Origin of Life: Follow-up on your comments

I always appreciate the opportunity to learn from your comments, the more so when I have ventured outside my expertise.  I was particularly excited to receive extended comments from Gary Hurd with references that were new to me and a pointer to one of my favorite biological free-thinkers, Carl Woese.  This is a brief response to Gary, with some expanded thoughts and clarifications.

I view evolution as an accelerating process.  At the same time that life has been evolving, evolution has been evolving.  That is to say, the process of evolution has become more and more efficient over time, a phenomenon I once referred to as Evolution Squared.  Recent stages of evolution have been remarkably efficient.  Multi-cellular life is only half a billion years old (at least in the form we know it, with cells specialized to form organs, appendages, circulation, nerves etc).  So the first 85% of life’s history was spent working on individual cells, their structure and metabolism.  I expect that the earliest stages of evolution were remarkably slow.

The very first self-reproducing systems had to appear by chance, and had to evolve progressively before life had really learned how to evolve.  My premise last week was surprise that the earliest cyanobacteria appeared so soon after the earth first cooled and solidified.  Cyanobacteria have a lot of cell structure and some very fancy metabolic chemistry.  This all had to be come together at a time when the evolutionary process was groping around in the dark.

I estimated that life had only 300 million years from loose alliances of molecules to cells that left a fossil record.  Gary said this number should be 500-700 million.  He’s probably right.  700 million years is the full time available from the first liquid water to the oldest fossils, and it is impossible to know whether it was late or early in that 700 million years that molecular life first self-organized.

 

Maybe LUCA was the vast blue sea

Gary pointed me to an article by Carl Woese with an alternate picture of the origin of life.

We’re accustomed to think that the Darwinian struggle for existence is a condition of life, and it has always been thus.  We imagine that cooperation arose after competition, as alliances became a potent aid in the struggle.

We get our genes from our parents, and micro-organisms get their genes from progenitor cells.  We read about bacteria that promiscuously share plasmids—“horizontal gene transfer”—and we think this is a bizarre, chimerical monstrosity.

We’re accustomed to thinking of life lived by individuals, each with its unique lineage extending back in time.  We imagine that individuals evolved first, that they diverged and competed, and later organized into predator-prey communities and more complex ecosystems.

The technology we have for inferring genetic relationship and ancient lineage is statistical analysis of the similarity of DNA sequences in widely-varying life forms today, using genes that perform the same core functions.  Presumably, these genes all derive from a common source, and the variations that they assume among present life forms tell the story of the path by which they were passed down.

Woese, who knew this evidence as well as anyone and thought about it in the broadest context, concludes that diverse branches of the tree of life cannot be traced to a single root.

The further back in evolutionary time we look, the more the notion of an “organismal lineage”—indeed, the very definition of “organism” itself—comes into question. It is time to release this notion of organismal lineages altogether and see where that leaves us.

The further we look back in time, the more horizontal gene transfer was the rule, and strict lineage the exception.  The picture that Woese invokes is of a time before separate selves, when all partook of the chemical commons, and genes were free-floating templates belonging to no one and everyone.

The universal ancestor is not a discrete entity. It is, rather, a diverse community of cells that survives and evolves as a biological unit. This communal ancestor has a physical history but not a genealogical one. Over time, this ancestor refined into a smaller number of increasingly complex cell types with the ancestors of the three primary groupings of organisms [archaea, bacteria & eukaryotes] arising as a result.

One day, an oily film walled off one little portion of the sea, and the chemicals therein spoke the word “mine” for the first time in history.

I am fascinated by this picture.  It comes from an eminent scientist, it seems plausible, and it aligns with diverse spiritual wisdom about the unity of life and with mythology of a time before our current Age of Separation.  It will be awhile before I am able to assimilate its implications.

 

Is it hard to create a self-replicating network of molecules?

I claimed last week that lab scientists had tried and failed to come up with self-replicating molecular cycles.  Gary pointed me to five reports in the literature of self-replicating chemistry.  After looking at them, I think we’re both right.  Indeed, there are examples of molecular systems that are able to copy themselves, but they work only when immersed in a soup of chemical feed that is already too complex to have arisen by chance.  Not only are the simplest molecules capable of self-replication not simple enough that they might ever have arisen in a whole pre-biotic sea of random molecules; but even these are able to assemble copies of themselves only when provided with constituents that are also too complex to be plausibly present before biology.

All present life requires three kinds of molecules: Proteins, DNA and RNA.  Proteins do the cell’s work, including the work of replicating DNA; but DNA holds the information that tells how to build a protein, so each is dependent on the other.  DNA and RNA have the essential property that they can act as templates for their own replication.  That’s the significance of the “double helix”—two strands of DNA or RNA can come unzipped, and each finds pieces to make a new mate for itself.  But in biology, this only happens with the aid of protein molecules that do the zipping and unzipping, and finding the constituents to build the copy.  To make a protein from a DNA template requires an RNA intermediary and a tiny molecular factory called a ribosome, which is itself a miracle of natural bioengineering.  This 3-component system is so complex that it could not have been the basis of the first life on earth.  So biochemists looking for a simple self-replicating system work either on proteins alone or with RNA alone.  (DNA alone is not considered viable because it is a passive informational molecule and is not capable of doing anything on its own.)

The “protein world” hypothesis has the advantage that proteins are made of amino acids, which are relatively easy to make and are plausible constituents of the pre-biotic soup.

The “RNA world” hypothesis has the advantage that RNA is both a workhorse molecule and a template for replication.  But the constituent pieces of RNA are nucleic acids which are, themselves, harder to synthesize and it is thought that the pre-biotic soup would contain only minuscule amounts of them compared to the amounts of amino acids, which were already rare (dilute) in an absolute sense.

The five papers Gary cites are interesting for what they accomplish, as well as for what they fail to accomplish:

  • Lee et al, Nature 1997   This group at Scripps Inst in La Jolla  works with a protein that is able to make more of the same protein (no RNA or DNA).  A particular protein of length 32 can act as a template to make copies of itself by joining together two pieces of length 17 and 15 residues.

A protein (or “peptide”) is a chain of amino acid molecules.  The individual pieces are called “residues” in this context.  Individual residues qualify as simple enough to have appeared by chance in the pre-biotic soup.  However, chaining them together can be done in many different ways.

For example, there are hundreds of known, simple residues.  20 of them are essential for today’s biology.  The number of different chains of length 32 that can be made using just the 20 known residues is 20 raised to the power 32=1041.

In other words, this is a hugely improbable molecule to appear spontaneously, and even so, it can’t assemble copies of itself from individual residues, but only from two halves of itself.

My judgment is that this is tremendously exciting work, it’s on the right path, but still both too complex and not effective enough to be a candidate for the first self-replicator.

  • Lincoln & Joyce, Science 2009.  This is another group at Scripps that works with RNA alone (no proteins).  The paper describes a pair of RNA molecules, each of which was effective in assembling a new copy of the other.

This is an example of a hypercycle, as I described last week—a set of molecules that are mutually auto-catalyzing.  The fully-assembed molecules are more than 100 bases in length, and they can be assembled from smaller pieces of themselves.  The smallest piece in the “feedstock” is 21 bases in length, and the largest is more than 60.

As with the protein work above, I would judge that this is tremendously exciting and promising work.  I’m grateful to Gary for pointing it out to me.  But we’re still a long way from having a candidate for the first pre-biotic chemical system.  These molecules are too large (= too complex=too improbable) to have plausibly appeared by chance in all the world’s oceans in 500 million years.  And even if one did appear by chance, it would require the other, and then the two would only be able to replicate if provided with smaller fragments.

  • Turk et al, PNAS 2010.  This group at UC Santa Cruz reports a crucial protein-building step performed by an RNA fragment that is only 5 bases long.   In order to support biology that includes both RNA and proteins, you need ribosomes, which can make a protein to order from a from an RNA blueprint.  But ribosomes are much too complex to be part of the first living things.  This paper reports that one piece of the work done by a ribosome can be accomplished by this simple 5-base RNA fragment.  5 bases linked together is a small enough molecule that it could plausibly have appeared by chance, before biology.

The Bottom Line

In summary:  I’m impressed with the progress that has been made in the search for the chemical basis of pre-biotic life, and I’m grateful to Gary for having pointed me to this literature.  We have a long way to go before we can say we understand how life got started, but we’ve made some promising steps in the right direction.

Specialists in this area of research remain divided in their fundamental pictures of the origin of life.  Some favor the protein world, some the RNA world, and some the view that I described last week, which is that life arrived on a meteor from an extra-terrestrial source.  A common criticism is that the extra-terrestrial hypothesis is vacuous, or superfluous, because it just “kicks the can down the road”.  You are still left having to explain how life got started on some other planet at some other time.  But I’d argue that the extra-terrestrial hypothesis contributes three things:

  • it helps explain why all life on earth is related, with a common chemical basis;
  • it helps explain why life arose relatively quickly after the birth of Planet Earth;
  • and it provides more time and space for the vastly improbable events that led to the first life.

The ET hypothesis makes a prediction that may someday be testable: If extraterrestrial life is discovered, or if we are visited, then the prediction is that these visitors will have metabolisms and genetics based on proteins and DNA, respectively, just like us.

Late Night Musings on the Origin of Life

The conventional view of the origin of life is that some combination of simple-enough chemicals was able to catalyze the synthesis of the same chemicals, and that was enough to begin a process of evolution that became more efficient as it became more intricate.  One problem with this idea is that no such self-reproducing combination of chemicals is known, or has ever been synthesized or engineered.  The simplest known self-replicating systems are enormously complex compared to anything that might plausibly have arisen by chance.  Improbable as is the conventional view, the alternatives are far stranger.

The paradox in a nutshell

Consider what we might deduce from these three facts.

  1. The oldest fossils are almost as old as the earth.  So life must have appeared on earth as soon as the earth was cool enough to have liquid water.
  2. Biochemists have devoted a great deal of ingenuity to the task of creating a molecule or network of molecules that can self-reproduce, when immersed in a bath with appropriate chemical feed-stock.  They haven’t made it to first base.
  3. All life on earth is related, all descended from the same proto-cell.

When we think of the transition from non-living matter to living systems, we imagine some network of molecules that formed a self-catalyzing loop.  Typical bio-molecules have thousands of carbon atoms arranged in a precise shape and structure that could never have come about by chance.  The earliest proto-living system did not have to be efficient, because there was no competition, but it had to be simple, because once you start combining more than a dozen or so carbon atoms together, the number of ways they can be linked is so large that any one combination would not be expected to appear even once in all the vast oceans over many millions of years.  So what we need is a system of molecules, for example A, B and C are all simple enough to have arisen by chance, and A makes it more likely that common molecules in the neighborhood will come together to form B, and B likewise catalyzes C, and C increases the probability of formation of A.

We think it must have happened somewhere, sometime.  In the early days of biochemistry, it was common to assume that this first step with self-replicating organic molecules must be easy.  In 1953, Stanley Miller and Harold Urey passed sparks through a tank of water, ammonia and methane, simulating the earth’s early atmosphere in the presence of lightning, and he found that some common organic molecules were created, including some amino acids.  Bingo!  Harlow Shapley wrote in Of Stars and Men (1957),

No longer is the origin of life a deep mystery.  Supernatural “intervention” in the biochemical development which we call life is not required.  Natural operations, most of them already known, will suffice.  We have bridged, at least provisionally, the gap between life and the lifeless.  The microbiologist probing down from cells toward the inanimate and the chemist moving up from atoms toward the animate are practically in contact.  Much detailed work, however, remains to be done.

Much detail, indeed.  We realize now that there is a mystery.  The gap between non-living and living systems seems wider now that we’ve spent 60 years trying to bridge it.  For comparison, the number of people playing with cellular automata is much smaller, but the self-replication problem has been solved handily in that context.  Cellular automata are “toy worlds” that obey simple, made-up rules, for propagating from one generation to the next.  The most famous is John Conway’s Game of Life, and here is a self-replicating pattern that works with those rules.

So Fact #1 would lead us to expect that maybe the first steps in the formation of life were easy and probable, while Fact #2 implies the opposite.

Fact #3 suggests maybe life appeared only once, adding more weight in favor of “difficult and improbable”.  Or maybe life evolved in many places at many times, but one of these simply out-competed the others, and so descendents of just this one life remain on earth today.  This is potentially the biggest loophole in my thesis, so I want to dwell on it for a few paragraphs.

 

All life on earth has a common ancestor.  Does this mean that life arose only once?

We know that all life on earth has a common ancestor because there are many things that all living cells have in common with each other, and some of them are quite arbitrary.  One example is the genetic code, which seems to be composed of three-letter “words” for specifying amino acids (= protein building blocks) which appears to be as arbitrary as any association between letters and meaning in a human language.  Another example is the fact that all biological amino acids are left-handed, and all nucleic acids are right-handed.  In other words, these molecules are different from their mirror images, and we know that a mirror image of all of life’s chemistry would behave identically to life as we know it (provided that all the molecules were mirror-imaged).  Inorganic chemical processes always create left- and right-handed molecules in equal numbers, but biochemical processes always create exclusively one handedness only.

I enjoy thinking about LUCA, the Last Universal Common Ancestor, a single cell existing perhaps 3 billion years ago from which you and I and every mushroom and mosquito and all life on earth has descended.  Strange as it seems, there is no alternative hypothesis that isn’t far stranger.

If we think life evolved from molecule to primitive cell within 300 million years, that suggests that there has been ample time and opportunity for life to have arisen in other times and places, before and since.  Why wouldn’t descendants of these other origins of life appear somewhere on earth today?

We are used to thinking in terms of varieties that vie for a niche, and one does a better job than the other, and so the former drives the latter to extinction and takes over.  It has been argued that once Life I got a head start, it might be so efficient that newly-formed Life II and Life XIX would not have a chance of invading its territory.

I am not convinced this is true.  Life forms that are very similar may vie for the same niche:  they are attacked by the same predators, get the same diseases, and rely on the same resources.  But why would Life II be vulnerable to Life I if the two were very different?  There is a mathematical theorem from evolutionary theory (Gause’s Law), purporting to prove that two varieties cannot coexist stably in the same niche.  Whichever reproduces faster will drive the other to exinction.  While this is true in theory, it seems that in richly productive ecosystems, the niches are sliced awfully thin, so that in tropical rainforests and coral reefs (the two most prolific ecosystems in the world), many species with very similar characteristics manage to co-exist and thrive together for long periods without getting in each other’s way.

How much more true would we expect this to be if two forms of life had an entirely different chemical basis!  Life II might be based on carbon chemistry, but using neither proteins (amino acids) for signaling and as workhorse molecules, nor DNA (nucleic acids) for information storage.  Life I would not eat Life II, because Life I lacks the enzymes necessary to digest Life II.  Even if it could be digested, it is unlikely that the chemical constituents of Life II would be useful to Life I.  We (Life I) can eat sugars and proteins, but we can’t digest diesel oil or polyethylene, even though these feedstocks contain chemical energy in abundance that could, in theory, be useful to us.

In what sense would Life I and Life II be competing at all?  Only in the sense of both needing water and an energy source – say mineral compounds at undersea vents, or sunlight.  Certainly it is probable that Life I or Life II might be much the more efficient at converting energy into biomass, and at rate of reproduction; still It is not at all clear that Life I and Life II would not be able to stably co-exist, or that one form would necessarily drive the other to extinction.

 

Life before LUCA

The (ultimate) energy source for most life today is sunlight.  Furthermore, the earliest fossils that we have are the blue-green algae (cyanobacteria), the alchemists that alone are able to capture the energy of the sun and store it as chemical energy.  This is the chemistry of chlorophyl and photosynthesis, and, as far as we know, it evolved only once.  The cyanobacteria had a monopoly on the process for more than 2 billion years, until they colonized early eukaryotes (complex nucleated cells) and were tamed by them as chloroplasts, which remain to this day the “green” in green plants, and the energy factories for everything from moss to Giant Sequoias.

And yet the biochemistry of photosynthesis is far too complex and sophisticated for us to imagine that cyanobacteria evolved first from non-living matter.  There must have been some intermediate life form with lower complexity, and we are not surprised that it left no fossil imprints.

There are many competing theories, many scenarios for the way in which life might have arisen from non-living matter.  My favorite, explored with a masterful knowledge of chemistry and a creative imagination comes from Nick Lane.  My point is that all these are descriptive, and lack detail.  There is nothing like a proof or demonstration that life could have arisen in the brief time in which we know life did appear, and, of course, there has been no success engineering a chemical system capable of reproduction in the laboratory, let alone a system simple enough that it might plausibly have arisen by chance.

 

If anything is worthy of cosmic wonder, surely it is this

Where all this is headed – the epiphany that started me writing this essay – is the improbability of the first life forms, the bridge that carried nonliving matter into the realm of the living.

(This is the original “chicken and egg” problem, and it carries us to the brink of Creationism.   To offer “God did it” as an explanation seems to me to offer no advantage compared to the simpler statement, “we don’t know” or “it is an enduring mystery”.  On the other hand, I think that evolutionary scientists have been less than honest in acknowledging the vulnerabilities and mysteries in the evolutionary process, in part because they have felt the need to take a hard line against attacks from fundamentalists.)

James Russell Lowell, the 19th Century transcendental poet, wrote

We pass unconscious o’er a slender bridge,
The momentary work of unseen hands
Which crumbles down behind us.  Looking back,
We see the other shore, the gulf between,
And, marveling how we won to wear we stand,
Content ourselves to call the builder Chance.

So I look as an (independent, heretical) scientist on the evidence, and I ask: what could explain the highly-improbable appearance of living forms on earth, so soon after the early earth cooled sufficiently to make life possible?

One answer is an extra-terrestrial origin for life.  Perhaps the earth was deliberately seeded by some advanced civilization (after all, the Universe was already 9 billion years old, ⅔ its present age, when sun and earth were born)…this leads to the Fermi Paradox and other mysteries.  Or else there are bacterial spores sufficiently resilient that they can ride a rock ejected from a planet by violent volcanism, then survive dormant for millions of years in interstellar space, and survive (yet again) the heat bath of re-entry into a planetary atmosphere.  The spores then detected water and hospitable temperatures, and they awakened from a long, long sleep.

Unlikely?  As I see it, the alternatives are Little Green Men or mysticism.  Panspermia is the hypothesis of a single origin for all life in the universe, a recognized and legitimate hypothesis (if not dignified by the Science establishment) with roots that go back to Anaxagoras, and a following that includes no less a luminary than Francis Crick.  Panspermia does not solve the riddle of the origin of life, but only pushes the question back to a previous planet in a previous epoch, but the available space and time for life to appear is vastly increased.

…or maybe the biochemists have overlooked something that’s not so difficult, and the origin of that first cell is not as improbable as it seems….or maybe there is a propensity for life that is woven into the behavior of matter, and shielded from our view by what Quantum Mechanics calls irreducible randomness, electrons and protons are biasing their trajectories in tiny ways that aim toward life, perhaps toward awareness.  The boundary between science and speculation is where I love to hang out.

 

Less meat, More life

Vegetarians outlive non-vegetarians by several years.  The result may be largely (or entirely) due to lower weight, and higher consumption of fresh vegetables and fruits, rather than to an adverse effect of meat per se.   Vegans have an even greater advantage than vegetarians who eat dairy and eggs, and again vegan weight trends even lower than other vegetarians.  It goes without saying that in this context a longer life goes hand-in-hand with a healthier life. Rates of diabetes, heart disease, and selected cancers are much lower in vegetarians, and yet lower in vegans.  

 

I have been a vegetarian since 1973, motivated (now) by years of habit and (then) by a hypnotic suggestion from my first yoga teacher.  One evening, about five months into my discovery of yoga, I was lying on the floor in savasana (deep relaxation) when the revered and beloved voice of my teacher suggested to the class that perhaps we might find our practice leading us to eat less meat.  I was startled awake, and sat bolt upright.  In previous weeks, she had suggested cutting back coffee and alcohol and TV and marijuana (this was Berkeley!) and cigarettes—it all went down smoothly because I had never been attracted to any of those things.  But what could she be thinking, classing meat with intoxicants and mind-altering drugs?  I had never questioned that a diet that was ultra-high in protein would keep me strong and healthy.  The phrase “new age hocum” hadn’t been invented yet, but those are just the words for which my mind was searching.

Six weeks later, I was a vegetarian.  My teacher’s hypnotic suggestion awakened my discomfort with surrogate killing of animals.  It had nothing to do with science.  Now there is evidence linking low meat consumption with longevity, but much less was known 40 years ago, and even that was unknown to me.  I became aware that I was uncomfortable eating animals, and I have never looked back.

Years later, I raised my two daughters to eat whatever they wanted to eat, and was secretly delighted when, as pre-teens, they each decided that (though they enjoyed the taste of meat), it was too unsettling for them to think of the animal who died to become their meal.  Both daughters have maintained their vegetarianism into adulthood, though everything else about them has changed.

As a public health advocate, I have been very cautious about suggesting vegetarianism to anyone.  I am still wary that my own habits and emotions may be affecting my judgment.  But more studies than ever support the role of vegetarianism in a life extension plan, and prompted by a recent ScienceDaily article, I’ll look at vegetarian diets in this week’s column.

 

Seventh Day Adventist Study

Studying the long-term consequences of a vegetarian diet is complicated by the fact that vegetarians are far from a random sample.  There are a lot more women than men, more liberals than conservatives, more environmental awareness, more health-consciousness, more propensity to exercise among vegetarians [2012 Gallup poll].  More surprisingly, vegetarianism is associated with fewer years of education, and there are a lot more Baby Boomer vegetarians than among younger generations.

41% of Seventh Day Adventists call themselves vegetarians, compared to 5% of Americans generally.  This makes SDA an ideal population to a study the effects of a vegetarian diet holding other factors fairly constant.  Vegetarianism among SDA cuts across racial and socio-economic divisions.

Consistent with past studies, the SDA study gave vegetarians 3 extra years of life.  Note that SDA men already live 7 years longer than other Americans (4½ years for women).  So the vegetarian advantage in SDA studies is on top of a large head start.  7 years is big! comparable to the difference between Japan (world’s highest life expectancy) and Mexico (representative of the worldwide average, outside Africa which is shockingly low) [Wikipedia list]

Benefits were reported for for heart disease (especially) and selective cancers, cancers of the digestive tract in particular.  Past studies have found that cardiovascular mortality is 24% lower among vegetarians.

Gary Fraser, an MD-PhD cardiologist at SDA-affiliated Loma Linda University, has written a great deal on the health benefits of vegetarian diets.  Here is a chart from his 2009 review of SDA and other data:

 

Diet groupBMIrel incidence
of Diabetes
rel incidence
of Hypertension
Nonvegetarian28.261.001.00
Semivegetarian27.000.720.77
Pescovegetarian25.730.490.62
Lactoovo-vegetarian25.480.390.45
Vegan23.130.220.25

Look at the diabetes rates for vegans compared to non-vegarians – only 1 / 5th as high!  Diabetes contributes to all the diseases of old age.

But look at the first column, BMI.  Non-vegetarians in the study had BMI of more than 28, compared to 25 – 26 for vegetarians and 23 for vegans.  Differences of this order could easily account for the entire 3 year life expectancy advantage [Oxford study, 2009].  There are theoretical reasons why vegetable protein might be helpful in modulating the metabolism in ways that keep weight down and insulin sensitivity up.

The vegetarian advantage appears in a much reduced incidence of early death, most apparent between ages 50 and 60.  (For younger decades, the death rate for both vegetarians and meat eaters is too low to make much difference, and at older ages, the advantage of vegetarianism is gradually overtaken by genetic and other factors affecting longevity.)

Findings about the advantage of fruit and (especially) green vegetable consumption should come as no surprise.  More interesting is a paper from the SDA study devoted just to nuts.  Eating a lot of nuts contributed to a lower risk of obesity and, to a lesser extent, metabolic syndrome.  Peanuts were not as helpful as other nuts.  Personally, I find that nuts are a convenient and tasty component of a low-carb vegetarian diet.

 

The Bottom Line

If you are inclined to a vegetarian diet for poliitcal or environmental or philosophic or religious reasons, then by all means enjoy the satisfaction of knowing that you are doing your body a favor, and your diet is conducive to health and longevity.  If your diet includes meat, keep in mind that the most important things you can do are to keep your weight down and expand on vegetables, nuts and fruits, with leafy greans at the top of the list.  If you are contemplating a change, I suggest that you try a vegetarian eating style for a week or even for a day at a time as a way to expand your culinary horizons and explore how it feels to you.