Regenesis (27 page)

Possibly predating agriculture were dense populations of animals, minerals, or vegetables that hunter-gatherer tribes concentrated and then began to trade and protect their resources. Advantages of concentrating people and their material goods included the scaling of construction—for example, the number of people within a walled enclosure goes up with the square of the material to build the wall. As the density of such wealth grew, so did civil engineering of buildings, walls, boats, and bridges. This required the invention of measurements of length, weight, and cost. The consequences of poor measurements could be fatal. The misalignment of a wall could result in the collapse of a building when tested by a storm or invaders. Ancient architects are said to have been required to stand under their arches when first load-tested. More recently, in 1999, the $328 million Mars climate orbiter mission failed due to the use of incorrect units of force (pound-force vs. newton).

The unwelcome consequences of the second industrial revolution and the resulting abundance included diseases of crowding. Cholera is caused by the gut bacterium
Vibrio cholerae
found in contaminated drinking water. The chance of such contamination rises sharply with the density of people and is fairly rare in other animals. Similarly,
Yersinia pestis
, the
causative agent of black plague, depends on high concentrations of grain, which bring rats, which in turn bring the fleas that harbor the plague organism. This phenomenon is often associated with two waves of plague, the Black Death, which spread from China to Europe between 1330 and 1360
CE.
The first documented instance of a plague epidemic occurred in 1200
BCE
, around the time that the Philistines stole the Ark of the Covenant from the Israelites and then returned it (possibly thought of as a means of escaping a curse). A recurrence of the plague in 540
CE
, in Ethiopia or central Asia via Egypt, spread by ships and caravans of the Emperor Justinian, killed as many as 100 million people. In the Middle Ages another 75 million died (roughly 50 percent of many European villages). Another 10 million died in Asia in 1885
CE.
Gabriele de'Mussi's contemporary account of the 1346 siege of the Crimean city of Caffa (currently Feodosia, Ukraine) describes Mongol soldiers catapulting plague-ridden Mongol corpses into the double-walled city, and constitutes one of the first documented instances of biological warfare.

Malaria arose from expanses of stagnant water in rice paddies and other irrigated crops. Celiac disease (a failure to digest food caused by a hyper-sensitivity to gluten in the small intestine) arose when wheat became plentiful in our diet before our genome had a chance to adapt—or more accurately stated, before those adaptations had spread to all wheat eaters. The convenience of monoculture crops brought with it monoculture pests, like locusts. Plowing removed meter-thick roots that fought erosion. The use of plants lacking nitrogen-fixing bacterial ecosystems resulted in soil depletion and the need to fertilize. Fertilization, in turn, resulted in runoff into ponds with consequent blooms of microbes, which consume so much oxygen that fish can't survive. So they go belly up.

The switch to agriculture had several further consequences. Whereas hunter-gatherers existed in small, mobile, roving bands, early farmers lived near their fields in order to protect them from predators and plunderers, as well as to harvest and process crops. Harvesting, in turn, required the
development and use of new tools and implements such as plows, sickles, and milling and grinding stones. Houses, community centers, and then villages, towns, and cities arose near these fertile areas. These city inhabitants led more sedentary lives than their hunting and gathering forebears. Social life became more complex, structured, and hierarchical than ever before.

Farmers often grew more food than they could use, which led them to develop storage vessels, bins, and storehouses. More important, the accumulations of foodstuffs prompted the early farmers to trade with other people, which helped create a working economy and led to new concentrations of wealth.

Further, whereas hunter-gatherers tended to exhaust the resources of a given region and then move on to the next, only to despoil it, the early farmers actually improved and increased the yield of a given piece of land through cultivation and irrigation. Instead of merely letting wild plants resow themselves wherever their seeds happened to fall, the farmers preferentially sowed seeds of plant types that were hardier, bore more fruit, were better looking, tastier, or otherwise viewed as more desirable than lesser species. This was a form of artificial selection, a favoring of one sort of plant type over another, and of increasing the numbers of the favored plant at the expense of those considered to be less attractive.

The domestication of plants and animals that occurred during the Neolithic era has clear parallels to synthetic biology—the attempt to domesticate microbial, plant, and animal genomes, including those of humans. Synthetic biology has progressed in three distinct phases. The first was the era of genetic engineering or basic biotechnology. Starting in the 1970s, this was the time in which researchers “domesticated” microorganisms by modifying their genomes manually. They first got
E. coli
to produce insulin, erythropoietin, monoclonal antibodies, and other such substances. The tools they used to modify genomes, while seemingly advanced for their time, are nowadays viewed as more or less Stone Age devices.

The second phase of synthetic biology is a period of growth and elaboration, with commercial synthetic genomics extended to a wider set of goals such as the discovery and production of new drugs, biofuels, and
genetically modified foods. It's also characterized by the use of more sophisticated tools in the form of automated techniques and machines, and the development of novel methodologies such as the use of induced pluripotent stem cells to create a range of narrowly targeted pharmaceuticals. Doing all this successfully on a mass, industrial scale further required the invention of implements that are comparable in their way to those developed in the mechanization and industrialization of agriculture by means of tractors, harvesters, threshers, combines, automatic cow-milking machines, and the like. In both instances, it was the age of commercial mass production of the respective commodities.

A third phase of synthetic genomic enterprises is now in the making. These commercial enterprises will try to make a living out of synthesizing entire new genomes. At first glance, this may seem like an unprecedented and entirely novel development. But in actual fact, this advance, like the others we have considered, only recapitulates what nature had already done. Nature, after all, was the pioneer genome synthesizer. Nevertheless, if and when we can duplicate what nature has done and create a new genome with never before seen functionality from scratch, then we might finally be in a position to claim that we really know and understand how life works, from the molecules up.

The immense impact that agriculture had on social complexity is paralleled by the impact of molecular technologies on the life science industry. In the Neolithic, the simplicity of spears and fire gave way to oxen pulling wheeled carts on roads, to food and seed storage, irrigation, and so on. In like manner, the simple elegance of the dawn of molecular biology can be seen in our ability to sketch out the essentials of the genetic code merely by looking at phage plaques on a petri plate and then binding oligoribonucleotides to ribosomes. That has changed beyond recognition.

Biotech research has since followed an amusing downhill path of “progress.” In the early days, organismal and molecular biologists would compete with each other to enact hands-on feats of bravado, toughness,
and self-reliance. They would hunt and gather in extreme, hostile locales (from snake-ridden jungles to biosafety fume hoods full of radioactive mutagens); they would stop whirring centrifuge rotors with their bare hands, make their own enzymes, and work with high levels of radioisotopes straight out of a nuclear reactor. Toiling for a couple weeks to make a single enzyme, however, people soon realized that it was just as easy to make enough to last them and all their friends a year as to make a batch that would last one person for a week. In the mid-1970s this realization prompted small companies, such as New England Biolabs and New England Nuclear, to make enzymes used for recombinant DNA and for labeling reagents. That development was similar to an earlier trend for making and supplying long lists of chemicals to researchers, for example, by Sigma and Aldrich (which merged in 1975).

So the next generation of biology students got lazier and less in touch with the basics underlying the synthesis of the enzymes and the chemicals and reagents; instead of making them, they purchased them (while the old-timers moaned). The next step in the devolution was the idea of kits. Researchers found that they had large collections of expensive stuff that failed to perform as expected. This could have been due to generally bad protocols and lack of training, for example. But the solution that appealed to companies was the idea of selling kits—a set of enzymes and chemicals (often including an exotic ingredient known as water) that were individually necessary and jointly sufficient for success at a common lab task, and all of it was attractively packaged and presented.

Big hit! Researchers suddenly became more productive, which meant more sales . . . and eventually repetitive stress syndrome.

Another next step in the evolutionary degeneration of lab researchers was “instruments.” The kits could lead researchers by the hand, as it were, but human errors were still possible: why read that fat manual anyway? The solution this time was to take the human out of the loop. Translate the manual into robot code. And while we're at it, have the robot use ninety-six pipettes instead of just one, so that ever more enzymes, chemicals, and reagents are needed. Lewis Carroll's Red Queen comes to mind: “Now,
here
, you see, it takes all the running you can do, to keep in the same
place. If you want to get somewhere else, you must run at least twice as fast as that!”

But then a proliferation of competing instruments, combined with high capital costs, steep learning curves, downtime, and rapid obsolescence led to even higher levels of stress than before. This time the inevitable solution was “services.” Centralized core facilities would own and operate the expensive machines and employ professionals (the priesthood) to maintain and upgrade the machines. This led to a deluge of data (and a need for bigger grants). But how would we handle all of this data? By building databases. Finally someone noticed that building a database wasn't the same as interpreting the data, and so we now have informatics services, cloud computing, and whatever else is out there on the horizon.

So in summary, the descent of man (the devolution of research persons) went like this: (1) DIY. (2) Buy parts. (3) Buy kits. (4) Buy machines. (5) Buy services. (6) Buy interpretation. This was “progress.”

As noted earlier, commercial synthetic genomics needed its own new set of tools, and so in 2004, nine biotechnology-minded scientists, including Drew Endy, Jay Keasling, and myself, among others, banded together to start an informal organization—the BioFab Group. By emulating the engineering practices that made silicon chip technology so successful, we hoped to make biological engineering into an equally revolutionary enterprise. What had hitherto been called genetic engineering, we were convinced, was not really engineering in the true sense of the word. Engineers normally had access to an ordered supply of well-defined, interchangeable, off-the-shelf parts, specification sheets, system plans, and so on. Genetic engineering, by contrast, worked largely by hit or miss, trial and error methods. It was more like an artisanal enterprise, or a craft, than an engineering discipline worthy of the name.