Concept

Minimal Cell

Intro

What is the simplest thing that can be alive? Not a virus, which has to hijack a cell to copy itself. The answer is a single cell that can feed itself, copy itself, and repair itself on its own. Scientists call the stripped-down version a minimal cell.

Even the simplest cell is a factory with many departments that all have to work at once. It needs a library of instructions (DNA). It needs a machine that reads those instructions and builds proteins (the ribosome), plus a set of matching keys that link each code word to the right amino acid. It needs a power plant (ATP synthase). It needs a wall with gates that let the right things in and out (the membrane). And it needs a copying system with proofreading, so the instructions survive from one generation to the next.

Here is the puzzle. These parts depend on each other in loops. DNA needs proteins to copy it, but proteins are built from DNA's instructions. Ribosomes build proteins, but ribosomes are partly made of proteins that only ribosomes can build. It is a chicken-and-egg problem stacked several layers deep.

In 2016 the J. Craig Venter Institute built the smallest free-living cell yet, called JCVI-syn3.0. It needed 473 genes, and for about 149 of them nobody knew exactly what they did, only that the cell could not live without them.

The leading attempt to escape the loops is the RNA World idea, that RNA once did everything alone. This page explains why the minimal cell is such a hard problem for an unguided origin of life, where the RNA World reply falls short, and how the numbers multiply when every part has to be there at once.

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In full

The minimal cell is the smallest set of genes, molecules, and structures that can sustain independent life: metabolism, self-maintenance, and self-reproduction without a host. It is approached from two directions: top-down, by deleting genes from a simple bacterium until it can no longer survive (the JCVI-syn3.0 program); and comparatively, by asking which genes are shared by the smallest known genomes (Mushegian and Koonin's 1996 comparison of two small bacterial genomes suggested a core of about 256 genes). Both routes converge on a system of several hundred genes whose products form interlocking causal loops: information storage, transcription, translation, energy capture, membrane transport, and replication each presuppose the products of the others. For abiogenesis research this means the threshold of life is not a single molecule but an integrated system. For the design argument it means that probabilities for independent requirements multiply, which is the bridge to the Universal Probability Bound.

What the simplest cell needs, all at once

1. Information storage. A genome of DNA carrying the instructions for every protein and functional RNA. See DNA.
2. A translation system. The ribosome, which joins amino acids into proteins, plus the transfer RNAs and about 20 aminoacyl-tRNA synthetases: the enzymes that attach each amino acid to its correct tRNA. The synthetases are the "matching keys" that actually implement the Genetic Code.
3. Energy. A way to make and use ATP, the cell's energy currency. In nearly all cells this includes ATP Synthase, a rotary molecular motor.
4. A membrane with selective gates. A lipid boundary that keeps the cell's contents together, with protein channels and pumps that let in nutrients and let out waste.
5. Replication with proofreading. Polymerases that copy the genome, and repair systems that correct errors, so that information is not lost to mutation each generation.

The JCVI-syn3.0 cell (Hutchison and colleagues, Science, 2016), built by trimming the genome of Mycoplasma mycoides, needed 473 genes. About 149 of them were of unknown function at the time. Even with every modern laboratory tool and a parent cell to start from, the investigators could not get below several hundred genes, and a large share of the essential set was not understood.

The chicken-and-egg loops

The problem is not just that there are many parts. It is that the parts produce one another in circles.

Each loop can run once it is running. None of them shows how it could start. A cell is, in this sense, a system in which nearly every component is both a product and a precondition.

Why mutation and selection cannot start the first cell

Natural selection acts on things that reproduce, and mutation is a copying error. Both presuppose a working replicator. Arguments about what mutation and selection can achieve apply only after life exists. Stephen Meyer puts the point this way:

Natural selection assumes the existence of living organisms with a capacity to reproduce. Yet self-replication in all extant cells depends upon information-rich proteins and nucleic acids (DNA and RNA), and the origin of such information-rich molecules is precisely what origin-of-life research needs to explain. (Stephen C. Meyer, Darwin's Doubt, PDF p. 8)

Meyer cites the geneticist Theodosius Dobzhansky, one of the architects of the modern synthesis, for the same verdict: "Pre-biological natural selection is a contradiction in terms" (as quoted in Meyer, Darwin's Doubt, PDF p. 8).

The RNA World reply and its problems

The main naturalistic answer to the loops is the RNA World hypothesis. RNA can store information like DNA and, as ribozymes, can catalyze some reactions like proteins. If one molecule once did both jobs, the DNA-protein loop might have been preceded by a simpler RNA-only stage. The ribosome's catalytic core being RNA is often cited as a relic of that stage.

The reply has real merit as a research program, but it does not dissolve the minimal-cell problem:

1. It moves the loop rather than breaking it. An RNA replicator still needs a sequence-specific RNA that copies RNA, which is itself a highly specified sequence. The chicken-and-egg problem becomes "which came first, the replicase or the RNA it copies?"
2. RNA is hard to make and hard to keep. Ribose is unstable, the four nucleotides are difficult to synthesize under realistic early-earth conditions, and in water RNA chains tend to break apart rather than lengthen.
3. No self-replicating ribozyme has been found. Laboratory ribozymes can extend short RNA strands under controlled conditions, but none copies itself end to end from realistic prebiotic ingredients.
4. The information problem remains. Eugene Koonin's own estimate for a minimal RNA-based replication and translation system gives odds so small that he appealed to an infinite multiverse to make them likely somewhere. See RNA World for the numbers.
5. It still has to reach the minimal cell. Even a successful RNA replicator would be far from a membrane-bound cell with a genetic code, a ribosome, an energy system, and proofreading. The transition to the DNA-protein world requires the very loops the hypothesis was meant to avoid.

DNA packing in a prokaryote

Even the simplest cells solve engineering problems of scale.

• Where the DNA lives. Bacteria and archaea have no nucleus. Their DNA sits in a region called the nucleoid, usually as a single circular chromosome. Many also carry small extra DNA circles called plasmids, which can carry genes such as antibiotic resistance and can be passed between cells.
• How much is packed. The chromosome of E. coli, if stretched out, is roughly 1.5 millimetres long. The cell itself is only about 2 micrometres long. The DNA is therefore on the order of a thousand times longer than the cell that holds it.
• How it fits. The DNA is coiled and supercoiled, folded into loops by DNA-binding proteins, and managed by enzymes (topoisomerases) that adjust the twisting so the molecule stays compact without tangling, while still being accessible to be read and copied.
• A point of comparison. Packing is not trivial: the cell must store its genome tightly and unpack exactly the right stretch on demand. Some cells dispense with the problem altogether: mature human red blood cells lose their nucleus as they develop and carry essentially no DNA, which is why they cannot divide or repair themselves.

Packing is itself performed by proteins encoded in the DNA being packed, another small instance of the loop.

Multiplied odds and the Universal Probability Bound

The minimal cell matters for probability arguments because independent requirements multiply.

• Borel's bound. The mathematician Émile Borel proposed that events less probable than about 1 in 10^50 should be treated as not happening on a human or earthly scale.
• Dembski's bound. William Dembski's Universal Probability Bound is 1 in 10^150, derived from the number of particles in the observable universe, the maximum number of state changes per second, and the number of seconds since the beginning.
• One protein. As reported by Meyer, Douglas Axe's experimental work estimated that roughly 1 in 10^77 amino-acid sequences 150 residues long will produce a specific functional protein fold (Darwin's Doubt, PDF p. 235). See Protein Sequence Space Argument.
• Debate precision. A single protein at 1 in 10^77 crosses Borel's line but not Dembski's 10^150. Citing one protein against the universal bound is an unforced error. But two independent proteins of that rarity give 1 in 10^154, already past the universal bound, and a minimal cell needs hundreds of proteins, plus the RNAs, the membrane, and the code to tie them together, all at once.
• Avoid the word "impossible." In mathematics an event of non-zero probability is not impossible. The accurate claim is that chance is not a credible explanation.

Honest limits

• Critics dispute Axe's figure, arguing that functional sequences are more common than his experiments indicate and that natural selection is not a single random draw. Note, though, that selection cannot operate before there is a replicator, which is exactly the minimal-cell situation.
• Critics call Dembski's bound arbitrary. Its components are physical maxima, so it is generous to chance, not stingy.
• Multiplying probabilities assumes the requirements are independent. Origin-of-life researchers hope for chemistry that links them; the burden is to show such linking chemistry, not to assume it.

Apologetic engagement

The minimal cell is where the Specified Complexity Argument, the Information Argument for Design, and Irreducible Complexity meet the origin-of-life question. Before natural selection can do anything, an integrated, information-rich, self-reproducing system has to exist. Meyer states the positive inference:

For this reason, the discovery of digital information in even the simplest living cells indicates the prior activity of a designing intelligence at work in the origin of the first life. (Stephen C. Meyer, Darwin's Doubt, PDF p. 6)

The argument does not rest on what science has not yet found. It rests on what is known: that systems in which information directs machinery that in turn reads and copies the information are, in every case where their origin is observed, products of mind. ris3n's paper Abiogenesis Under the Microscope develops the probabilistic case at length.

Scripture names God as the one who giveth to all life, and breath, and all things (Acts 17:25), and says his everlasting power and divinity are clearly seen, being perceived through the things that are made (Romans 1:20). The smallest living cell is one of those things.

See also

• Abiogenesis, parent concept hub
• RNA World, the main naturalistic reply to the chicken-and-egg loops
• Universal Probability Bound, why multiplied requirements matter
• Specified Complexity Argument, the formal design inference
• Protein Sequence Space Argument, the rarity of functional proteins
• Genetic Code, the code the synthetases implement
• DNA, the information store
• ATP Synthase, the cell's rotary power plant
• LUCA, the reconstructed last universal common ancestor, already a complex cell
• Law of Biogenesis, life from life in every observed case
• Biogenesis Argument, the argument built on it
• Irreducible Complexity, interdependent parts as a design signature
• Information Argument for Design, information as the mark of mind
• Miller-Urey Experiment, the classic first step that stopped far short of a cell
• Douglas Axe, source of the protein-fold estimate
• William Dembski, author of the universal probability bound
• Eugene Koonin, minimal-genome researcher and critic of naive origin-of-life scenarios
• Stephen Meyer, leading design theorist on the origin of life
• 100 Questions for Evolutionists, which presses the minimal-cell question in debate form