Molecular Technology Today

One dictionary definition of a machine is "any system, usually of rigid bodies, formed and connected to alter, transmit, and direct applied forces in a predetermined manner to accomplish a specific objective, such as the performance of useful work." Molecular machines fit this definition quite well.

To imagine these machines, one must first picture molecules. We can picture atoms as beads and molecules as clumps of beads, like a child's beads linked by snaps. In fact, chemists do sometimes visualize molecules by building models from plastic beads (some of which link in several directions, like the hubs in a Tinkertoy set). Atoms are rounded like beads, and although molecular bonds are not snaps, our picture at least captures the essential notion that bonds can be broken and reformed.

If an atom were the size of a small marble, a fairly complex molecule would be the size of your fist. This makes a useful mental image, but atoms are really about 1/10,000 the size of bacteria, and bacteria are about 1/10,000 the size of mosquitoes. (An atomic nucleus, however, is about 1/100,000 the size of the atom itself; the difference between an atom and its nucleus is the difference between a fire and a nuclear reaction.)

The things around us act as they do because of the way their molecules behave. Air holds neither its shape nor its volume because its molecules move freely, bumping and ricocheting through open space. Water molecules stick together as they move about, so water holds a constant volume as it changes shape. Copper holds its shape because its atoms stick together in regular patterns; we can bend it and hammer it because its atoms can slip over one another while remaining bound together. Glass shatters when we hammer it because its atoms separate before they slip. Rubber consists of networks of kinked molecules, like a tangle of springs. When stretched and released, its molecules straighten and then coil again. These simple molecular patterns make up passive substances. More complex patterns make up the active nanomachines of living cells.

Biochemists already work with these machines, which are chiefly made of protein, the main engineering material of living cells. These molecular machines have relatively few atoms, and so they have lumpy surfaces, like objects made by gluing together a handful of small marbles. Also, many pairs of atoms are linked by bonds that can bend or rotate, and so protein machines are unusually flexible. But like all machines, they have parts of different shapes and sizes that do useful work. All machines use clumps of atoms as parts. Protein machines simply use very small clumps.

Biochemists dream of designing and building such devices, but there are difficulties to be overcome. Engineers use beams of light to project patterns onto silicon chips, but chemists must build much more indirectly than that. When they combine molecules in various sequences, they have only limited control over how the molecules join. When biochemists need complex molecular machines, they still have to borrow them from cells. Nevertheless, advanced molecular machines will eventually let them build nanocircuits and nanomachines as easily and directly as engineers now build microcircuits or washing machines. Then progress will become swift and dramatic.

Genetic engineers are already showing the way. Ordinarily, when chemists make molecular chains - called "polymers" - they dump molecules into a vessel where they bump and snap together haphazardly in a liquid. The resulting chains have varying lengths, and the molecules are strung together in no particular order.

But in modern gene synthesis machines, genetic engineers build more orderly polymers - specific DNA molecules - by combining molecules in a particular order. These molecules are the nucleotides of DNA (the letters of the genetic alphabet) and genetic engineers don't dump them all in together. Instead, they direct the machine to add different nucleotides in a particular sequence to spell out a particular message. They first bond one kind of nucleotide to the chain ends, then wash away the leftover material and add chemicals to prepare the chain ends to bond the next nucleotide. They grow chains as they bond on nucleotides, one at a time, in a programmed sequence. They anchor the very first nucleotide in each chain to a solid surface to keep the chain from washing away with its chemical bathwater. In this way, they have a big clumsy machine in a cabinet assemble specific molecular structures from parts a hundred million times smaller than itself.

But this blind assembly process accidentally omits nucleotides from some chains. The likelihood of mistakes grows as chains grow longer. Like workers discarding bad parts before assembling a car, genetic engineers reduce errors by discarding bad chains. Then, to join these short chains into working genes (typically thousands of nucleotides long), they turn to molecular machines found in bacteria.

These protein machines, called restriction enzymes, "read" certain DNA sequences as "cut here." They read these genetic patterns by touch, by sticking to them, and they cut the chain by rearranging a few atoms. Other enzymes splice pieces together, reading matching parts as "glue here" - likewise "reading" chains by selective stickiness and splicing chains by rearranging a few atoms. By using gene machines to write, and restriction enzymes to cut and paste, genetic engineers can write and edit whatever DNA messages they choose.

But by itself, DNA is a fairly worthless molecule. It is neither strong like Kevlar, nor colorful like a dye, nor active like an enzyme, yet it has something that industry is prepared to spend millions of dollars to use: the ability to direct molecular machines called ribosomes. In cells, molecular machines first transcribe DNA, copying its information to make RNA "tapes." Then, much as old numerically controlled machines shape metal based on instructions stored on tape, ribosomes build proteins based on instructions stored on RNA strands. And proteins are useful.

Proteins, like DNA, resemble strings of lumpy beads. But unlike DNA, protein molecules fold up to form small objects able to do things. Some are enzymes, machines that build up and tear down molecules (and copy DNA, transcribe it, and build other proteins in the cycle of life). Other proteins are hormones, binding to yet other proteins to signal cells to change their behavior. Genetic engineers can produce these objects cheaply by directing the cheap and efficient molecular machinery inside living organisms to do the work. Whereas engineers running a chemical plant must work with vats of reacting chemicals (which often misarrange atoms and make noxious byproducts), engineers working with bacteria can make them absorb chemicals, carefully rearrange the atoms, and store a product or release it into the fluid around them.

Genetic engineers have now programmed bacteria to make proteins ranging from human growth hormone to rennin, an enzyme used in making cheese. The pharmaceutical company Eli Lilly (Indianapolis) is now marketing Humulin, human insulin molecules made by bacteria.

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