Regenesis (10 page)

A truly synthetic cell is one that we create ourselves, from the ground up. This could be a new form of living matter fabricated out of pure ingredients. Such a cell might tell us something about the original cells that arose at the dawn of life on earth. Arguably, life originated when a group of molecules and molecular structures first organized themselves into living systems, but precisely what those molecules were and how they arranged themselves so that life emerged from the mix is an open, possibly unanswerable question. Nevertheless, successfully creating a synthetic cell would represent a key advance in the understanding of living processes. For life, like a machine, cannot be understood simply by studying it and its parts; life, to be understood, must also be put together from its parts.

How then do we create a truly minimal living cell that is also genuinely synthetic? In 2006 a colleague and I advanced a proposal for the creation of a minimal cell that in addition would be a substantially synthetic living organism. My colleague is Anthony Forster, then of Vanderbilt University
Medical Center, now of the University of Uppsala, and our object was to build, from the molecules up, a chemical system capable of replication and evolution. As opposed to Venter's reductionist biology, this would be an example of
constructive
biology, the putting together of a living entity from its constituent parts.

The work would proceed by starting with the smallest molecular components and arranging them into subsystems, then having those subsystems self-assemble into larger units, and so on.

We designed our genome by looking for genes that have homologues, closely related sequences, in the genomes of several groups of organisms. The rationale is that genes that appear in many groups of organisms are somehow “required” for those species. This method, along with others from genetics and biochemistry, suggested a genome that consists of only 151 genes and is only 113,000 base pairs long. Our plan is to construct the genome, place it inside a lipid-bilayer membrane-sphere filled with the macromolecular enzymes encoded by the 151 genes and a minimal inventory of small molecules needed for life. The entire system could finally be bootstrapped into existence by the addition of synthetic ribosomes, translation factors, and other structures inspired by similar components existing in natural cells such as
E. coli
.

Eventually this approach will produce a synthetic, self-replicating, and self-sustaining minimal cell. To prevent the cell from replicating outside the laboratory, we are building into it a deliberate dependence on nutrients not found outside the lab environment.

Unlike the synthetic bacterial genome, where many genes are of unknown structure or function, the end result would be a functionally and structurally well-understood self-replicating biosystem, synthetic but nevertheless alive and well. If and when it happens, it will be a major milestone in the history of biology: civilizing, taming, and domesticating the basic processes of life. This synthetic minigenome presents a clear path to the mirror world introduced in
Chapter 1
. The synthetic minimal cell would enable the production of materials too large or otherwise incompatible with the more elaborate functioning systems of a complex cell. It also represents
our best shot at a general nanotech assembler, the dream of Eric Drexler and many nanotechnology enthusiasts since he first described it in his 1986 book
Engines of Creation
. We could then harness these synthetic minimal cells and put them to use in drug, vaccine, chemical, and biofuel development.

The Mirror World and the Explosion of Diversity. How Fast Can Evolution Go and How Diverse Can It Be?

Mirror life, including mirror humans, may sound like something out of science fiction, an outlandish concept unrealizable in practice even if conceivable in theory.

But mirror life is a real possibility, not just a flight of fancy. To convince you of this I'd like to show you how it can be created. But first we need a deeper understanding of life itself, in all of its complexity.

What, then, is life?

Erwin Schrödinger's short 1944 book
What Is Life
? inspired physicists such as Maurice Wilkins and others to establish the field of molecular biology. Schrödinger championed the idea of life as based on an “aperiodic solid,” a suggestion that anticipated DNA as the sequenced biopolymer in which the genetic information is encoded.

Many people think that life is an all-or-none, black-or-white, on-or-off, matter-antimatter phenomenon, with no in between. However, let's consider
the possibility that life is a continuous, scalable, and measurable property. Similarly, many thinkers are tempted to argue that life is “the pinnacle of complexity.” But let's consider replacing complexity with the notion of replicated complexity (which can be shortened to “replexity”), or mutual information. Two images composed of scads of random ink dots seem equally complex, equally likely or unlikely. Similarly, the atomic arrangement of two stones may seem equally complex. But if we see an image of a complex set of dots with a mirror duplication (like a Rorschach inkblot) or a “living stone” (
Lithopsjulii
), we experience the feeling that so much information is unlikely to be duplicated or transformed in a predictable manner from page to page, leaf to leaf, or cell to cell within those leaves. Two complex random patterns seem unremarkable consequences of an inorganic, lifeless world, but two complex patterns that look precisely alike are a hallmark of life.

From an information theory standpoint, we need fewer bits by far to convey an image of a grain of salt and an ice crystal than a movie of a liquid mixture of the two. The chaotically changing solution is more complex than either of the two crystals. Complexity increases with chemical randomness or entropy. Chemical systems tend to spontaneously go toward random, complex mixtures. In information science, entropy refers to the number of bits needed to transmit a complex message. Both from a chemical and an information entropy viewpoint, a living system is less complex than the solution but more complex than the crystals. It would have higher replexity than both because the living system requires more bits to describe its repeating motifs (e.g., its nearly identical DNA, proteins, and cells) than the strict and simple repeating motifs of the crystals or the disordered and weakly repeating structure of the solution. So too the chemical imperative for randomness is satisfied in the solution.

The notion of replicated complexity directly addresses seven counter-examples that have challenged previous definitions of life.

(1) Life as a growing and replicating system. Fire, then, may seem to be a living thing, as it can grow and replicate itself. It can even “evolve” to have new properties; for example, while devouring a succession of materials with different flash points (gasoline at -40 C, ethanol at 13 C, diesel at 62
C, vegetable oil at 327 C, Mg metal at 634 C). Indeed, a flame can replicate in a wide variety of environments while many endangered species can't survive even with tender loving care in a zoo. However, a flame has little long-range order and so would have a low replexity value.

(2) Replexity also removes difficulties with apparently living things such as mules (the sterile offspring of a male donkey and a female horse) that normally cannot reproduce and thus lack a defining characteristic of life: the ability to self-replicate. But mules have reasonably high replexity for three reasons. First, they have a non-zero probability of whole-organism replication. Second, their cells and subcellular components replicate. And third, they are closely related to organisms that do replicate (i.e., their parents).

(3) Life as a steadily increasing reservoir of replexity. A lone herbivore could destroy a complex plant ecosystem and then die, resulting in a net decrease in replexity. This is an average property, not a guarantee. This is analogous to the laws of thermodynamics, which describe the average behavior of vast numbers of molecules, not the instantaneous motion of a few molecules.

(4) Should life display motion? “What about a frozen animal?” you might ask. “That doesn't seem very alive.” Many complex organisms survive a freeze-thaw protocol (e.g., human IVF embryos and
Chironomous
larvae). In principle, a frozen organism could be assembled one molecule at a time with small tweezers such as those of an atomic force microscope. (This has not been done yet, but I addressed the idea of assembly from parts among the five grand challenges to vitalism discussed in
Chapter 1
and in the context of booting up minimal genomes in
Chapter 2
.) If we wanted to email a description to specify that organism reliably, we could determine the minimum number of bits needed to transmit the specifications of the organism's structure so that it would be in a living state on construction and warming. The replexity of frozen animals reflects both their origin from a replicating entity as well as probability of replicating again on thawing.

(5) Life as machines (e.g., photocopiers or 3-D printers) that make copies of unique complex objects. So far, these cannot self-replicate. We
can make “trivial” self-assembling robots that simply catalyze assembly from two (or a few) already complex, nearly functional partial robots. But here the increase in replexity due to replication is minuscule and the inherent replexity of the parts is due to life (indeed, the intelligent human life that created the partial robots). There is no real barrier to someday having 3-D printers that replicate and evolve. Indeed these properties may be useful for space missions, and due to the vast yet harsh resources, such printers could become considered more alive than all of earth-bound life combined.

(6) Life as translation from one polymer type to another (e.g., from RNA to proteins or from computer bits to DNA). How do we weigh the significance of such translation? Various precise translations are more impressive than replicated complexity. We can measure the amount of structural identity between two polymers—something called homology by computationally inclined biologists. In most living beings, the oligonucleotide AUGUUU would encode the dipeptide Met-Phe. A mutated copy AUGUUG would be called homologous to AUGUUU, while the relation between AUGUUU and Met-Phe would constitute mutual information and not homology, since those two molecules differ structurally; indeed they are related only by a translational code and a molecular machine that embodies that code. A large amount of mutual information relative to homologous copies found in comparing two objects constitutes evidence for increasingly advanced and adaptable life. In other words, statistically significant connections (indicative of causal connections) among diverse and detailed objects is one of the most impressive aspects of life (and of intelligence as well).

(7) What about the repeating motifs of geological strata or inorganic mold replication processes? We might find hundreds of mineralogically distinctive layers, some globally replicated (e.g., the iridium layers indicative of a large global dust cloud from the largest meteors to hit earth). But the precision of patterns and placement is weak (a roughly millimeter to meter scale). The fossils found in those layers can have micron-scale precision both for the surfaces of the solid “negative” molds of originally complex plants and animals and then the “positive” replica formed by inorganic
minerals replacing the decaying organic cell structures. Nearly all of the replexity in this case is due to the original replexity of the trapped living beings. And even given that, the replexity has diminished by at least a billion-fold from cubic nanometer– to cubic micron–scale replicas in the imprecise mineralization process. (Positive/negative molds and the profound idea of structural complementarity are discussed in
Chapter 1
.)