and how we can observe, detect and measure the world Scientific tools are our lenses, sensors, amplifiers, separators, accelerators, and dataprocessers—vast extensions of our eyes, hands and minds. Without them, most of the universe would remain invisible and unknown. With them, we can see living cells, weigh single atoms, edit genes, detect black holes, experiment with medical treatments and model climate systems. Our best methods and tools are the foundation of science. But how do our best tools exactly expand the boundaries of discovery? Let us look at the top ten methods and instruments most used to trigger nobel-prize discoveries. Optical and electron microscopes, x-ray methods and spectrometers vastly extend our visual scope: revealing unimagined worlds of microorganisms, cells, protein complexes and galaxies. Statistical and mathematical methods massively expand our cognitive capacity to reason across vast amounts of data: whether mapping how diseases spread, reconstructing past climate conditions from ice cores or modelling human behaviour. These few general methods and tools are the most universal ones in sparking discovery: each one is used across physics, chemistry, medicine and biology. Then there is chromatography, electrophoresis and centrifuges that give us the power to isolate substances and better understand them—from proteins and DNA to viruses. Particle accelerators and detectors let us collide and track matter at the smallest scales—and peer into the fundamental building blocks of the universe. Lasers give us astonishing precision to measure ultrafast interactions in matter, probe the structure of molecules and calculate vast distances in deep space. Each time we expand our toolbox with a powerful new method, our horizon of possible discoveries moves. As we work through the book, we will dig deeper into the power of these extraordinary tools. Our powerful tools are a core defining feature of a field. It is difficult to imagine physics without particle accelerators, mathematical methods, lasers and spectrometers. Or biology without microscopes, centrifuges and controlled studies. Or economics without statistics, algebraic equations and equilibrium analysis. Or astronomy 34 T HE ENGINE OF SCIENTIFIC DISCOVERY without radio and space telescopes (Appendix Figure 1.7). So why do some tools transform science more than others? It is because impactful tools are much better at extending our sensory and cognitive range: giving us greater resolving power, higher sensitivity, more computational strength, greater statistical power and entirely new measurement domains we could not reach before. That is when deeper layers of nature become accessible to us. Take x-ray instruments—among the most transformative tools of discovery that science has. In fact, the first year the Nobel prize in physics was awarded to the German Wilhelm Röntgen for discovering x-rays. In 1895, Röntgen stumbled on a breakthrough observation: he saw an image of one of his keys on a photographic plate he happened to place next to a discharge tube (a Crookes tube) that was developed in 1875. It was the discharge tube that generated the unexpected image. When he took an exposure of his wife's hand, her bones and wedding ring appeared starkly on the plate; she reportedly said: 'I have seen my death' . He immediately published the finding. This landmark discovery triggered a cascade of breakthrough developments: from x-ray diffraction in 1912 and x-ray crystallography in 1913 to improved xray telescopy in 1962 (Figure 1.1). Over 20 nobel-prize discoveries—across medicine, chemistry and physics—have been uncovered with x-ray instruments. What is striking is that using x-ray tools to spark a number of discoveries was not intuitively clear before we had these tools—from uncovering the inner architecture of viruses to revealing the structure of ribosomes and cholesterol. The lesson repeats: before the tool, these worlds were largely hidden; after the tool, they became data. Box 1.2 How Max von Laue developed x-ray diffraction—triggering advances in chemistry, physics and biology X-ra y diffraction and crystallography opened a new window into matter—and represent another one of the ten methods and tools most used to make nobel-prize discoveries. The remarkable technique would go on to unlock the structure of proteins and viruses. It began with the German Max von Laue. What inspired him to invent the method? Von Laue said that after he joined the University of Munich, his interest was constantly drawn on by 'the influence of Röntgen's work at this University and subsequently by Sommerfeld's active interest in X-rays' . These strange, invisible rays could pass through flesh—but what exactly were they? It was in 1912, at the age of 33, when von Laue conceived the method—and he discussed it with his colleagues while on a skiing trip, but they were sceptical. Yet von Laue went ahead with the design and worked with two technicians at the university, Friedrich and Knipping. X-ray diffraction is surprisingly straightforward: shine a beam of x-rays through a copper sulfate crystal—and then record the pattern they create on a photographic plate. What it revealed was stunning: a pattern of spots in circles ( Picture 1.3 ). These diffraction patterns offered the first proof that x-rays are waves—not particles—and that crystals have regular, repeating atomic structures. It marked the creation of a new method that could reveal the structure of matter itself. S Picture 1.3 X-ray diffraction pattern from a crystal. Reproduced from Nobel Prize 1914. The x-ray diffraction instrument he developed is simple: an x-ray tube on one side (the left), a small crystal in the centre, and a photographic plate on the other (the right)—as seen in Picture 1.4 . These materials were purchased at low costs. It was yet another case of science's most important methods and tools designed without large funding or a large research lab. Scientists quickly recognised the importance of this exceptional method—and he received the Nobel prize just two years later, in 1914. This method immediately opened the way for William and Lawrence Bragg's research on new techniques for analysing crystal structures with x-rays. The techniques spurred new fields like x-ray crystallography, x-ray spectroscopy and molecular biology—and sparked a series of breakthroughs in organic and inorganic chemistry. William and Lawrence Bragg then received the Nobel prize in 1915 for extending these essential x-ray methods. Today, these tools are still at the cutting edge—used to design new materials, study batteries and semiconductors— and even model protein structures for drug discovery. Picture 1.4 Laue's instrument, 1912. Reproduced from Eckert 2012. Some of the most powerful tools in science are not designed for the fields that end up using them most. Breakthrough methods are often born in one corner of science, are adopted and then spark breakthroughs in entirely different disciplines. What is fascinating is how this happens in ways the original inventor never predicted. Lasers and particle accelerators for example were initially rooted in physics, but they also drive discoveries in chemistry—while they are even applied in biology and medicine. Today, they are used to manipulate biological cells, treat cancer and even guide eye surgeries. Both medicine and chemistry use for instance chromatography, the PCR method and blotting techniques to separate and transfer 36 T HE ENGINE OF SCIENTIFIC DISCOVERY proteins or DNA—and these methods are even used in forensic science and environmental testing. Both physics and medicine employ for example cathode-ray oscilloscopes and counters to measure radioactivity—whether for cancer treatment or nuclear experiments—and they are even used in environmental science and biochemistry. Such widely used tools spread across a shared interdisciplinary methods space—a web of methods and tools that link fields together (Appendix Figure 1.8). Chemistry, medicine and biology share the most tools, followed by physics and chemistry. The scientific community is largely a tightly knit method community. In fact, the scientific world is far more unified by shared tools than most realise. While theories can differ across fields, methods often move between and across them. This points to a key insight: a method or tool can often be the key unifying thread across discoveries and fields, not just theory. This becomes clear looking at how highly interdisciplinary tools—like electron microscopes, x-ray methods, spectroscopes and Geiger-Müller counters—are each leveraged to trigger discoveries across physics, chemistry, medicine and biology, like no theory can. Yet economics and social sciences largely only share statistical methods with other fields. Take the radiocarbon dating method—invented by the American physical chemist Willard Libby in 1949 at the University of Chicago. What is radiocarbon dating and how does it work? The method is simple: carbon is a component in biological organisms—including all living animals and plants—and when an organism dies, the carbon-14 content decays at a constant rate; and that is used to measure how much carbon-14 remains in a sample—and to determine its age. To develop the method, he used a Geiger counter, a detector for measuring radioactive decay originally invented in physics. Libby's ingenious method enables us to measure the carbon-14 content of bones, wood, fabrics and fossils—and establish their age with unprecedented accuracy. Libby published the breakthrough method in a paper in Science titled Age determination by radiocarbon content: world-wide assay of natural radiocarbon. His technique offered something archaeologists had only dreamed of: a clock for prehistory. It earned him the Nobel prize. Before inventing it, we were heavily constrained in estimating the age of organic material—it was often guesswork. After it, we had reliable data. For the first time, we could date human settlements, extinct animals and climate changes going back tens of thousands of years—with astonishing precision. Nothing has been more important than this method in developing the fields of archaeology and earth science—and reconstructing the history of our species on our planet. Theories and grant funds have not had as much impact as this simple but essential tool across these domains and discoveries.
When we think of discovery, many imagine a researcher using an existing dominant scientific method or tool. Here we dig deeper to ask: what are the actual channels through which our innovations in tools spark breakthroughs? Examining S the over 750 discovery-making studies, we find that breakthroughs do not emerge from conventional methods. Instead, they can be categorised into one of three pathways: • method-to-discovery by the discoverer : a researcher develops a new method or tool themselves that they use to make the scientific discovery. • method-to-discovery by another researcher : a researcher develops a new method or tool that another researcher applies—sometimes in an entirely different field—to make the scientific discovery. • method-to-method by the discoverer: a researcher develops a new method or tool that is the major discovery itself, and does so by building on other methods. Across all nobel-prize discoveries, these three pathways account for 25%, 47% and 28% of discoveries (Figure 1.4). Discoveries are thus not just experimental or theoretical, but 28% were awarded for a method breakthrough (149 times out of all 533 nobel-prize discoveries). So how does this breakdown give us a deeper picture of how science works? It helps understand not just where innovation starts, but how it happens and spreads. The first pathway—where the discoverer makes both the needed method and the discovery—highlights how tool innovation directly spurs breakthroughs. And this strategy is rare in conventional research. Take the experimental physicist Kamerlingh Onnes—who developed an improved liquefier in 1906 along with a sensitive thermometer in 1907 for measuring temperatures as low as absolute zero. Using these tools, he discovered liquid helium in 1908 and superconductivity in 1911—the surprising phenomenon where certain materials, when cooled to extremely low temperatures, conduct electric current with zero resistance. Superconductivity did not just advance physics—it changed technology. Today, it powers instruments from magnetic resonance image (MRI) scanners in hospitals to particle accelerators and quantum computers. Then there is the father and son duo, William and Lawrence Bragg—who designed an x-ray spectrometer in 1912 that enabled them to discover the structure of crystals just a year later. Their groundbreaking paper The reflection of X-rays by crystals published in the Proceedings of the Royal Society led to the spread of x-ray crystallography. Crystals, after all, make up an important building block of part of our world—they are in the ice, table salt and sugar we consume. By studying crystals, we can understand the structure of compounds and how the biomolecules of our muscles and bones function. John Vane, a pharmacologist at the Wellcome Research Lab in England, devised a new bioassay technique in 1964—called cascade superfusion, allowing scientists to study how drugs interact with live tissues in real time. He used his technique to make a life-saving discovery in 1976: prostacyclin, a molecule that prevents blood clots. The breakthrough explained how aspirin works—the most used drug in the world to alleviate pain—and it helped shape modern cardiovascular treatments. Moore and Stein, at the Rockefeller Institute, invented the first automatic amino acid analyzer in 1958—a device that could analyse proteins faster and more precisely than ever before. Later that same year, they used their 38 T HE ENGINE OF SCIENTIFIC DISCOVERY device to discover the chemical makeup of ribonuclease, a molecule that breaks down RNA. RNA is the molecular messenger that turns DNA into proteins— essential to nearly every function in our body. Each of these scientists earned a Nobel prize for their discovery. In short: many great discoverers do not wait but invent entirely new methods as part of the scientific process—or methodological process of discovery. These discoverer-inventors identified the missing methodological link: building the instruments that make it possible to find new answers. The second pathway we have seen throughout the chapter—a researcher uncovers a discovery using a method another researcher invents. Then there is the third pathway—where the new methods are the discoveries themselves. Again, method breakthroughs (like experimental and theoretical breakthroughs) build on other methods and tools. Method discoveries are remarkably common in some fields: 39% of all nobel-prize discoveries in physics and 36% in chemistry have been awarded for developing a major new method or tool, with medicine and biology at 10% (Figure 1.4b). Take frequency comb spectroscopy, created in 2000. This laser-based technique lets scientists measure light frequencies with extraordinary precision— for example when searching for earth-like planets. The RCT method for poverty alleviation introduced in 2003 enables measuring how effective government policies are. An advanced single-molecule microscope invented in 2006 made it possible to track and image how proteins fold, how viruses invade cells and how drugs interact with receptors—through super resolution. The breakthrough genome-editing technique CRISPR developed in 2012 gives us the extraordinary ability to modify the genes of living organisms and offers us hope for curing inherited diseases. In fact, the share of these method discoveries has been rising over time (see Figure 1.4a). The time around the 17th century, when some of the most foundational scientific tools were born, marks an exception—and we will explore that in detail in Chapter 7. A striking finding emerges: discoverers are unique in realising—although only for an individual discovery—how to better study a phenomenon with new methods they develop along the way. Some develop a better method or tool they used (pathway one), others make a breakthrough method itself (pathway three). When combined, the two apply to about half of all nobel-prize discoveries (53%). These incredible researchers did not wait for others, they grasped the extraordinary power of improving the way they perceive and measure the world to catalyse discovery. They built lenses, detectors and models needed to find the answers. In chemistry, physics and astronomy, this combined number is higher—more than 60% of discoverers. It shows how powerful it can be when we see not just a problem—but a better way to measure or explore it. It is also a strong sign that science is not just idea-driven or theory-driven—it is tool-driven. So two key strategies we have to gain knowledge in science are: by tracking changes over time (historical analysis) and comparing different groups in a population to spot differences (comparative analysis). Just studying part of a population at one point in time offers one part of the evidence. When we analyse both, we can uncover the bigger picture: how discovery differs across time and fields (Figure 1.4). 28 3 69 23 32 45 12 29 59 16 31 53 24 23 53 28 25 48 44 39 17 0 20 40 60 80 100 Percentage of all discoveries <1600 1600–1699 1700–1799 1800–1899 1900–1949 1950–1999 2000–2022 Evolution of science: all major discoveries over time Discoveries are the new method/tool (method discoveries) Discoveries made using method/tool developed by discoverer Discoveries made using method/tool developed by others 10 27 63 18 47 35 31 12 58 36 30 34 39 22 38 0 20 40 60 80 100 Percentage of all nobel-prize discoveries medicine/biol astronomy econ/social chemistry physics Contemporary science: all nobel-prize discoveries - by field Discoveries are the new method/tool (method discoveries) Discoveries made using method/tool developed by discoverer Discoveries made using method/tool developed by others Figure 1.4 The three pathways of how new methods and tools drive new breakthroughs—across time and fields The data reflect science's 761 major discoveries (Figure a)—and all 533 nobel-prize discoveries (which we can think of as a measure of contemporary science) (Figure b). Here we expand the analysis across these five fields in Figure b to include major non-nobel discoveries made over the same time period—bringing the total to 633 discoveries. The results are similar: the share of method discoveries for example is 9%, 12%, 28%, 35% and 36% (left to right). This consistency suggests that the pattern is not just driven by nobel-prize discoveries, but reflects a broader dynamic across contemporary science. 40 T HE ENGINE OF SCIENTIFIC DISCOVERY Box 1.3 How Kary Mullis created PCR—a simple method that transformed medicine, genetics and biochemistry We now move from the broad patterns that connect diverse discoveries to zoom in on one of the most powerful methods used by almost all scientists studying genetic material: the polymerase chain reaction (PCR) method. During the global coronavirus pandemic, PCR tests became a term familiar to people worldwide—and many of us have taken them to test if we had the virus. The method was invented by the American Kary Mullis. In 1979, Mullis joined the biotech company Cetus in San Francisco, where there were several biotech firms and research groups working on improving methods for DNA synthesis. His lab used an instrument that turned out short DNA strands (oligonucleotides) faster than they could be used. This research environment provided him inspiration for creating faster ways to copy DNA. In 1985, Mullis—at the age of 41—conceived the PCR method, reportedly while driving in the Californian mountains at night. In his words, during the long drive, 'I stopped the car … found some paper and a pen. I confirmed that two to the tenth power was about a thousand and that two to the twentieth power was about a million, and that two to the thirtieth power was around a billion, close to the number of base pairs in the human genome' . Back in the lab, he ran experiments to see if it worked—applying the Southern blotting technique developed in 1975, together with other methods such as electrophoresis, DNA annealing and a centrifuge. He was successful. Mullis published the findings in the journal Science. The experiment proved that he found a solution to one of the biggest problems in DNA chemistry. Here is how PCR works: take a DNA sample—from blood or saliva for example—and apply heat to separate the two strands, and the fragments bind to each strand, and an enzyme called DNA polymerase begins building new DNA strands. With each cycle, the amount of DNA doubles. Repeat the process, again and again, and we have millions—or even billions—of copies in a few hours (Picture 1.5). As Mullis points out its simplicity, 'The reaction is easy to execute: it requires no more than a test tube, a few simple reagents and a source of heat' . In fact, the PCR method is so simple and cheap that Mullis initially struggled convincing his peers of its value. The cost of developing this simple but extraordinary method was less than a few hundred US dollars. PCR is now applied in medical diagnosis to detect diseases like HIV infections or identify genetic disorders and even in palaeontology to retrieve DNA from fossils of extinct animals. We also use PCR in police investigations to analyse the DNA of a drop of blood or a hair strand. After creating PCR, Mullis soon left Cetus— receiving a 10,000 US$ bonus for discovering the new method. The company later sold the rights to PCR for 300 million US$. Yet in 1993, Mullis was awarded the Nobel prize—and then turned to his passion, writing. As we uncover with other cutting-edge methods across science, the PCR method is just another example of how we make low-cost but major new methods and discoveries. S Chemically synthesised DNA fragments Many millions of copies of replicated DNA obtained Picture 1.5 The PCR method. Reproduced from Nobel Prize 1993a.