What is the difference between an unsolved problem and a mystery? A mystery is a problem that, by definition, cannot be solved. For example, if you ask: “Why there is it something instead of nothing?”- you are bound to meet a mystery, and not a problem which can be solved. The general point here is that something can be a mystery, or simply an unsolved problem, depending upon the approach used to tackle the question.

The origin of life (from now on, ool) is still unsolved, we do not know how life originated on our planet, despite the work and progress in the field operated by excellent chemists and molecular biologists in the last 50-60 years. There are theories and hypotheses, of course, including the idea that life comes from other places in the cosmos - but this is not the answer.

Let’s start from the beginning. We generally accept the view of our friends, cosmologists, that all life started with the big-bang over 13 Gya, billions years ago, and that the solar system, with our Earth, is about 5 Gya old. At that time the Earth was a fire ball, not the best condition for our organic life. But then: already at 3.8 (and somebody says at 4 Gya) the Earth was rich of life, in the form of active unicellular organisms –microbes. And so the question: there was no life, then it was all full of life. How did life arise?

This kind of question wold not have been a real question till the middle of the nineteen century. In those times, people were pious and good-natured and believed firmly that God has created the world and all living forms, once and for all. It would have been a blasphemy to doubt such a simple truth. And the blasphemy arrived in the form of a book written in 1859 by a British scientist named Charles Darwin, who refused the idea that living forms were fixed, saying instead that they were changing with time, and that they were evolving from a common ancestor. Darwin – adding one blasphemy to the other – arrived to postulate that life might have originated from natural causes. And generally, in that time philosophers and biologists were increasingly accepting the idea of an origin of life based on natural laws.

It was a brilliant Russian chemist, Alexander Ivanovic Oparin, much influenced by Darwin and by the Marxist dialectic materialistic philosophy of Soviet Union in that time, who in 1924 published a little book on the natural origin of life. Accordingly, life comes from inanimate matter, as illustrated by the simple cartoon in fig.2, whereby small molecules would assemble into larger ones, and by a process of spontaneous increase of complexity and functionality, closed spherical structures (the first cells or protocells) were formed, which able to grow and multiply.

There is no divine intervention, no spirituality in this view of life on Earth-at least at the level of the first unicellular forms of life. Coming back to Oparin’s idea: he postulated that the prebiotic atmosphere was composed mostly by four gaseous components: hydrogen, methane, water, ammonia (H2, CH4, H20, NH3) and that by their combination, thanks to the energy of lightening, amino acids were formed.

An American Ph.D. student, Stanley Miller, in the early 1950s, fascinated by Oparin’s idea, made his famous experiment. He filled a flask with the four gaseous components assumed by Oparin to be the constituents of prebiotic, reductive atmosphere: hydrogen, ammonia, methane, and water vapor (see Figure 1). By passing electrical discharges through this flask to simulate primordial lightening energy, he was able to witness the formation of several α-amino acids and other substances having biological importance. The experiment was published in 1953, the same year as the discovery of the double helix by Watson and Crick, a memorable year indeed for biochemistry.

The key point here is that relatively complex biochemical, amino acids in particular, can be formed from a mixture of very simple gaseous components in a chemical pathway that can indeed be regarded as prebiotic (prebiotic= before life). In fact, this experiment also signed the beginning of a new field of inquire, the chemical “bottom-up” approach to the origin of life. Many other important molecules and processes (i.e. self-replication) have been discovered by chemists using prebiotic perspectives.

And the chemist at this point thinks: if life is only chemical interactions, and if the basic constituents of life can be synthesized under prebiotic conditions, then it should be possible to construct life in the laboratory….. But…there is an important but: to have amino acids does not mean to have life. Amino acids make up all proteins of our life, but they are simple non-living bricks. The same should be said for all small molecules, the so called low molecular weight compounds, including the mononucleotides, the monomeric constituents of nucleic acids. In fact, the chemist can have in his lab all low molecular weight compounds of this earth- amino acids, mono-nucleotides, lipids, sugars, metal ions, etc... and he would not be able to make life. Why is it so? Let’s give a first answer, which touches the real core of the matter.

Life is essentially determined by macromolecules, i.e., long chains of amino acids, or nucleotides (in the case of DNA or RNA). All proteins, including all enzymes, all genes, are long, ordered sequences. The term ordered is the critical one. Every protein is not simply a random chain of amino acid, but is characterized by a strict sequential order. As shown in Fig.3 in the example of the enzyme bovine ribonuclease, the amino acid number 10, Arginine (Arg), must be preceded by glutamic acid (Glu), and followed by glutamine (Gln), then methionine (Met) and Histidine (His) ; and so on for all other elements of the chain. There is a precise sequential order. And: all protein molecules of bovine ribonuclease are identical to each other-another extremely high level of order. And this is true for every protein of our life, and the same is true for the sequences of RNA or DNA. And in fact the main problem in the origin of life is (still): how could this high degree of sequential order in many identical copies be achieved under prebiotic conditions?

We do not know how to do that, neither experimentally nor theoretically, and this is why I repeat (see also my recent book) that we are not close to the solution of the origin of life. Most of the researchers on the origin of life proceed, ignoring or bypassing this point - the prerequisite necessity of sequential order. For example, in the vision of the origin of life in the so-called RNA world, usually researchers start from already formed RNA macromolecules, or even from ribozymes (RNA molecules which have catalytic properties). And there is a basic incongruence in all this. In fact, assume to start from a RNA or ribozyme solution containing only one billionth of milligram of this compound (10-12 g-which in chemical terms may means 10-16 molar solution of that compound). Well, this would mean (remembering the value of the Avogadro number, which is 6.1023) that this solution contains from the start, already several millions of identical RNA (or ribozyme) molecules.

Who or what made this highly ordered state? Obviously there must be a preliminary mechanism, a black box, capable to make such ordered macromolecules. This black box, I call “origin of life”. Seriously, consider that you cannot be asking how life arises from non-life, and start with sequentially well ordered macromolecules- or viruses or viroid. Building a house starting from the roof. Of course from this kind of research beautiful collateral results may be and are obtained, but the main question, how life came out from non-life, remains untouched.

Most of the present day research on the ool is characterized by this situation, which is a kind of reductionist attitude based on the misleading equation: life= DNA (or RNA). I asked in the title whether the ool is an unsolved problem or a mystery. I believe that, until the reductionist attitude persists (we are in the century of the gene, as Evelyne Fox-Keller was saying) with the DNA or RNA-centered prejudice, it will remain a mystery- unsolvable- and will maybe become a solvable problem when a novel and fresh systems view of life will characterize research in the field. Just forget the roof, and start working from the foundation.

References
E. Fox-Keller, The Century of the Gene, Harvard Univ. Press, 2002
S. Miller, Science, 117 (1953) 2351-61
P.L. Luisi, The Emergence of Life, second edition, Cambridge Univ. Press, 2016
F. Capra, P.L. Luisi, The Systems View of Life - an unifying Vision, Cambridge Univ. Press, 2014
A.I. Oparin, The Origin of Life, Mac Millan, New York, 1938 (from the original 1924 Russian edition)