, one Jack-of-all-trades molecule could do the work of all of them.

In 2000, the RNA World hypothesis was gifted a dramatic piece of supporting evidence.

Thomas Steitz had spent 30 years studying the structures of the molecules in living cells. In the 1990s he took on his biggest challenge: figuring out the structure of the ribosome.

Every living cell has a ribosome. This huge molecule reads instructions from RNA and strings together amino acids to make proteins. The ribosomes in your cells built most of your body.

The ribosome was known to contain RNA. But in 2000 Steitz's team produced a detailed image of the ribosome's structure, which showed that the RNA was the catalytic core of the ribosome.

This was critical, because the ribosome is so fundamental to life, and so ancient. The fact that this essential machine was based on RNA made the RNA World even more plausible.

RNA World supporters were ecstatic at the discovery, and in 2009 Steitz would receive a share of a Nobel Prize. But since then, doubts have crept back in.

Right from the start, there were two problems with the RNA World idea. Could RNA really perform all the functions of life by itself? And could it have formed on the early Earth?

It is 30 years since Gilbert set out the stall for the RNA World, and we still do not have hard evidence that RNA can do all the things the theory demands of it. It is a handy little molecule, but it may not be handy enough.

One task stood out. If life began with an RNA molecule, that RNA must have been able to make copies of itself: it should have been self-replicating.

But no known RNA can self-replicate. Nor can DNA. It takes a battalion of enzymes and other molecules to build a replica copy of a piece of RNA or DNA.

So in the late 1980s, a few biologists started a rather quixotic quest. They set out to make a self-replicating RNA for themselves.

Jack Szostak of the Harvard Medical School was one of the first to get involved. As a child he was so fascinated with chemistry that he had a lab in his basement. With a splendid disregard for his own safety, he once set off an explosion that embedded a glass tube into the ceiling.

In the early 1980s, Szostak helped to show how our genes protect themselves against the ageing process. This early research would eventually net him a share of a Nobel Prize.

But he soon became fascinated by Cech's RNA enzymes. "I thought that work was just really cool," he says. "In principle, there might be a possibility for RNA to catalyse its own replication."

In 1988, Cech found an RNA enzyme that could build a short RNA molecule about 10 nucleotides long. Szostak set out to improve on the discovery by evolving new RNA enzymes in the lab. His team created a pool of random sequences and tested them to see which ones showed catalytic activity. They then took those sequences, tweaked them, and tested again.

After 10 rounds of this, Szostak had produced an RNA enzyme that made a reaction go seven million times faster than it naturally would. They had showed that RNA enzymes could be truly powerful. But their enzyme could not copy itself, not even close. Szostak had hit a wall.

The next big advance came in 2001 from Szostak's former student David Bartel, of the Massachusetts Institute of Technology in Cambridge. Bartel made an RNA enzyme called R18 that could add new nucleotides to a strand of RNA, based on an existing template. In other words, it was not just adding random nucleotides: it was correctly copying a sequence.

This was still not a self-replicator, but it was edging towards it. R18 consisted of a string of 189 nucleotides, and it could reliably add 11 nucleotides to a strand: 6% of its own length. The hope was that a few tweaks would allow it to make a strand 189 nucleotides long – as long as itself.

The best attempt came in 2011 from Philipp Holliger of the Laboratory of Molecular Biology in Cambridge, UK. His team created a modified R18 called tC19Z, which copies sequences up to 95 nucleotides long. That is 48% of its own length: more than R18, but not the necessary 100%.

An alternative approach has been put forward by Gerald Joyce and Tracey Lincoln of the Scripps Research Institute in La Jolla, California. In 2009 they created an RNA enzyme that replicates itself indirectly.

Their enzyme joins together two short pieces of RNA to create a second enzyme. This then joins together another two RNA pieces to recreate the original enzyme.

This simple cycle could be continued indefinitely, given the raw materials. But the enzymes only worked if they were given the correct RNA strands, which Joyce and Lincoln had to make.

For the many scientists who are sceptical about the RNA World, the lack of a self-replicating RNA is a fatal problem with the idea. RNA does not seem to be up to the job of kick-starting life.

The case has also been weakened by chemists' failure to make RNA from scratch. It looks like a simple molecule compared to DNA, but RNA has proved to be enormously difficult to make.

The problem is the sugar and the base that make up each nucleotide. It is possible to make each of them individually, but the two stubbornly refuse to link together.

This problem was already clear by the early 1990s. It left many biologists with a nagging suspicion that the RNA World hypothesis, while neat, could not be quite right.

Instead, maybe there was some other type of molecule on the early Earth: something simpler than RNA, which really could assemble itself out of the primordial soup and start self-replicating. This might have come first, and then led to RNA, DNA and the rest.

In 1991, Peter Nielsen of the University of Copenhagen in Denmark came up with a candidate for the primordial replicator.

It was essentially a heavily-modified version of DNA. Nielsen kept the bases the same – sticking with the A, T, C and G found in DNA – but made the backbone out of molecules called polyamides instead of the sugars found in DNA. He called the new molecule polyamide nucleic acid, or PNA. Confusingly, it has since become known as peptide nucleic acid.

PNA has never been found in nature. But it behaves a lot like DNA. A strand of PNA can even take the place of one of the strands in a DNA molecule, with the complementary bases pairing up as normal. What's more, PNA can coil up into a double helix, just like DNA.

Stanley Miller was intrigued. Deeply sceptical about the RNA World, he suspected that PNA was a more plausible candidate for the first genetic material.

In 2000 he produced some hard evidence. By then he was 70 years old, and had just suffered the first in a series of debilitating strokes that would ultimately leave him confined to a nursing home, but he was not quite done. He repeated his classic experiment, which we discussed in Chapter One, this time using methane, nitrogen, ammonia and water – and obtained the polyamide backbone of PNA.

This suggested that PNA, unlike RNA, might have formed readily on the early Earth.

Other chemists have come up with their own alternative nucleic acids.

In 2000, Albert Eschenmoser made threose nucleic acid (TNA). This is basically DNA, but with a different sugar in its backbone. Strands of TNA can pair up to form a double helix, and information can be copied back and forth between RNA and TNA.

What's more, TNA can fold up into complex shapes, and even bind to a protein. This hints that TNA could act as an enzyme, just like RNA.

Similarly, in 2005 Eric Meggers made glycol nucleic acid, which can form helical structures.

Each of these alternative nucleic acids has its supporters: usually, the person who made it. But there is no trace of them in nature, so if the first life did use them, at some point it must have utterly abandoned them in favour of RNA and DNA. This might be true, but there is no evidence.

All this meant that, by the mid-2000s, supporters of the RNA World were in a quandary.

On the one hand, RNA enzymes existed and they included one of the most important pieces of biological machinery, the ribosome. That was good.

But no self-replicating RNA had been found, and nobody could figure out how RNA formed in the primordial soup. The alternative nucleic acids might solve the latter problem, but there was no evidence they ever existed in nature. That was less good.

The obvious conclusion was that the RNA World, neat as it was, could not be the whole truth.

Meanwhile, a rival theory had been steadily gathering steam since the 1980s. Its supporters argue that life did not begin with RNA, or DNA, or any other genetic substance. Instead it began as a mechanism for harnessing energy.

Illustration of an ATPase enzyme embedded in a cell membrane (Credit: Equinox Graphics Ltd)

Life needs energy to stay alive (Credit: Equinox Graphics Ltd)

Chapter 4. Power from protons

We saw in Chapter Two how scientists divided into three schools of thought about how life began. One group was convinced that life began with a molecule of RNA, but they struggled to work out how RNA or similar molecules could have formed spontaneously on the early Earth and then made copies of themselves. Their efforts were exciting at first, but ultimately frustrating. However, even while this research was progressing, there were other origin-of-life researchers who felt sure that life began in a completely different way.

The RNA World theory relies on a simple idea: the most important thing a living organism can do is reproduce itself. Many biologists would agree with this. From bacteria to blue whales, all living things strive to have offspring.

However, many origin-of-life researchers do not believe reproduction is truly fundamental. Before an organism can reproduce, they say, it has to be self-sustaining. It must keep itself alive. After all, you cannot have kids if you die first.

We keep ourselves alive by eating food, while green plants do it by extracting energy from sunlight. You might not think that a person wolfing down a juicy steak looks much like a leafy oak tree, but when you get right down to it, both are taking in energy.

This process is called metabolism. First, you must obtain energy; say, from energy-rich chemicals like sugars. Then you must use that energy to build useful things like cells.
This process of harnessing energy is so utterly essential, many researchers believe it must have been the first thing life ever did.

What might these metabolism-only organisms have looked like? One of the most influential suggestions was put forward in the late 1980s by Günter Wächtershäuser. He was not a full-time scientist, but rather a patent lawyer with a background in chemistry.

Wächtershäuser proposed that the first organisms were "drastically different from anything we know". They were not made of cells. They did not have enzymes, DNA or RNA.

Instead, Wächtershäuser imagined a flow of hot water streaming out of a volcano. The water was rich in volcanic gases like ammonia, and held traces of minerals from the volcano's heart.

Where the water flowed over the rocks, chemical reactions began to take place. In particular, metals from the water helped simple organic compounds to fuse into larger ones.

The turning point was the creation of the first metabolic cycle. This is a process in which one chemical is converted into a series of other chemicals, until eventually the original chemical is recreated. In the process, the entire system takes in energy, which can be used to restart the cycle – and to start doing other things.

All the other things that make up modern organisms – like DNA, cells and brains – came later, built on the back of these chemical cycles.

These metabolic cycles do not sound much like life. Wächtershäuser called his inventions "precursor organisms" and wrote that they "can barely be called living".

But metabolic cycles like the ones Wächtershäuser described are at the core of every living thing. Your cells are essentially microscopic chemical processing plants, constantly turning one chemical into another. Metabolic cycles may not seem life-like, but they are fundamental to life.

Over the 1980s and 1990s, Wächtershäuser worked out his theory in considerable detail. He outlined which minerals made for the best surfaces and which chemical cycles might take place. His ideas began to attract supporters.

But it was all still theoretical. Wächtershäuser needed a real-world discovery that backed up his ideas. Fortunately, it had already been made – a decade earlier.

In 1977, a team led by Jack Corliss of Oregon State University took a submersible 1.5 miles (2.5km) down into the eastern Pacific Ocean. They were surveying the Galápagos hotspot, where tall ridges of rock rise from the sea floor. The ridges, they knew, were volcanically active.

Corliss found that the ridges were pockmarked with, essentially, hot springs. Hot, chemical-rich water was welling up from below the sea floor and pumping out through holes in the rocks.

Astonishingly, these "hydrothermal vents" were densely populated by strange animals. There were huge clams, limpets, mussels, and tubeworms. The water was also thick with bacteria. All these organisms lived on the energy from the hydrothermal vents.

The discovery of hydrothermal vents made Corliss's name. It also got him thinking. In 1981 he proposed that similar vents existed on Earth four billion years ago, and that they were the site of the origin of life. He would spend much of the rest of his career working on this idea.

Corliss proposed that hydrothermal vents could create cocktails of chemicals. Each vent, he said, was a kind of primordial soup dispenser.

As hot water flowed up through the rocks, the heat and pressure caused simple organic compounds to fuse into more complex ones like amino acids, nucleotides and sugars. Closer to the boundary with the ocean, where the water was not quite as hot, they began linking into chains – forming carbohydrates, proteins, and nucleotides like DNA. Then, as the water approached the ocean and cooled still further, these molecules assembled into simple cells.

It was neat, and caught people's attention. But Stanley Miller, whose seminal origin-of-life experiment we discussed in Chapter One, was not convinced. Writing in 1988, he argued the vents were too hot.

While extreme heat would trigger the formation of chemicals like amino acids, Miller's experiments suggested that it would also destroy them. Key compounds like sugars "would survive… for seconds at most". What's more, these simple molecules would be unlikely to link up into chains, because the surrounding water would break the chains almost immediately.

At this point the geologist Mike Russell stepped into the fray. He thought that the vent theory could be made to work after all. What's more, it seemed to him that the vents were the ideal home for Wächtershäuser's precursor organisms. This inspiration would lead him to create one of the most widely-accepted theories of the origin of life.

Russell had spent his early life variously making aspirin, scouting for valuable minerals and – in one remarkable incident in the 1960s – coordinating the response to a possible volcanic eruption, despite having no training. But his real interest was in how Earth's surface has changed over the eons. This geological perspective has shaped his ideas on the origin of life.

In the 1980s he found fossil evidence of a less extreme kind of hydrothermal vent, where the temperatures were below 150C. These milder temperatures, he argued, would allow the molecules of life to survive far longer than Miller had assumed they would.

What's more, the fossil remains of these cooler vents held something strange. A mineral called pyrite, which is made of iron and sulphur, had formed into tubes about 1mm across.

In his lab, Russell found that the pyrite could also form spherical blobs. He suggested that the first complex organic molecules formed inside these simple pyrite structures.

Around this time, Wächtershäuser had begun publishing his ideas, which relied on a stream of hot chemical-rich water flowing over a mineral. He had even proposed that pyrite was involved.

So Russell put two and two together. He suggested that hydrothermal vents in the deep sea, tepid enough for the pyrite structures to form, hosted Wächtershäuser's precursor organisms. If Russell was correct, life began at the bottom of the sea – and metabolism appeared first.

Russell set all this out in a paper published in 1993, 40 years after Miller's classic experiment. It did not get the same excited media coverage, but it was arguably more important. Russell had combined two seemingly separate ideas – Wächtershäuser's metabolic cycles and Corliss's hydrothermal vents – into something truly convincing.

Just to make it even more impressive, Russell also offered an explanation for how the first organisms obtained their energy. In other words, he figured out how their metabolism could have worked. His idea relied on the work of one of modern science's forgotten geniuses.

In the 1960s, the biochemist Peter Mitchell fell ill and was forced to resign from the University of Edinburgh. Instead, he set up a private lab in a remote manor house in Cornwall. Isolated from the scientific community, his work was partly funded by a herd of dairy cows. Many biochemists, including, initially, Leslie Orgel, whose work on RNA we discussed in Chapter Two, thought that his ideas were utterly ridiculous.

Less than two decades later, Mitchell achieved the ultimate victory: the 1978 Nobel Prize in Chemistry. He has never been a household name, but his ideas are in every biology textbook.

Mitchell spent his career figuring out what organisms do with the energy they get from food. In effect, he was asking how we all stay alive from moment to moment.

He knew that all cells store their energy in the same molecule: adenosine triphosphate (ATP). The crucial bit is a chain of three phosphates, anchored to the adenosine. Adding the third phosphate takes a lot of energy, which is then locked up in the ATP.

When a cell needs energy – say, if a muscle needs to contract – it breaks the third phosphate off an ATP. This turns it into adenosine diphosphate (ADP) and releases the stored energy.

Mitchell wanted to know how the cells made the ATP in the first place. How did they concentrate enough energy onto an ADP, so that the third phosphate would attach?

Mitchell knew that the enzyme that makes ATP sits on a membrane. So he suggested that the cell was pumping charged particles called protons across the membrane, so that there were lots of protons on one side and hardly any on the other.

The protons would then try to flow back across the membrane to balance out the number of protons on each side – but the only place they could get through was the enzyme. The stream of protons passing through gave the enzyme the energy it needed to make ATP.

Mitchell first set out this idea in 1961. He spent the next 15 years defending it from all comers, until the evidence became irrefutable. We now know that the process Mitchell identified is used by every living thing on Earth. It is happening inside your cells right now. Like DNA, it is fundamental to life as we know it.

The key point that Russell picked up on is Mitchell's proton gradient: having lots of protons on one side of a membrane, and few on the other. All cells need a proton gradient to store energy.

Modern cells create the gradients by pumping protons across a membrane, but this involves complex molecular machinery that cannot have just popped into existence. So Russell made one more logical leap: life must have formed somewhere with a natural proton gradient.

Somewhere like a hydrothermal vent. But it would have to be a specific type of vent. When Earth was young the seas were acidic, and acidic water has a lot of protons floating around inside it. To create a proton gradient, the water from the vent must have been low in protons: it must have been alkaline.

Corliss's vents would not do. Not only were they too hot, they were acidic. But in 2000, Deborah Kelley of the University of Washington discovered the first alkaline vents.

Kelley had to battle just to become a scientist in the first place. Her father died as she was finishing high school, and she was forced to work long hours to support herself through college.

But she succeeded, and became fascinated both by undersea volcanoes and the searing hot hydrothermal vents. Those twin loves eventually led her to the middle of the Atlantic Ocean. There, Earth's crust is being pulled apart and a ridge of mountains rises from the sea floor.

On this ridge, Kelley found a field of hydrothermal vents that she called "Lost City". They are not like the ones Corliss found. The water flowing from them is only 40-75C, and mildly alkaline. Carbonate minerals from this water have clumped into steep, white "chimneys" that rise from the sea bed like organ pipes. Their appearance is eerie and ghost-like, but this is misleading: they are home to dense communities of microorganisms that thrive on the vent water.

These alkaline vents were the perfect fit for Russell's ideas. He became convinced that vents like those of Lost City were where life began.

But he had a problem. Being a geologist, he did not know enough about biological cells to make his theory truly convincing.

So Russell teamed up with biologist William Martin, a pugnacious American who has spent most of his career in Germany. In 2003 the pair set out an improved version of Russell's earlier ideas. It is arguably the most fleshed-out story of how life began.

Thanks to Kelley, they now knew that the rocks of alkaline vents were porous: they were pocked with tiny holes filled with water. These little pockets, they suggested, acted as "cells". Each pocket contained essential chemicals, including minerals like pyrite. Combined with the natural proton gradient from the vent, they were the ideal place for metabolism to begin.

Once life had harnessed the chemical energy of the vent water, Russell and Martin say, it started making molecules like RNA. Eventually it created its own membrane and became a true cell, and escaped from the porous rock into the open water.

This story is now regarded as one of the leading hypotheses for the origin of life.

It found powerful support in July 2016, when Martin published a study reconstructing some of the features of the "last universal common ancestor" (LUCA). This is the organism that lived billions of years ago and from which all existing life is descended.

We will probably never find direct fossil evidence of LUCA, but we can still make an educated guess as to how it might have looked and behaved by looking at microorganisms that do survive today. This is what Martin did.

He examined the DNA of 1,930 modern microorganisms, and identified 355 genes that almost all of them had. This is arguably evidence that these 355 genes have been passed down, from generation to generation, ever since those 1,930 microbes shared a common ancestor – roughly at the time that LUCA was alive.

The 355 genes included some for harnessing a proton gradient, but not genes for generating one – exactly as Russell and Martin's theories would predict. What's more, LUCA seems to have been adapted to the presence of chemicals like methane, which suggests it inhabited a volcanically-active environment – like a vent.

Despite this, RNA World supporters say the vent theory has two problems. One could potentially be fixed: the other might be fatal.

The first problem is that there is no experimental evidence for the processes Russell and Martin describe. They have a step-by-step story, but none of the steps have been seen in a lab.

"The people who think replication was first, they continuously provide new experimental data," says origin-of-life expert Armen Mulkidjanian. "The people who favour metabolism-first do not."

That could change, thanks to Martin's colleague Nick Lane of University College London. He has built an "origin of life reactor", which will simulate the conditions inside an alkaline vent. He hopes to observe metabolic cycles, and perhaps even molecules like RNA. But it is early days.

The second problem is the vents' location in the deep sea. As Miller pointed out in 1988, long-chain molecules like RNA and proteins cannot form in water without enzymes to help them.

For many researchers, this is a knock-down argument. "If you have a background in chemistry, you cannot buy the idea of deep-sea vents, because you know the chemistry of all these molecules is incompatible with water," says Mulkidjanian.

Regardless, Russell and his allies remain bullish.

But in the last decade, a third approach has come to the fore, bolstered by a series of extraordinary experiments. This promises something that neither the RNA World nor the hydrothermal vents have so far managed: a way to make an entire cell from scratch.

Illustration of a protocell (Credit: Equinox Graphics Ltd)

Arguably there can be no life without cells (Credit: Equinox Graphics Ltd)

Chapter 5. How to make a cell

By the early 2000s, there were two leading ideas about how life could have begun. Supporters of the "RNA World" were convinced that life began with a self-replicating molecule. Meanwhile, scientists in the "metabolism-first" camp had developed a detailed narrative about how life could have begun in hydrothermal vents in the deep sea. However, a third idea was about to come to the fore.

Every living thing on Earth is made of cells. Each cell is basically a squishy ball, with a tough outer wall or "membrane".

The point of a cell is to keep all the essentials of life together. If the outer wall gets torn open, the guts spill out and the cell dies – just as a person who has been disembowelled generally does not have long to live.

The outer wall of the cell is so essential, some origin-of-life researchers argue that it must have been the first thing that emerged. They think that the "genetics first" efforts discussed in Chapter Three and the "metabolism first" ideas discussed in Chapter Four are misguided. Their alternative – "compartmentalisation-first" – has its champion in Pier Luigi Luisi of Roma Tre University in Rome, Italy.

Luisi's reasoning is simple and hard to argue with. How could you possibly set up a working metabolism or a self-replicating RNA, each of which relies on having a lot of chemicals in one place, unless you first have a container to keep all the molecules in?

If you accept this, there is only one way life could have begun. Somehow, in the heat and tempest of the early Earth, a few raw materials must have assembled into crude cells, or "protocells". The challenge is to make this happen in a lab: to create a simple living cell.

Luisi can trace his ideas all the way back to Alexander Oparin and the dawn of origin-of-life science in the USSR – discussed in Chapter One. Oparin highlighted the fact that certain chemicals form into blobs called coacervates, which can hold other substances in their cores. He suggested that these coacervates were the first protocells.

Any fatty or oily substance will form blobs or films in water. These chemicals are collectively known as lipids, and the idea that they formed the first life has been called the "Lipid World".

But just forming blobs is not enough. The blobs need to be stable, they need to be able to divide to form "daughter" blobs, and they need at least some control over what travels in and out of them – all without the elaborate proteins that modern cells use to achieve these things.

The challenge was to make the protocells out of just the right stuff. Despite trying many substances over the decades, Luisi has never made anything lifelike enough to be convincing.

Then in 1994, Luisi made a daring suggestion. He proposed that the first protocells must have contained RNA. What's more, this RNA must have been able to replicate inside the protocell.

It was a big ask, and it meant abandoning the pure compartmentalisation-first approach. But Luisi had good reasons.

A cell with an outer wall, but no genes inside it, could not do anything much. It might be able to divide into daughter cells, but it could not pass on any information about itself to its offspring. It could only start evolving and becoming more complex if it contained some genes.

This idea would soon gain a crucial supporter in Jack Szostak, whose work on the RNA World hypothesis we explored in Chapter Three. While Luisi was a member of the compartmentalisation-first camp, Szostak supported genetics-first, so for many years they had not seen eye-to-eye.

"We would meet at origins meetings and get into these long arguments about which was more important and which came first," recalls Szostak. "Eventually, we realised that cells have both. We came to a consensus that for the origin of life, it was critical to have both compartmentalisation and a genetic system."

In 2001, Szostak and Luisi set out their case for this more unified approach. Writing in Nature, they argued that it should be possible to make simple living cells from scratch, by hosting replicating RNAs in a simple, fatty blob.

It was a dramatic idea, and Szostak soon decided to put his money where his mouth was. Reasoning that "we can't put out that theory without anything backing it up", he decided to start experimenting with protocells.

Two years later, Szostak and two colleagues announced a major success.
They had been experimenting with vesicles: spherical blobs, with two layers of fatty acids on the outside and a central core of liquid.

Trying to find a way to speed up the creation of the vesicles, they added small particles of a kind of clay called montmorillonite.

This made the vesicles form 100 times faster. The surface of the clay acted as a catalyst, just like an enzyme would.

What's more, the vesicles could absorb both montmorillonite particles and RNA strands from the clay surface. These protocells now contained genes and a catalyst, all from one simple setup.

The decision to add montmorillonite was not done on a whim. Several decades of work had suggested that montmorillonite, and clays like it, could be important in the origin of life.

Montmorillonite is a common clay. Nowadays it is used for all sorts of things, including making cat litter. It forms when volcanic ash is broken down by the weather. Since the early Earth had lots of volcanoes, it seems likely that montmorillonite was abundant.

Back in 1986, chemist James Ferris had shown that montmorillonite is a catalyst that helps organic molecules form. He later found that it also accelerates the formation of small RNAs.

This had led Ferris to speculate that this ordinary-looking clay was the site of the origin of life. Szostak took that idea and ran with it, using montmorillonite to help build his protocells.

One year later, Szostak's team found that their protocells could grow of their own accord.

As ever more RNA molecules were packed into a protocell, the outer wall came under increasing tension. It was as if the protocell had a full stomach and might go pop.

To compensate, the protocell picked up more fatty acids and incorporated them into its wall, allowing it to swell to a larger size and releasing the tension.

Crucially, it took the fatty acids from other protocells that contained less RNA, causing them to shrink. This meant the protocells were competing, and the ones with more RNA were winning.

This suggested something even more impressive. If the protocells could grow, maybe they could also divide. Could Szostak's protocells reproduce themselves?

Szostak's first experiments had shown a way to make protocells divide. Squeezing them through small holes stretched them out into tubes, which then broke into "daughter" protocells.

This was neat, because no cellular machinery was involved: just the application of pressure. But it was not a great solution, because the protocells lost some of their contents in the process. It also implied that the first cells could only divide if they were pushed through tiny holes.

There are lots of ways to make vesicles divide: for example, adding a strong water current that creates a shearing force. The trick was to make the protocells divide without spilling their guts.

In 2009, Szostak and his student Ting Zhu found a solution. They made slightly more complex protocells, with several concentric outer walls a bit like the layers of an onion. Despite their intricacy, these protocells were still easy to make.

As Zhu fed them with ever more fatty acids, the protocells grew and changed shape, elongating into long, rope-like strands. Once a protocell was long enough, a gentle shearing force was enough to make it shatter into dozens of small daughter protocells.

Each daughter protocell contained RNAs from the parent protocell, and hardly any of the RNA was lost. What's more, the protocells could perform the cycle repeatedly, with daughter protocells growing and then dividing themselves.

In later experiments, Zhu and Szostak have found even more ways to persuade the protocells to divide. This aspect of the problem, at least, seems to be solved.

However, the protocells were still not doing enough. Luisi had wanted the protocells to host replicating RNA, but so far the RNA was simply sitting in them doing nothing.

To really show that his protocells could have been the first life on Earth, Szostak needed to persuade the RNA inside them to replicate itself.

That was not going to be easy, because despite decades of trying – outlined in Chapter Three – nobody had managed to make an RNA that could self-replicate. That was the very problem that had stymied Szostak in his early work on the RNA World, and which nobody else had managed to solve.

So he went back and re-read the work of Leslie Orgel, who had spent so long working on the RNA World hypothesis. There were valuable clues buried in those dusty papers.

Orgel had spent much of the 1970s and 1980s studying how RNA strands get copied.

In essence it is simple. Take a single strand of RNA and a pool of loose nucleotides. Then, use those nucleotides to assemble a second strand of RNA that is complementary to the first one.

For example, a strand of RNA that reads "CGC" will produce a complementary strand that reads "GCG". If you do this twice, you will get a copy of the original "CGC", just in a roundabout way.

Orgel found that, under certain circumstances, RNA strands could copy in this way without any help from enzymes. This could have been how the first life made copies of its genes.

By 1987, Orgel could take an RNA strand 14 nucleotides long and create complementary strands that were also 14 nucleotides long. He did not manage anything longer, but that was enough to intrigue Szostak. His student Katarzyna Adamala tried to get this reaction going in the protocells.

They found that the reaction needed magnesium to work, which was a problem because the magnesium destroyed the protocells. But there was a simple solution: citrate, which is almost identical to the citric acid in lemons and oranges, and which is found in all living cells anyway.

In a study published in 2013, they added citrate and found that it latched onto the magnesium, protecting the protocells while allowing the template copying to continue.
In other words, they had achieved what Luisi had proposed in 1994. "We started to do RNA replication chemistry inside these fatty acid vesicles," says Szostak.

In just over a decade of research, Szostak's team has accomplished something remarkable.

They have built protocells that hold onto their genes while taking in useful molecules from outside. The protocells can grow and divide, and even compete with each other. RNA can replicate inside them. By any measure, they are startlingly life-like.

They are also resilient. In 2008, Szostak's team found that the protocells could survive being heated to 100C, a temperature that would obliterate most modern cells. This boosted the case that the protocells were similar to the first life, which must have endured scalding heat from constant meteor impacts.

"Szostak is doing great work," says Armen Mulkidjanian.

Yet on the face of it, Szostak's approach went against 40 years of work on the origin of life. Instead of focusing on "replication-first" or "compartmentalisation-first", he found ways to get both to happen pretty much simultaneously.

That would inspire a new unified approach to the origin of life, which attempts to jumpstart all the functions of life at once. This "everything-first" idea has already accumulated a wealth of evidence, and could potentially solve all the problems with the existing ideas.

Illustration of a ribosome making a protein using messenger RNA as a template (Credit: Equinox Graphics Ltd)

The molecules of life behave in incredibly complex ways (Credit: Equinox Graphics Ltd)

Chapter 6. The great unification

Throughout the second half of the 20th Century, origin-of-life researchers have worked in tribes. Each group favoured their own narrative and, for the most part, rubbished competing hypotheses. This approach has certainly been successful, as evidenced by the previous chapters, but every promising idea for the origin of life has ultimately come up against a major problem. So a few researchers are now trying a more unified approach.

This idea got its first big boost a few years ago from a result that, on the face of it, seemed to support the traditional, replication-first RNA World.

By 2009, supporters of the RNA World had a big problem. They could not make nucleotides, the building blocks of RNA, in a way that could plausibly have happened on the early Earth. This, as we learned in Chapter Three, led people to suspect that the first life was not based on RNA at all.

John Sutherland had been thinking about this problem since the 1980s. "I thought, if you could demonstrate that RNA could self-assemble that would be a cool thing to do," he says.

Fortunately for Sutherland, he had secured a job at the Laboratory of Molecular Biology (LMB) in Cambridge, UK. Most research institutions force their staff to constantly churn out new findings, but the LMB does not. So Sutherland could think about why it was so hard to make an RNA nucleotide, and to spend years developing an alternative approach.

His solution would lead him to propose a radical new idea about the origin of life, namely that all the key components of life could be formed at once.

"There were certain key aspects of RNA chemistry that didn't work," says Sutherland. Each RNA nucleotide is made of a sugar, a base and a phosphate. But it had proved impossible to persuade the sugar and base to join up. The molecules were simply the wrong shape.

So Sutherland started trying totally different substances. Eventually his team homed in on five simple molecules, including a different sugar and cyanamide, which as the name suggests is related to cyanide. The team put these chemicals through a series of reactions that ultimately produced two of the four RNA nucleotides, without ever making standalone sugars or bases.

It was a slam-dunk success, and it made Sutherland's name.

Many observers interpreted the findings as further evidence for the RNA World. But Sutherland himself does not see it like that at all.

The "classic" RNA World hypothesis says that, in the first organisms, RNA was responsible for all the functions of life. But Sutherland says that is "hopelessly optimistic". He believes RNA was heavily involved, but it was not the be-all-and-end-all.

Instead, he takes inspiration from the recent work of Jack Szostak, which – as discussed in Chapter Five – combines the "replication-first" RNA World with Pier Luigi Luisi's "compartmentalisation-first" ideas.

But Sutherland goes further. His approach is "everything-first". He aims to make an entire cell assemble itself, from scratch.

His first clue was an odd detail about his nucleotide synthesis, which at first seemed incidental.

The last step in Sutherland's process was to bolt a phosphate onto the nucleotide. But he found that it was best to include the phosphate in the mix right from the start, because it accelerated the earlier reactions.

On the face of it, including the phosphate before it was strictly needed was a messy thing to do, but Sutherland found that this messiness was a good thing.

This led him to think about how messy his mixtures should be. On the early Earth, there must have been dozens or hundreds of chemicals all floating around together. That sounds like a recipe for a sludge, but maybe there was an optimum level of mess.

The mixtures Stanley Miller made back in the 1950s, which we looked at in Chapter One, were far messier than Sutherland's. They did contain biological molecules, but Sutherland says they "were in trace amounts and they were accompanied by a vast number of other compounds, which are not biological".

For Sutherland, this meant that Miller's setup was not good enough. It was too messy, so the good chemicals got lost in the mixture.

So Sutherland has set out to find a "Goldilocks chemistry": one that is not so messy that it becomes useless, but also not so simple that it is limited in what it can do. Get the mixture just complicated enough and all the components of life might form at once, then come together.

In other words, four billion years ago there was a pond on the Earth. It sat there for years until the mix of chemicals was just right. Then, perhaps within minutes, the first cell came into existence.

This may sound implausible, like the claims of medieval alchemists. But Sutherland's evidence is mounting. Since 2009, he has shown that the same chemistry that made his two RNA nucleotides can also make many of the other molecules of life.

The obvious next step was to make more RNA nucleotides. He has not yet managed this, but in 2010 he made closely-related molecules that could potentially transform into the nucleotides.

Similarly, in 2013 he made the precursors of amino acids. This time he needed to add copper cyanide to make the reactions go.

Cyanide-related chemicals were proving to be a common theme, and in 2015 Sutherland took them even further. He showed that the same pot of chemicals could also produce the precursors of lipids, the molecules that make up cell walls. The reactions were all driven by ultraviolet light, involved sulphur, and relied on copper to speed them up.

"All the building blocks [emerge] from a common core of chemical reactions," says Szostak.

If Sutherland is right, then our entire approach to the origin of life for the last 40 years has been wrong. Ever since the sheer complexity of the cell became clear, scientists have been working on the assumption that the first cells must have been constructed gradually, one piece at a time.

Following Leslie Orgel's proposal that RNA came first, researchers have been "trying to get one thing before another thing, and then have that invent the other", says Sutherland. But he thinks the best way is to make everything at once.

"What we've done is to challenge the idea that it's too complicated to make everything in one go," says Sutherland. "You certainly could make the building blocks for all the systems at once."

Szostak now suspects that most attempts to make the molecules of life, and to assemble them into living cells, have failed for the same reason: the experiments were too clean.

The scientists used the handful of chemicals they were interested in, and left out all the other ones that were probably present on the early Earth. But Sutherland's work shows that, by adding a few more chemicals to the mix, more complex phenomena can be created.

Szostak experienced this for himself in 2005, when he was trying to get his protocells to host an RNA enzyme. The enzyme needed magnesium, which destroyed the protocells' membranes.

The solution was a surprising one. Instead of making the vesicles out of one pure fatty acid, they made them from a mixture of two. These new, impure vesicles could cope with the magnesium – and that meant they could play host to working RNA enzymes.
What's more, Szostak says the first genes might also have embraced messiness.

Modern organisms use pure DNA to carry their genes, but pure DNA probably did not exist at first. There would have been a mixture of RNA nucleotides and DNA nucleotides.

In 2012 Szostak showed that such a mixture could assemble into "mosaic" molecules that looked and behaved pretty much like pure RNA. These jumbled RNA/DNA chains could even fold up neatly.

This suggested that it did not matter if the first organisms could not make pure RNA, or pure DNA. "I've really come back to the idea that the first polymer was something pretty close to RNA, a messier version of RNA," says Szostak.

There might even be room for the alternatives to RNA that have been cooked up in labs, like the TNA and PNA we met in Chapter Three. We do not know if any of them ever existed on Earth, but if they did the first organisms may well have used them alongside RNA.

This was not an RNA World: it was a "Hodge-Podge World".

The lesson from these studies is that making the first cell might not have been as hard as it once seemed. Yes, cells are intricate machines. But it turns out that they still work, albeit not quite as well, when they are flung together slapdash from whatever is to hand.

Such clumsy cells might seem unlikely to survive on the early Earth. But they would not have had much competition, and there were no threatening predators, so in many respects life may have been easier then than it is now.

There is one problem that neither Sutherland nor Szostak have found a solution for, and it is a big one. The first organism must have had some form of metabolism. Right from the start, life had to obtain energy or it would have died.

On that point, if on nothing else, Sutherland agrees with Mike Russell, Bill Martin and the other supporters of Chapter Four's metabolism-first theories. "While the RNA guys were fighting with the metabolism guys, both sides had a point," says Sutherland.

"The origins of metabolism have to be in there somehow," says Szostak. "The source of chemical energy is going to be the big question."

Even if Martin and Russell are wrong about life beginning in deep-sea vents, many elements of their theory are almost certainly correct. One is the importance of metals for the birth of life.

In nature, many enzymes have a metal atom at their core. This is often the "active" part of the enzyme, with the rest of the molecule essentially a support structure. The first life cannot have had these complex enzymes, so instead it probably used "naked" metals as catalysts.

Günter Wächtershäuser made this point when he suggested that life formed on iron pyrite. Similarly, Russell emphasises that the waters of hydrothermal vents are rich in metals, which could act as catalysts – and Martin's study of LUCA found a lot of iron-based enzymes.

In light of this, it is telling that many of Sutherland's chemical reactions rely on copper (and, incidentally, on the sulphur that Wächtershäuser also emphasised), and that the RNA in Szostak's protocells needs magnesium.

It may yet be that hydrothermal vents will turn out to be crucial. "If you look at modern metabolism, there's all these really suggestive things like iron-sulphur clusters," says Szostak. That fits the idea that life began in or around a vent, where the water is rich in iron and sulphur.

That said, if Sutherland and Szostak are on the right track, one aspect of the vent theory is definitely wrong: life cannot have begun in the deep sea.

"The chemistry we've uncovered is so dependent on UV [ultraviolet light]," says Sutherland. The only source of ultraviolet radiation is the Sun, so his reactions can only take place in sunny places. "It rules out a deep-sea vent scenario."

Szostak agrees that the deep sea was not life's nursery. "The worst thing is that it's isolated from atmospheric chemistry, which is the source of high-energy starting materials like cyanide."

But these problems do not rule out hydrothermal vents altogether. Perhaps the vents were simply in shallow water, where sunlight and cyanide could reach them.

Armen Mulkidjanian has suggested an alternative. Maybe life began on land, in a volcanic pond.

Mulkidjanian looked at the chemical makeup of cells: specifically, which chemicals they allow in and which they keep out. It turns out that all cells, regardless of what organism they belong to, contain a lot of phosphate, potassium and other metals – but hardly any sodium.

Nowadays, cells achieve this by pumping things in and out, but the first cells cannot have done so because they would not have had the necessary machinery. So Mulkidjanian suggested that the first cells formed somewhere that had roughly the same mix of chemicals as modern cells.

That immediately eliminates the ocean. Cells contain far higher levels of potassium and phosphate than the ocean ever has, and far less sodium.

Instead, it points to the geothermal ponds found near active volcanoes. These ponds have exactly the cocktail of metals found in cells.

Szostak is a fan. "I think my favourite scenario at the moment would be some kind of shallow lakes or ponds on the surface, in a geothermally-active area," he says. "You have hydrothermal vents but not like the deep-sea vents, more like the kind of vents we have in volcanic areas like Yellowstone."

Sutherland's chemistry might well work in such a place. The springs have the right chemicals, the water level fluctuates so some places will dry out at times, and there is plenty of ultraviolet radiation from the Sun.

What's more, Szostak says the ponds would be suitable for his protocells.

"The protocells could be relatively cool most of the time, which is good for RNA copying and other kinds of simple metabolism," says Szostak. "But every now and then they get heated up briefly, and that helps the strands of RNA come apart ready for the next round of replication." There would also be currents, driven by the streams of hot water, which could help the protocells divide.

Drawing on many of the same lines of argument, Sutherland has put forward a third option: a meteorite impact zone.

Earth was pounded by meteorites throughout its first half-billion years of existence – and has been occasionally struck ever since. A decent-sized impact would create a setup rather similar to Mulkidjanian's ponds.

First, meteorites are mostly made of metal. The impact zones tend to be rich in useful metals like iron, as well as sulphur. And crucially, meteorite impacts melt the Earth's crust, leading to geothermal activity and hot water.

Sutherland imagines small rivers and streams trickling down the slopes of an impact crater, leaching cyanide-based chemicals from the rocks while ultraviolet radiation pours down from above. Each stream would have a slightly different mix of chemicals, so different reactions would happen and a whole host of organic chemicals would be produced.

Finally the streams would flow into a volcanic pond at the bottom of the crater. It could have been in a pond like this that all the pieces came together and the first protocells formed.

"That's a very specific scenario," says Sutherland. But he chose it on the basis of the chemical reactions he has found. "It's the only one we can think of that's compatible with the chemistry."

Szostak is not sure either way, but he agrees that Sutherland's idea deserves careful attention. "I think the impact scenario is nice. I think the idea of volcanic systems might also work. There's some arguments in favour of each."

For now that debate looks set to rumble on. But it will not be decided on a whim. The decision will be driven by the chemistry and the protocells. If it turns out that one of the scenarios is missing a key chemical, or contains something that destroys protocells, it will be ruled out.

This means that, for the first time in history, we have the beginnings of a comprehensive explanation for how life began.

"Things are looking a lot more achievable," says Sutherland.

So far, the "everything-at-once" approach of Szostak and Sutherland offers only a sketchy narrative. But those steps that have been worked out are supported by decades of experiments.

The idea also draws on every approach to the origin of life. It attempts to harness all their good points, while at the same time solving all their problems. For instance, it does not so much try to disprove Russell's ideas about hydrothermal vents, but rather to incorporate their best elements.

We cannot know for sure what happened four billion years ago. "Even if you made a reactor and out pops E. coli on the other side… you still can't prove that we arose that way," says Martin.

The best we can ever do is to draw up a story that is consistent with all the evidence: with experiments in chemistry, with what we know about the early Earth, and with what biology reveals about the oldest forms of life. Finally, after a century of fractious effort, that story is coming into view.

That means we are approaching one of the great divides in human history: the divide between those who know the story of life's beginning, and those who never could.

Every single person who died before Darwin published Origin of Species in 1859 was ignorant of humanity's origins, because they knew nothing of evolution. But everyone alive now, barring isolated groups, can know the truth about our kinship with other animals.

Similarly, everyone born after Yuri Gagarin orbited the Earth in 1961 has lived in a society that can travel to other worlds. Even if we never go ourselves, space travel is a reality.

These facts change our worldview in subtle ways. Arguably, they make us wiser. Evolution teaches us to treasure every other living thing, for they are our cousins. Space travel allows us to see our world from a distance, revealing how unique and fragile it is.
Some of the people alive today will become the first in history who can honestly say they know where they came from. They will know what their ultimate ancestor was like and where it lived.

This knowledge will change us. On a purely scientific level, it will tell us about how likely life is to form in the Universe, and where to look for it. And it will tell us something about life's essential nature. But beyond that, we cannot yet know the wisdom the origin of life will reveal.

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