Regenesis (book review)

George Church and Ed Regis, 2012

My father was in his mid-thirties before DNA was decoded by Crick and Watson. A generation later, genetics was still largely theoretical, understood in principle but not practical – like flying cars or space lasers. Not anymore. Today teams of high-school students modify organisms for the iGEM competition; a library of over 20,000 biological parts made of DNA sequences (promoters, translators, ends, spacers, vectors, receivers, measurement) are listed on a public site; the ability to both read and write DNA is speeding up ten times per year; and the first proof of concept has been done to resurrect an extinct species. Synthetic biology is quickly coming of age.

Pyrenean ibex – first extinct species resurrected (briefly)

The book Regenesis by the Harvard geneticist George Church and the journalist Ed Regis is technically and conceptually daunting until you get past the first few chapters. You might even have moments of existential dread. If you have never seriously considered resurrecting a species, creating mirror humans, or building a “reduced instruction set organism,” this will be a wake-up call to the possibilities inherent in our growing toolkit with the machinery of life.

A glance at the table of contents, with titles marking eras such as the Cambrian, Carboniferous, Paleocene, and Neolithic,  may mislead you into thinking that Regenesis is a standard survey of evolution. Rather than a textbook review, each chapter outlines the biological events of a period as background for introducing a particular aspect of synthetic biology. One might restate the underlying message of the book thus: if ontogeny recapitulates phylogeny, then synthetic biology recapitulates evolution.

We are in the ramp-up to a biological revolution that challenges our very sense of humanity and life itself. The slow development of genetics over the last sixty years, this long tail of an exponential curve, has lulled the scientific and general public into a false sense of security that the revolution won’t be coming for a long time. Let the next generation worry about these questions, we say. Do these invisible snippets of DNA really make a difference? And even if we understand the science, when it comes to genetics, most of us have an innate revulsion at the very thought of altering the forms of life – whether this aversion comes from our biological makeup, religious teachings, or moral considerations. A discussion about altering the human being makes us uneasy at best, angry and reactionary at worst. We push it out of our minds, put it off for another few years. Meanwhile, the curve climbs.

Twenty years ago, even ten years ago, after the Genome Project was finished, it was still possible to postpone grappling with genetics. Journalists hemmed and hawed, talked about all the work that remained to be done, noted that it cost $3 billion to get one genome sequenced. No rush. But times have changed. The last seven years have seen an explosion in the field, one that shows no indication of slowing down.

Let’s look at the pace of acceleration that synthetic biology has been going through since 2004. Until 2004 the technology (roughly, the ability to read and write DNA sequences) was keeping pace with computers, speeding up about 1.5 times per year. At that relatively slow rate of change (Moore’s Law), computer power changes a thousand-fold in ten years, a million-fold in twenty years, and a billion-fold in thirty years. Improving 1.5 times per year turned building-sized mainframes into smartphones in a single lifetime. Nothing to sneeze at.

As difficult to understand as exponential change in computer technology has been, genetics is leaving it in the dust. The speed of reading and writing the genome is increasing ten-fold in one year, which means improving ten billion-fold in ten years. (Ten the first year, then a hundred the second, a thousand the third, and so on. That reaches 1010 in ten years – which equals ten billion.) At that pace, it will speed up as much in the next decade as it took the computer industry to do in forty years. Imagine what would have happened if between 1970 and 1980, computers had gone from mainframes to smartphones, brain-mind interfaces, GPS, and the rest of the bag of today’s info-magic tricks.

The promises are astonishing, and so are the risks. One consequence that will break upon the public consciousness soon is personalized medicine (tailoring treatment to each person’s unique biochemistry, as well as to the unique characteristics of a disease). Bacteria and cancers can now be sequenced, as well as the human genome, and the optimal type of therapy determined. Looking back on today’s medicine we may consider it barbaric and random in comparison.

Being able to determine the best therapy for a specific person will be revolutionary. In psychiatry, for example, finding an effective medication is largely a trial and error process, often extending for years. Or consider common infections, like a cold, or the flu. What will health care look like 10-15 years from now if you can breathe into a tube and have your supersmartphone identify and sequence the virus, upload the data to the CDC, determine the exact strain, compare it to your unique biochemical/genomic characteristics, and in a few minutes tell you the best antiviral medication to use? “Personalized” medicine sounds obvious and folksy, like an idea that everybody always knew about (who wants impersonal medicine?), but the coming era is something entirely different.

When I was entering the field of health care in the 1980’s there was great hope for monoclonal antibodies (MoAb); they were going to be the magic biochemical bullet, a way of targeting individual cells, bacteria, and conditions. Over the subsequent years, however, MoAbs didn’t pan out. But wait. In the 1990’s “researchers… realized that it would be possible to insert enough human gene sequences into a laboratory mouse genome to create a transgenic, or ‘humanized’ mouse. … The theory was that the monoclonal antibodies derived from a humanized mouse would not be recognized as foreign by a human recipient’s immune system, and therefore would not be rejected by the body. As it turned out, the second magic bullet scheme worked,” and the FDA has approved these for “various illnesses including rheumatoid arthritis, auto-inflammatory syndrome diseases, psoriasis, and chronic lymphocytic leukemia.”

There are other esoteric branches of genomics which are speeding ahead. One of the most surprising is “DNA origami” – building structures with precision. Church writes “The only working nanotechnology right now is bionanotechnology” – and it is, in fact, starting to work.  Because the bases that make up DNA lock into each other in a fixed manner, and the process is vastly simpler than putting together proteins, the field of DNA origami has catapulted into prominence in the last five years. DNA has been built to create channels through the cell wall; to deliver small-interfering RNA (siRNA) which can be used to knock out (interfere with) any gene – in essence, regulate anything in the cell; or to create a box 18 nanometers on a side (about 1,000 times smaller than a typical human cell), for delivering drugs.

Smart DNA nano-box

In discussing the business and history of synthetic biology, Church lays out six broad engineering approaches in use. First is classical recombinant DNA, what was learned several decades ago: using plasmids to slice up and recombine sequences of DNA. Second is bio-mimetics, building structures and functions that mimic nature. Third is biobricks, creating standard components, the same plug-and-play standardization that drove the industrial revolution. Fourth is harnessing the power of evolution. Fifth is advancing  instrumentation, such as the MAGE/CAGE process described below. And sixth is engineering whole genomes.

Regenesis covers a mind-bending array of possibilities: bringing back extinct species (believe it or not, already proven through nuclear transfer cloning), creating a synthetic cell, speeding up human evolution, conferring complete resistance to HIV by giving someone a new immune system (done in 2007 – old news), or creating “mirror humans” that would be immune from every known virus and bacteria. (Unfortunately, they would also be unable to eat any food – so, would have to create a mirror ecology for them. Probably not coming soon.)

Throughout the book Church begins the discussion of each possibility, such as biofuels, with a consideration of real-world advantages and disadvantages – in the extreme, stupendous utopias and unthinkable disasters. Ultimately he applies this to the most unsettling topic of all, transhumanism. On the question whether we can engineer biological minds, he comes to a similar conclusion as Rudy Rucker. “It may turn out that many of the most interesting things to model…are already computed at high-speed by nature… for example, the folding of polymers into developing humans.” Rather than changing the form of the human body, we may more usefully engage in “individual control over [our] own body genetics and… changing traits by changing environments, drugs, and devices.” This is the voice of a scientist who loves the world. Perhaps there are efficiencies built into nature as it is, and we will do best by working with the given.

No matter what, “genomic engineering will become more common, less expensive, and more ambitious and radical in the future as we become more adept at reprogramming living organisms, as the cost of lab machinery drops while its efficiency rises, and as we are motivated to maximize the use of green technologies.” Church describes the combination of two techniques that his lab developed (MAGE and CAGE, multiplex automated genome engineering and conjugative assembly genome engineering). These methods, through automating thousands of changes at a single time, “would allow researchers to start with an intact genome of one animal, and, by making the necessary changes, convert it to a functional genome of another animal. You could start, for example, with an elephant’s genome and change it into a mammoth’s.” Then he goes on to explain how. And continues: “The same technique would work for the Neanderthal…”

The last question in the book – “Will we become a new species?” – is moot by the time we get to it. “We are already using parts from hundreds of previously separate species/kingdoms in human-induced pluripotent stem cells.” The writing is in the cell, literally. “The interspecies barrier is falling as fast as the Berlin Wall did in 1989. Not just occasional horizontal transfer [the exchange of a single gene], but massive and intentional exchange – there is a global marketplace for genes.”

As a species we have been taming and altering the physical world for 10,000 years, starting with agriculture and most recently mastering information itself, that ephemeral no-thing that connects every science, every technology. A recurring worry through history is that mechanization and standardization will erases individuality, freedom, even the soul itself. On a deeper view science is not erasing the individual, but rather expanding possibilities, increasing diversity. In What Technology Wants Kevin Kelly argues this in depth, that no technology ever becomes obsolete, and that we are headed for more diversity – that diversity is inherent in the very direction of technology itself. Church ends on a similar note: “the future promises to be replete with diversity.” And that by itself may be more valuable than “following an ever-accelerating exponential rate curve as championed in the singularity view.”

“Exponential,” “singularity,” “transhumanism” – these all sound like far-fetched, far-future, and far-out ideas, more Buck Rogers than garage mechanics. But garage mechanics is exactly where the science of synthetic biology has moved in the last few years. Three years ago two people set up a research lab in their garage in Mountain View, California, and “started doing paid anti-cancer research.” This turned into a community laboratory where “for a monthly fee of about $200 [anyone] could perform their own molecular biology experiments, everything from DNA sequencing to the rite-of-passage project of inserting green fluorescent protein genes into bacteria.”

Meanwhile the “international genetically-engineered machines” competition (iGEM), which started in 2004 with the challenge to “design and build a genetically-encoded, finite state machine” (the first step to building a general-purpose biological computer), has grown so that by 2010 it included “schemes, plans, and designs that ranged from the whimsical to the incredible, and from the trivial to serious attempts to address global medical problems by means of artfully rewired microbes.”

One team’s goal was to create microbial hard drives for storing information; another was to assist in terraforming the planet Mars by producing a yeast that would create a dark pigment, thereby raising the temperature; a third was trying to create a whole range of new antibiotics. These “powerful biological structures” were coming from “the ranks of university, college, and even secondary school students, who were doing it mainly in the the spirit of advanced educational recreation.”

The race is on. These are groups of biological engineers, students working with the tools and parts of life itself. And succeeding. The 2012 honorable mention in the high school division went to the BioScience Dragons from Arizona, who proposed working with a strain of E. coli that produces biofuel. They would force it to stop using oxygen, so that it would then start using light as an energy source for producing fuel. The winning team, from Greece, worked on increasing the nitrogen yield from bacteria in the soil – and then determined to educate the entire country, in order to increase soil fertility, help unemployment, and prepare students for the future –  as long as “people won’t fight Synthetic Biology and politicians won’t ruin the whole plan.”

Re-creation, re-genesis, the remaking of life itself. Ray Bradbury caught the essence of this vision in Dandelion Wine, the moment when twelve year old Douglas wakes to an astounding and intense revelation: “The world, like a great iris of an even more gigantic eye, which has just opened and stretched out to encompass everything, stared back at him. And he knew what it was that had leaped upon him to stay and would not run away now. I’m alive…”

Cover for 50th anniversary edition of Dandelion Wine

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