Invisible Frontiers is an underappreciated gem of science writing, easily one of the best books I've read about biotechnology. Hall manages to capture the thrill of biological discovery and the human personalities that push at the boundaries of human understanding with a richness and complexity rivaled only in Werth's The Billion Dollar Molecule. The book is now out of print, but it is easily one of the best accounts of the early biotechnology revolution and well worth tracking down.

Hall builds his narrative around the efforts to produce synthetic human insulin, but he uses this driving action to tell the larger story of recombinant DNA technology. Beginning with the classic Boyer-Cohen experiment demonstrating that restriction enzymes can be used to insert exogenous DNA into bacterial plasmids for reproduction, Hall weaves the discovery of reverse transcriptase, the invention of Maxam-Gilbert & Sanger sequencing, the early days of DNA synthesis chemistry, and the daily electrophoresis rituals of molecular biology into the plot.

In presenting each of these technologies, Hall adeptly threads the needle by simplifying and clarifying the complex technical details, without being overly reductive. There are few popular science descriptions of my own field that I feel comfortable illuminating in this way.

Hall performed repeated, in-depth interviews with many of the central actors in the early recombinant DNA field, presenting lucid portraits of the scientists involved while refraining from either hagiography or demonization. The real characters in Hall's narrative are neither heroes nor villains, despite their sometimes acrimonious views of one another. Too often in science, even among scientists, the individuals behind the great discoveries that pushed our field forward are reduced to the stories of a few experiments, the author lists on landmark papers. Hall provides each of the players in his story a three-dimensional space to navigate, where they alternatively stumble and inspire.

Who moves science forward?

In these characterizations, Hall is one of but a few popular science writers who properly describes the collaborative, multi-disciplinary nature of modern biology, refusing to reduce the credit for recombinant DNA technology down to a lone genius narrative about a principal investigator who has gone decades without wielding a pipette. One of the most opaque facets of modern life science to the general public is that most work is performed by trainees — young, undercompensated individuals working 80+ hour weeks for minimal pay to expand the boundaries of human knowledge. Too often, these trainees are written out of the accolades that follow major discoveries as the popular press shorthands the work of a dozen individuals with the name of the principal investigator responsible for writing the relevant federal grant.

Hall spends as much, if not more time providing these trainees with space to describe their experiences than he provides to the principal investigators of early biotech fame (Boyer, Cohen, Gilbert, Goodman, Rutter). He goes so far as to include long quotes from a student produced parody newspaper out of Walter Gilbert's group and to interview a PhD student pushed out of a relevant project who could easily have been forgotten.

Hall also does an admirable job of apportioning credit, a mysteriously and needlessly finite substance akin to gold-standard fiat, **among the players involved. It would have been simple for his account to christen Herb Boyer and Robert Swanson as the true geniuses of the recombinant DNA revolution, but he rejects this oversimplification in favor of extensive accounts of the contributions of postdoctoral fellows within academia and individual scientists in the nascent industry. Ironically, it seems from Hall's account that Boyer & Swanson would be two of the characters most taken with this expansive version of history, most incensed by the counter-factual apotheosis that failed to acknowledge their colleagues.

Exposing the maw of scientific careers

In this exploration of who deserves accolades, Hall also details the exacting trajectory of careers in American academic science, aptly referring to large R1 institutions as postdoc mills. As a UCSF alumni, I am at once somewhat offended by the seeming pejorative but sympathetic to this 10,000 foot view. As has been written by those more intelligent and more experienced than I (Alberts et. al. 2014, PNAS), the issues of credit and recognition present in the insulin story arise from systemic issues in the way scientists are trained and (often not) rewarded in the American system. Hall provides a window onto these difficulties for the American public that rarely glimpses the internal machinations of the hyperproductive, hypercompetitive scientific enterprise they fund (see also: Inventing the NIH: Federal biomedical research policy 1887-1937).

I completed my PhD at UCSF in the very same Department of Biochemistry & Biophysics that serves as the setting for much of the recombinant DNA revolution. One of my labs was in Genentech Hall, a building financed in part with the spoils of intellectual property claims that emerged from the recombinant DNA revolution. The other hovered beyond the twin towers of Parnassus hospital where insulin was cloned.

UCSF Genentech Hall at Mission Bay. My former lab is on the third floor, a few hundred yards from this image. The building was financed in part by intellectual property proceeds from the recombinant DNA era.

UCSF Genentech Hall at Mission Bay. My former lab is on the third floor, a few hundred yards from this image. The building was financed in part by intellectual property proceeds from the recombinant DNA era.

UCSF Eli and Edythe Broad Center for Regenerative Medicine at Parnassus. The building is on a hill behind the Parnassus hospital due to a complex mixture of early aughts federal regulation and a 1970's era construction agreement with Inner Sunset anti-growth neighborhood activists.

UCSF Eli and Edythe Broad Center for Regenerative Medicine at Parnassus. The building is on a hill behind the Parnassus hospital due to a complex mixture of early aughts federal regulation and a 1970's era construction agreement with Inner Sunset anti-growth neighborhood activists.

It was remarkable for me to learn post-hoc that I had often inhabited the same hallways where historic arguments occurred, nodded off during an 18 hour experiment amidst the same benches, learned from many of the same people. UCSF is not always reflected well in Hall's account, and many of the criticisms he levies appear deserved given actions at the time. Nonetheless, I can't help but feeling pride in my former institution for its role in bringing about the new biological epoch.

It also seems to me that many of the interpersonal and political scars left on the Department by the insulin race had a hormetic effect. My time at UCSF was characterized by diligent mentorship, an empathetic scientific community, and a spirit of mutual discovery, seemingly far removed from the conflicts of credit and intellectual property. The conflicts of the recombinant DNA era are discussed openly as cautionary tails in the graduate training program, serving as examples of how not to build effective and mutually enriching collaboration. Perhaps a singular positive aspect to the trials of that era is that those lessons have helped build a Departmental culture that nurtures trainees and supports their independence above and beyond that provided by peer institutions.

Moonshots do not always produce direct value

I was pleasantly surprised to find that Hall's account did not end with the Genentech press conference announcing the expression of human insulin in E. coli.

Rather, Hall follows the story further, to the difficulties of manufacturing and distributing therapeutic products Genentech immediately faced. Prior to reading Hall's account, I was unaware that human insulin had few benefits over the porcine variety in production before Humulin, having myself been so taken with the thrill and beauty of the recombinant DNA approach.

This latter point is especially useful to highlight in the minds of young scientists that advances in patient care are often very distant from advances at the bench, that new technologies do not necessarily beget improvements in patients’ lives unless they are applied judiciously to the most salient, unmet needs.

In this regard, the cloning of insulin is similar to the eponymous "moonshot" that has come to dominate the lexicon of innovation. Neither landing on the moon nor cloning insulin yielded large scale, immediate value. Rather, the objectives served as a focusing instrument that expedited the development of technologies that revolutionized the capabilities of their respective fields, yielding compounding dividends in the future.