PLANET OBSERVER/UNIVERSAL IMAGES GROUP/GETTY

FeatureLife might have begun in bodies of water on land, perhaps in craters similar to Canada’s Lake Manicouagan, formed by an ancient impact.

THE WATER PARADOXAND THE ORIGINS OF LIFE

Water is essential for life, but it breaks down DNA and other key molecules. So how did the firstcells deal with such a necessary and dangerous substance? By Michael MarshallOn 18 February next year, a NASA
spacecraft will plummet throughthe Martian atmosphere, fire its
retro-rockets to break its fall andthen lower a six-wheeled rover
named Perseverance to the surface. If all goes according to plan,
the mission will land in Jezero Crater, a 45-kilometre-wide gash near the planet’s
equator that might once have held a lake ofliquid water.
Among the throngs of earthlings cheering

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on Perseverance, John Sutherland will be paying particularly close attention. Sutherland, abiochemist at the MRC Laboratory of Molecular Biology in Cambridge, UK, was one of thescientists who lobbied NASA to visit Jezero
Crater, because it fits his ideas about where life
might have originated — on Mars and on Earth.
The choice of landing site reflects a shift inthinking about the chemical steps that transformed a few molecules into the first biological cells. Although many scientists have longspeculated that those pioneering cells arosein the ocean, recent research suggests that the
key molecules of life, and its core processes,
can form only in places such as Jezero — a relatively shallow body of water fed by streams.
That’s because several studies suggestthat the basic chemicals of life require ultraviolet radiation from sunlight to form, andthat the watery environment had to become
highly concentrated or even dry out completely at times. In laboratory experiments,
Sutherland and other scientists have produced
DNA, proteins and other core components ofcells by gently heating simple carbon-based
chemicals, subjecting them to UV radiationand intermittently drying them out. Chemists have not yet been able to synthesize sucha wide range of biological molecules in conditions that mimic seawater.
The emerging evidence has caused many
researchers to abandon the idea that life
emerged in the oceans and instead focus onland environments, in places that were alternately wet and dry. The shift is hardly unanimous, but scientists who support the idea ofa terrestrial beginning say it offers a solution
to a long-recognized paradox: that althoughwater is essential for life, it is also destructive
to life’s core components.
Surface lakes and puddles are highly promising, says David Catling, a planetary scientist
at the University of Washington in Seattle.
“There’s a lot of work that’s been done in thelast 15 years which would support that direction.”

Primordial soup
Although there is no standardized definitionof life, most researchers agree that it needs
several components. One is information-carrying molecules — DNA, RNA or somethingelse. There must have been a way to copy
these molecular instructions, although theprocess would have been imperfect to allow
for mistakes, the seeds of evolutionary change.
Furthermore, the first organisms must have
had a way to feed and maintain themselves,
perhaps using protein-based enzymes.
Finally, something held these disparate parts
together, keeping them separate from theirenvironment.
When laboratory research into life’s origins
started in earnest in the 1950s, many researchers assumed that life began in the sea, with arich mix of carbon-based chemicals dubbed
the primordial soup.
This idea was independently proposed in
the 1920s by biochemist Alexander Oparin, in
what was then the Soviet Union, and geneticist
J. B. S. Haldane in the United Kingdom. Eachimagined the young Earth as a huge chemical factory, with multitudes of carbon-based
chemicals dissolved in the waters of the earlyoceans. Oparin reasoned that increasingly
complicated particles were formed, culminating in carbohydrates and proteins: what
he called “the foundation of life”.
In 1953, a young researcher named Stanley
Miller at the University of Chicago in Illinois
described a now-famous experiment that wasseen as confirming these ideas1. He used a glass
flask holding water to mimic the ocean, andanother flask containing methane, ammonia
and hydrogen to simulate the early atmosphere. Tubes connected the flasks, and anelectrode simulated lightning. A few days ofheating and electric shocks were enough tomake glycine, the simplest amino acid andan essential component of proteins. Thissuggested to many researchers that life arosenear the surface of the ocean.
But many scientists today say there’s a fundamental problem with that idea: life’s cornerstone molecules break down in water. This isbecause proteins, and nucleic acids such as
DNA and RNA, are vulnerable at their joints.
Proteins are made of chains of amino acids,
and nucleic acids are chains of nucleotides.
If the chains are placed in water, it attacks thelinks and eventually breaks them. In carbon
chemistry, “water is an enemy to be excluded
as rigorously as possible”, wrote the late biochemist Robert Shapiro in his totemic 1986
book Origins, which critiqued the primordial
ocean hypothesis2.
This is the water paradox. Today, cells solve
it by limiting the free movement of water intheir interiors, says synthetic biologist Kate
Adamala at the University of Minnesota in
Minneapolis. For this reason, popular imagesof the cytoplasm — the substance inside thecell — are often wrong. “We are taught thatcytoplasm is just a bag that holds everything,and everything is swimming around,” sheadds. “That’s not true, everything is incredibly scaffolded in cells, and it’s scaffolded in“Wet–dry cycles are
everywhere. It’s as simple as
rainwater evaporating on
wet rocks.”a gel, not a water bag.”
If living things keep water controlled, thenthe implication, say many researchers, is obvious. Life probably formed on land, where water
was only intermittently present.

Land start
Some of the key evidence in favour of this idea
emerged in 2009, when Sutherland announced
that he and his team had successfully made twoof the four nucleotides that comprise RNA3.
They started with phosphate and four simple
carbon-based chemicals, including a cyanide
salt called cyanamide. The chemicals weredissolved in water throughout, but they werehighly concentrated, and crucial steps required
UV radiation. Such reactions could not takeplace deep in an ocean — only in a small pool orstream exposed to sunlight, where chemicals
could be concentrated, he says.
Sutherland’s team has since shown that thesame starter chemicals, if they are treated subtly differently, can also produce precursors toproteins and lipids4. The researchers suggestthat these reactions might have taken place ifwater containing cyanide salts was dried out by
the Sun, leaving a layer of dry, cyanide-related
chemicals that was then heated by, say, geothermal activity. In the past year, his teamhas produced the building blocks of DNA— something previously thought implausible — using energy from sunlight and some ofthe same chemicals at high concentrations5.
This approach has been extended bybiochemist Moran Frenkel-Pinter at the
NSF–NASA Center for Chemical Evolution in
Atlanta, Georgia, and her colleagues. Last year,
they showed that amino acids spontaneously
linked up to form protein-like chains if they
were dried out6. And those kinds of reaction
were more likely to occur with the 20 aminoacids found in proteins today, compared withother amino acids. That means intermittent
drying could help to explain why life uses only
those amino acids, out of hundreds of possibilities. “We saw selection for today’s aminoacids,” says Frenkel-Pinter.

Wet and dryIntermittent drying out can also help to drivethese molecular building blocks to assemble
into more-complex, life-like structures.
A classic experiment along these lines
was published in 1982 by researchers David
Deamer and Gail Barchfeld, then at the University of California, Davis7. Their aim was to study
how lipids, another class of long-chain molecule, self-organize to form the membranes
that surround cells. They first made vesicles:
spherical blobs with a watery core surroundedby two lipid layers. Then the researchers dried
the vesicles, and the lipids reorganized intoa multi-layered structure like a stack of pancakes. Strands of DNA, previously floating in
the water, became trapped between the layers.
When the researchers added water again, thevesicles reformed — with DNA inside them.
This was a step towards a simple cell.
“These wet–dry cycles are everywhere,” says
Deamer, who is now at the University of California, Santa Cruz. “It’s as simple as rainwater
evaporating on wet rocks.” But when they areapplied to biological chemicals such as lipids,
he says, remarkable things happen.
In a 2008 study, Deamer and his team mixed
nucleotides and lipids with water, then put
them through wet–dry cycles. When the lipids
formed layers, the nucleotides linked up into
RNA-like chains — a reaction that would not
happen in water unaided8.
Other studies are pointing to a different
factor that seems to be a key part of life’s
origins: light. That’s one of the conclusions
coming from the team of synthetic biologist
Jack Szostak at Massachusetts General Hospital in Boston, which works with ‘protocells’— simple versions of cells that contain a handful of chemicals, but can grow, compete andreplicate themselves. The protocells display
more-lifelike behaviours if they are exposed toconditions similar to those on land. One study,
on which Adamala was a co-author, found thatthe protocells could use energy from light todivide, in a simple form of reproduction9.

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Feature

Water, but not too much
Such studies have given momentum to theidea that life began on a well-lit surface with alimited amount of water. However, there is still
debate over how much water was involved, andwhat part it played in starting life.
Like Deamer, Frenkel-Pinter argues thatwet–dry cycles were crucial. Dry conditions,she says, provided an opportunity for chain
molecules such as proteins and RNA to form.
But simply making RNA and other molecules is not life. A self-sustaining, dynamic
system has to form. Frenkel-Pinter suggeststhat water’s destructiveness could have helped
to drive that. Just as prey animals evolved to

run faster or secrete toxins to survive predators, the first biological molecules might have
evolved to cope with water’s chemical attacks— and even to harness its reactivity for good.
This year, Frenkel-Pinter’s team followed
up on its previous study6 showing that drying
caused amino acids to link up spontaneously.
The team found that their proto-proteins
could interact with RNA, and that both became
more stable in water as a result11. In effect,
water acted as a selection pressure: only thosecombinations of molecules that could survive
in water would continue, because the others
would be destroyed.
The idea is that, with each cycle of wetting,
the weaker molecules, or those that could
not protect themselves by binding to others,
were destroyed. Bonfio and her team demonstrated this in a study this year12, in which theyattempted to convert simple fatty acids into
more-complex lipids resembling those foundin modern cell membranes. The researchers
created mixtures of lipids, and found that thesimple ones were destroyed by water, while thelarger, more complex ones accumulated. “At
some point, you would have enough of theselipids for them to form membranes,” she says.
In other words, there might be a Goldilocks
amount of water: not so much that biologicalIn experiments in the 1950s, Stanley Miller created amino acids from simple building blocks.

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molecules are destroyed too quickly, but not
so little that nothing changes.

Warm little ponds
Where might all this have happened? On thispoint, there is a generational divide in thefield. Many senior researchers are committed
to one scenario or another, whereas younger
researchers often argue that the question is
wide open.
The open ocean is unviable, says
Frenkel-Pinter, because there is no way forchemicals to become concentrated. “That’s
really a problem,” agrees Bonfio.
An alternative marine idea has been championed since the 1980s by geologist Michael
Russell, an independent researcher formerly at
the Jet Propulsion Laboratory in Pasadena, California. Russell argues that life began in ventson the seabed, where warm alkaline water
seeps up from geological formations below.
Interactions between warm water and rocks
would provide chemical energy that would
first drive simple metabolic cycles, which
would later start making and using chemicals
such as RNA.
Russell is critical of Sutherland’s approach.
“He’s doing all these fantastic bits of chemistry,” he says, but for Russell, none of it isrelevant. That’s because modern organisms
use completely different chemical processes
to make substances such as RNA. He argues
that these processes must have arisen first, notthe substances themselves. “Life, it picks very
particular molecules. But you can’t pick themfrom the bench. You’ve got to make them fromscratch and that’s what life does.”
Sutherland counters that once RNA, proteins and so forth had formed, evolution would
have taken over and enabled proto-organisms
to find new ways to make these molecules andthus sustain themselves.
Meanwhile, many researchers haveexpressed scepticism about Russell’s alkaline-vent hypothesis, arguing that it lacks
experimental support.
By contrast, chemical experiments thatsimulate surface conditions have made thebuilding blocks of nucleic acids, proteins andlipids. “None of that synthesis exists in thatdeep-sea hydrothermal vent hypothesis. It justsimply hasn’t been done, and possibly because
it can’t be done,” says Catling.
Frenkel-Pinter is also critical of the ventidea, because the molecules she works withwouldn’t survive long in those conditions.
“The formation of these protopeptides is notvery compatible with hydrothermal vents,”
says Frenkel-Pinter.
A possible solution was proposed in May
by geochemist Martina Preiner, a postdoc
at the University of Düsseldorf in Germany,and her colleagues. She argues that in therocks beneath hydrothermal vents, heat andchemical reactions bind up water molecules

BETTMANN/GETTY

Similarly, Claudia Bonfio, now also at the
MRC Laboratory of Molecular Biology, and hercolleagues showed in 2017 that UV radiation
drives the synthesis of iron-sulfur clusters10,
which are crucial to many proteins. These
include those in the electron transport chain,
which helps to power all living cells by driving
the synthesis of the energy-storage moleculeATP. The iron–sulfur clusters would breakapart if they were exposed to water, but Bonfio’s team found they were more stable if theclusters were surrounded by simple peptides
3–12 amino acids long.

ESA/FU-BERLIN

or break them apart — creating dry spaces13.
“There are rock–water interactions getting
rid of the water to a certain extent,” she says.
Intermittently, more seawater would trickle in,giving “something like a wet–dry cycling”. Thisought to make the deep-sea rocks much moresuitable for the formation of key molecules,
argues Preiner, although she acknowledges
this is still a hypothesis. “Of course, you still
have to do the according experiments to provethat this could do certain reactions.”
At present, however, that evidence doesn’t
exist. Meanwhile, experimental support isgrowing for the idea that life started in small
bodies of water on land.
Sutherland favours a meteorite impact
crater, heated by the Sun and by the residualenergy of the impact, with multiple streams
of water running down the sloping sides,
and finally meeting in a pool at the bottom.
This would have been a complex, 3D environment with mineral surfaces to act as catalysts,
where carbon-based chemicals could havebeen alternately dissolved in water and driedout in the Sun. “You can say with some degreeof confidence we need to be on the surface,
we can’t be deep in the ocean or 10 kilometres
down in the crust,” says Sutherland. “Then weneed phosphate, we need iron. A lot of those
things are very easily delivered by iron–nickel
meteorites.” The impact scenario has a further advantage: meteorite impacts shock
the atmosphere, producing cyanide, says
Sutherland.
Deamer has long championed a different
suggestion: volcanic hot springs. In a study thisyear, he and his colleague Bruce Damer argued
that lipids would have formed protocells in the
hot waters14, as his earlier experiments indicated. The wet–dry cycles on the edges of thepools would have driven the formation andcopying of nucleic acids such as RNA.
Deamer has conducted several experiments
in modern volcanic hot springs to test his ideas.
In 2018, his team showed that vesicles could
form in hot spring water15, and even enclose
nucleic acids — but they would not form in seawater. A follow-up study last year found thatwhen the resulting vesicles were dried, nucleotides linked up to form RNA-like strands16.
Narrowing down the location where life
started will require understanding of thebroader picture of prebiotic chemistry: how
the many reactions fit together, and the rangesof conditions under which they occur. Thatmammoth task has been attempted by a groupled by chemist Sara Szymkuć, president of thestart-up firm Allchemy in Highland, Indiana.
The team published a comprehensive study in
September that used a computer algorithm to
explore how a vast network of known prebiotic
reactions could have produced many of thebiological molecules used in life today17.
The network was highly redundant, so key
biological compounds could still form evenNASA’s Perseverance rover will search for signs of life in Jezero Crater on Mars.

if multiple reactions were blocked. For thisreason, Szymkuć argues that it is too early
to rule out any of the scenarios for where life
originated. That will require systematicallytesting a range of different environments, tosee which reactions occur where.

Beyond EarthIf experiments such as Sutherland’s do point
the way to how life began on Earth, they canalso help to explore where life might havestarted elsewhere in the cosmos.
Mars has attracted the most attention,
because there is clear evidence it once hadliquid water on its surface. The landing site forNASA’s Perseverance rover, the Jezero Crater,
was chosen in part because it seems to haveonce been a lake — and could have hosted the“You can say with somedegree of confidence weneed to be on the surface, we
can’t be deep in the ocean.”chemistry Sutherland has studied. He helped
to write a 2018 presentation to NASA led by
Catling, which summarized the prebiotic
chemistry findings and advised on where
Perseverance should look. “We presented thischemistry and said this Jezero Crater, which is
the one they eventually chose, is the one where
there was the highest likelihood of this chemistry playing out,” says Sutherland.
It will be two months before Perseverance
reaches Mars — and years before the samples itcollects are returned to Earth by an as-yet-unnamed future mission. So, there is still a longwait before we find out whether Mars harbours
life, or if it did so billions of years ago. But even
if it did not, it might reveal traces of prebiotic
chemistry.

The best case, says Catling, is that
Perseverance finds complicated carbon-based
molecules in the layers of Martian sediment,such as lipids or proteins, or their degradedremains. He also hopes for evidence of
wet–dry cycles. This might come in the formof carbonate layers that formed when a lakedried and refilled many times. He suspects
that “life didn’t get particularly far on Mars”,
because we haven’t seen any obvious signs ofit, such as clear fossils or carbon-rich blackshales. “What we’re looking for is pretty simple, maybe even to the point of being prebiotic
rather than the actual cells themselves.”
It could be that Mars took only the first few
chemical steps towards life, and did not go all
the way. In that case, we might find fossils — notof life, but of pre-life.
Michael Marshall is a science writer basedin Devon, UK, and the author of The Genesis
Quest.
1. Miller, S. L. Science 117, 528–529 (1953).
2. Shapiro, R. Origins: A Skeptic’s Guide to the Creation ofLife on Earth (Summit, 1986).
3. Powner, M. W., Gerland, B. & Sutherland, J. D. Nature 459,
239–242 (2009).
4. Patel, B. H., Percivalle, C., Ritson, D. J., Duffy, C. D. &Sutherland, J. D. Nature Chem. 7, 301–307 (2015).
5. Xu, J. et al. Nature 582, 60–66 (2020).
6. Frenkel-Pinter, M. et al. Proc. Natl Acad. Sci. USA 116,
16338–16346 (2019).
7. Deamer, D. W. & Barchfeld, G. L. J. Mol. Evol. 18, 203–206(1982).
8. Rajamani, S. et al. Orig. Life Evol. Biosph. 38, 57–74 (2008).
9. Zhu, T. F., Adamala, K., Zhang, N. & Szostak, J. W. Proc.
Natl Acad. Sci. USA 109, 9828–9832 (2012).
10. Bonfio, C. et al. Nature Chem. 9, 1229–1234 (2017).
11. Frenkel-Pinter, M. et al. Nature Commun. 11, 3137 (2020).
12. Bonfio, C., Russell, D. A., Green, N. J., Mariani, A. &Sutherland, J. D. Chem. Sci. 11, 10688–10697 (2020).
13. do Nascimento Vieira, A., Kleinermanns, K., Martin, W. F. &Preiner, M. FEBS Lett. 594, 2717–2733 (2020).
14. Damer, B. & Deamer, D. Astrobiology 20, 429–452 (2020).
15. Milshteyn, D., Damer, B. Havig, J. & Deamer, D. Life 8, 11(2018).
16. Deamer, D., Damer, B. & Kompanichenko, V. Astrobiology
19, 1523–1537 (2019).
17. Wołos, A. et al. Science 369, eaaw1955 (2020).

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