Musings of a Cancer Doctor (2021)

genetics: geneticsSometime around 120,000 years ago, an early member of our species fashioned a set of what archeologists think were clothes-making tools. The tools, fashioned from bone, were recently excavated from the charmingly named Smugglers' Cave in Morocco. They are, as far as we can tell, the first identifiable tools specifically made to produce clothes. Things moved at a slower pace in those days, so we can safely say that had Popular Science or Scientific American been around this would have qualified as the most important invention of the millennium. If your ultimate goal as a species was to expand from your African heartland to the Eurasian land mass and beyond, then having a clothes-making toolkit certainly qualified as a major achievement. Of course, Popular Science wasn't around, nor writing, nor any oral tradition we might rely on, so we can't identify the inventor. But we can identify with that nameless person, because making new things, useful things, is what we do as a species. One suggested alternative name for Homo sapiens is Homo faber, Latin for “tool man,” or if you prefer, “man the maker.” Homo faber was sitting by a fire in Smugglers' Cave. Though it may well have been “tool woman,” not “tool man.” I have a fascination with technology. I'm not particularly handy, but tools fascinate me, as do their history. Take the humble screwdriver. The principle of the screw itself has been around a long time, first described (and perhaps invented) by Archimedes in the third century BC, at which time it was used as a screw pump to lift water from the Nile. From ancient Greco-Roman times through to around the 15th century, the principle of the screw was used primarily in olive and grape presses. Perhaps Archimedes, like many basic scientists, wasn't all that great at translating things from brilliant concept to public utility. No VC firms were around in 250 BC. The screw was a great idea stuck in mediocrity, a failure of imagination and inadequate development. Screws as fasteners didn't come into their own until late in the Medieval era, when they started being used to put pieces of armor together; basically, they were military technology. We get some sense of this in Shakespeare's Macbeth, where Lady Macbeth tells her wavering husband to “screw your courage to the sticking place/And we'll not fail.” It's an odd-sounding phrase to modern ears. Literary scholars suggest that the imagery refers to a crossbow, where a string is pulled taut by turning a wooden screw to its fullest extent, hence the “sticking place,” before firing the crossbow bolt. Screwdrivers were invented somewhere in Germany or France. Their first recorded appearance is in the Housebook of Wolfegg Castle, an illustrated DIY handbook written sometime between 1475 and 1490. As with the proto-technologists of Smugglers' Cave, we don't know the inventor. Early screwdrivers were slotted, or flat-blade. We still have them in our toolkits. Both screws and screwdrivers were little used until the Industrial Revolution, when Job and William Wyatt of Staffordshire, England, created a screw-making machine; by 1780 their 30-worker shop was making 16,000 screws a day. Screws were suddenly cheap and ubiquitous. The Phillips screw, and the Phillips screwdriver, also to be found in my toolkit, weren't invented until the 1930s. The Phillips screw, named after the American industrialist Henry F. Phillips, is now the most popular one on the planet, widely used in a myriad of industrial processes and in every home. It is the perfect industrial invention primarily because the screwdriver self-centers on the screw, something the flat-blade screwdriver could not do, and therefore does not slide off the screw on a busy assembly line. Phillips convinced General Motors to use the screw in Cadillacs, and the rest, as they say, is history. At least we know the name of the inventor. It wasn't Phillips, who bought it from an engineer named John J. Thompson. The names don't matter much, of course, but the lowly, homely—literally homely—screwdriver is a pretty good template for toolmaking by Homo faber. It began with a brilliant scientist conceptualizing (or describing or inventing: we're not sure) the screw, but for something like 1,800 years no one could think of any use for it beyond crushing grapes. Its use as a fastener required some unknown tinkerers, one of whom made the first screwdriver. Even then, it was another three centuries before anyone figured out how to make cheap screws, and yet another century before someone made the intellectual leap to the modern cruciform screw-head and its cognate screwdriver, perhaps its ultimate practical destination. Our tools evolve, often in response to our needs, definitely as part of a larger body of knowledge and experience, through progressive experimentation and tinkering, until they become so commonplace that we never give them a moment's thought. One of my favorite books is Francis Bacon's Novum Organum, first published in 1612. It outlines the agenda for the modern scientific revolution. I sometimes think that, were every other scientific textbook to disappear, and a mind-wipe cleared the scientific method from our collective consciousness, we would be fine if Novum Organum remained. I'm always surprised how few scientists have ever heard of it. The men who created the Royal Society considered Bacon's work to be the foundation stones of modern science. Bacon's work is full of pithy aphorisms. “Knowledge is power” is the best-known, though I have always liked “Nature, to be commanded, must be obeyed.” But Novum Organum is important primarily because it champions observation and experience over pure reasoning, particularly observation used to test a hypothesis. Central to this testing is our use of tools. Again, quoting Novum Organum: “Neither the naked hand nor the understanding left to itself can effect much. It is by instruments and helps that the work is done, which are as much wanted for the understanding as for the hand.” As much wanted for the understanding as for the hand. I love that phrase. When I think of what has happened to the biologic sciences during my career, and in consequence to the medical sciences, it is the new “instruments and helps” that have mattered the most. Technology is science in action. For better or worse, and sometimes both. I'm a breast cancer doctor. If I were asked to point to the greatest single advance in my field in the past 30 years, I could point to trastuzumab for HER2-positive disease, the first in a long line of targeted therapies that have transformed the disease. But I would be wrong. The real advance was a tool: monoclonal antibodies made in hybridomas. I was a resident when Kohler and Milstein created the first hybridoma, and (the innocence of those days) refused to patent the idea. By the time I became a fellow, in the early 1980s, my mentors were already discussing all the current uses: as a tool for pathologists and laboratory scientists, and as a therapeutic both in its naked form and as an antibody-drug conjugate. It took a while, but the future was implicit in the act of creation. It was the tool that created all the other tools that made progress possible. And hybridomas were just the beginning. Polymerase chain reaction (PCR) technology appropriately won its inventor a Nobel prize, as did CRISPR/Cas9 gene editing its inventors. Neither is the equal of the decoding of the double helix in terms of basic scientific discoveries. PCR was a fairly minor riff on what was already known in terms of the biology of life, a cobbling together of existing techniques. CRISPR, let's face it, is important to bacteria but not very important in human biology. It's value, like that of PCR, is as a tool. And what great, transformative tools both are, as much wanted for the understanding as for the hand. What will be the next great tool in our scientific toolkit? CRISPR was an immediate hit, as were monoclonals. Other technologies may represent slow burns, perhaps not requiring the same time scale as the evolution of the screw/screwdriver dyad, but not overnight successes either. One current technique that fascinates me is the recently described re-engineering of the genetic code to create novel types of proteins. For those of my readers who have not seen this, read either the original article by Robertson and colleagues in Science (2021; 372:1057-62) or the elegant discussion by Liu in the New England Journal of Medicine (2021;385:1045-49). The basic idea is simple yet fascinating. As we were all taught in high school biology, the 20 amino acid building blocks are the progeny of 3-nucleotide codons. There are 61 “sense” codons, with multiple codons coding for the same amino acid. This redundancy dates to some early point in evolutionary history but isn't really necessary for life. Robertson and colleagues “liberated” three of these redundant codons and assigned a new, unnatural amino acid to each. This in turn creates novel proteins that have never existed in the history of life. How cool is that? I don't have a clue where this will lead, though one immediate result is that E. coli engineered to contain “liberated” codons are resistant to viral infection, as the codons that have been liberated are no longer available for “normal” virus-induced protein synthesis. I'm not suggesting that we start CRISPRing “liberated” codons into human eggs, and indeed I have no clue whether this technology will have any practical applications, but such a clever idea is sure to appeal to the scientific wanderlust of an enormous number of molecular biologists. More to come, I suspect. I began this journey in Smugglers' Cave. Caves play an important role in the history of philosophy. Plato's allegory of the cave suggested that we are like prisoners trapped in a cave in which we only see flickering shadows of reality on the cave's wall: our senses are usually incapable of perceiving the true forms of nature, and those who escape Plato's Cave are feared and hated by those who remain behind. Bacon, in Novum Organum, was undoubtedly thinking of Plato when describing “Idols of the Cave,” our individual prejudices that keep us from seeing the world clearly. In a time where science is under constant attack by cable TV pundits, it is easy to believe Plato's sad diagnosis for the human race. But I like to think that human history is the history, not of Plato's dismal cave, nor its idols, but of Smugglers' Cave, where from the beginning progress has been driven by our ability to invent and create new tools. Those tools have, admittedly, been a mixed blessing for humanity, but our creative ability is what defines us as a species and represents our best hope for the future. Homo faber is always finding new things in Smugglers' Cave. GEORGE W. SLEDGE, JR., MD, is Professor of Medicine and Chief of the Division of Oncology at Stanford University. He also is Oncology Times' Editorial Board Chair. His OT writing experience has been recognized with an APEX Award for Publication Excellence and a FOLIO: Eddie Honorable Mention Award. Comment on this article and previous postings on his OT blog at bit.ly/OT-Sledge.George W. Sledge, Jr., MD: George W. Sledge, Jr., MD