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The compass of biomedicine

2022; Wiley; Volume: 236; Issue: 1 Linguagem: Inglês

10.1111/apha.13856

1748-1716

Tomas L. Bothe, Niklas Pilz, Laura J. Dippel,

Cancer Genomics and Diagnostics

There are things so fundamentally brilliant that their implications literally reach into every aspect of our lives – mostly unnoticed and underappreciated by us and our fellow humans. Sir Isaac Newton's 1686 opus Philosophiae Naturalis Principia Mathematica is quite likely the most influential single piece of scientific writing ever produced.1 It introduced the ultimate toolbox, three simple laws, for describing and predicting the behavior of physical objects. Without Newton, there would be no car, computer, or fairly, any piece we might consider "technology." "But everybody knows Newton," you might rightfully claim. It remains questionable whether the often harrowing experiences of high school physics really do justice to one of the greatest minds of human history; or can you explain Newton's second law of motion of the top of your head? There are, however, fundamental breakthroughs that are even less subject to public appreciation. A prime example is the concept of navigation by universal directions. Determining where you are and where you need to go becomes much easier when there are well-defined points of reference. The idea of discriminating between the directions of north, south, east, and west enabled us to share unequivocal spatial information. Determining directions by using the earth's magnetic field and a ferromagnetic needle floating on water was the essential breakthrough for advanced navigation, exploration, and trade. The 11th-century Chinese are said to be the first to use such a device, called a compass, for navigation.2 Their point of reference was south, as the Chinese sea and most of the Chinese land-based exploration of the time, striving for power and wealth, was fittingly oriented south.3 Southern was a good address for exiting discoveries, at least some 900 years later. In this case, Southern was not a direction, but a scientist: Edwin M. Southern. He established a method to split up DNA via electrophoresis and detect specific sequences by hybridization – the Southern blot.4 Methods for detecting specific proteins5 and RNA sequences6 were established soon after, based on the same principle. They were named Western and Northern blot, both because of the technical similarities and out of appreciation for Edwin Southern's work. So, there it is, the almost completed compass of blotting (a method called Eastern blotting was proposed but never caught relevant traction). "Blotting" has undoubtedly revolutionized biochemistry, but how profound are its implications for all of medical science? The compass has altered navigation forever – has "blotting" done the same for biomedicine? When considering physiology, it most certainly has. Acta Physiologica caters to a wide variety of research efforts related to physiology – itself one of if not the most diverse discipline of biomedical research. Subsequently, searching recent Acta Physiologica publications for references to "blotting" should provide a reliable and lower bound estimate of the prominence of "blotting" in biomedicine. The results boggle the mind: Of the plethora of papers published in Acta Physiologica from 2006 to May 2022 (not considering Errata and conference abstracts) 26% feature "blotting," in any way shape or form. References are made to Western blotting,7 immunoblotting,8 electroblotting,9 Northern blotting,10 and so forth. 26% of articles features a single, adapted methodological principle. "Not too many" you might think? 26% of articles are more than twice the combined number of articles featuring the Nobel prize winning methods of genome sequencing11 (6%) and patch/voltage clamp12 (7%) – the latter being rightfully considered one of the showpieces of contemporary physiology. There is even more to these findings: Not only is "blotting" featured in more than one-quarter of physiology-related articles, but there is a steep trend: the number of articles featuring "blotting" is rising and it is rising quickly. In 2021, "blotting" was to be found in 31% of all Acta Physiologica articles. The share rises constantly, at a rate of about 0.7% per year – statistically underlined by a correlation of R2 = 0.60 (p < 0.001) between the year of publication and the proportion of articles featuring blots (Figure 1). Is it reasonable to extrapolate this trend to predict the future? Maybe so. Physiology surely is evolving into a more molecular science, more focused on mechanisms inside the cell than just on large, functional entities. "Blotting" had existed for nearly 30 years when the first articles included in this analysis were published. We can be adequately sure that this trend is not caused by a run for a new and exciting method everyone wants to try out. The method is trending up, for very mundane reasons: "Blotting" is cheap, by comparison easily learned, and can answer a lot of questions. Will this trend continue endlessly until Acta Physiologica will only publish articles featuring blotting almost a 100 years from now in October 2121? Most certainly not. But as of now, there is no telling when or where this trend will stop – or which technological advances or new scientific questions in the focus of research will set a limit to the influence of "blotting" in physiological research. The articles featuring "blotting" depict the broad applicability of this methodology. As expected, most featured articles are focussing (keyword in the abstract) on signaling or pathways (41%). More surprisingly, other subjects are not far behind, with muscle physiology (39%) coming in as a close second and five other subjects in double-digits (Figure 2). A closer look at the actual research questions underlines this even more: Researchers examined a plethora of topics, ranging from the influence of microbiota on the epithelial regeneration,13 or metabolic syndrome14, 15 to the reasons for modified gene expression16 or assessment of subcellular protein localization17 in skeletal muscle. Behind the praise, there are caveats, even for a method as profound and flexible as "blotting." There are a lot of possibilities for errors when performing a blot which can easily lead to fallacious or no results at all. The reasons for unwanted (due to technical errors, not wrong hypotheses) results are not always easily attained, and searching for errors can be tedious and nerve-wracking. Moreover, there are certain limitations to the questions "blotting"-techniques can sufficiently answer. For these reasons, new and exciting methods like single-cell sequencing were introduced recently and are welcomed emphatically by the scientific community, eagerly awaiting more dependable and powerful methods.18 Even more advanced technological possibilities are on the horizon, hopefully combining the low-cost and high-throughput of "blotting" with the enormous potential of single-cell or full-genome sequencing. For all our history, we as humans have had the need to know where we are and where we need to go – this is true geographically as well as it is in science: Experiments need to be planned cautiously,19 and their results interpreted competently, focusing on what really matters.20, 21 When conducting experiments in physiological research, the compass of "blotting" has been an increasing default starting point for experiments, conducted on single cells,22 organoids,23 and animals24 alike. For all its glory, it is a good idea to keep an open mind and explore the fantastic opportunities the ever-advancing technology offers. Even Newton was not entirely correct – a smart guy named Einstein figured out. His work enabled clocks to correct for the relativity of spacetime on satellites25 – building the fundament for satellite navigation. And just as modern sailors have upgraded their navigation from maps, sextants, and compasses, biomedicine will keep evolving its methods to meet the growing demands of excellent research, now and in the future. Luckily so! We thank Christian G. Schneider for inspiring discussions that led to the conception of this work. There is no conflict of interest to declare.