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Of Wonder and Questions

Science is a work in progress, motivated by wonder and the urge to find out and explain how things work. That is the thesis of this opinion piece by Professor Chris Packard , one of the world’s most renowned cardiovascular experts. In this article a clear message emerges about the need to step back from making premature judgments about the nature of scientific explanation. It resonates with the Sir John Templeton commentary on progress: “How little we know; how eager to learn.”

Motives and methods in scientific endeavour

On a clear night the star-filled heavens elicited wonder in the shepherd and the sage; the former wrote of his awe, the latter noted with care the precision of the movement of the constellations across the sky. Star-gazing still generates a sense of wonder, and with the enhanced senses of today – space telescopes and neutrino detectors - we learn of the history of the universe and our place in it. Archimedes wondered how to determine the volume of an irregular body and found in a Eureka moment the answer in a bath that overflowed. ‘Wonder’ describes a feature of human nature that both inspires and intrigues; is the greater mystery the vista that is set before us, or the fact that we have the capacity for wonder itself?

Wonder begets appreciation in the aesthetic sense - our ancestors and Neandertal cousins recorded on cave walls what entranced them about their world – and the desire to know more, to discover, to explore that distant horizon. A mountain range acts as both a barrier and challenge. Everest and Mount Fuji are for many natural objects of grandeur that remind us of our smallness and limitations, but for the intrepid climber present a challenge that must be met with determination and skill. Nature offers many such challenges and we strive to unlock its secrets in our restless quest for knowledge and understanding. We are capable of wonder but this is matched with an insatiable curiosity that leads to discovery. Over the centuries we have developed methods of investigating and knowing – a systematised curiosity – that incorporates rational, incremental knowledge gathering, interspersed with moments of insight and inspiration. We can appreciate the wonder of what we are seeing and accompany that with an intense desire to understand.

Of systematised curiosity, falsification and uncertainty

The workings of the natural world provoke questioning as to why things happen as they do. With the coming of Isaac Newton and the ‘scientific age’ we learned to answer these questions not on the basis of thought alone (the approach of Aristotle) but on observation, and a conviction that a rational examination of cause and effect would lead to evidence-based understanding and a secure accretion of knowledge. Modern ‘science’ is that accumulated body of knowledge based on a systematised curiosity in which we accept the discipline of the ‘scientific method’ as a robust approach to evidence gathering.

An observation is made – the apple falls from the tree, the ball rolls down the slope, people who get heart disease early have high cholesterol levels. We construct a question – does high blood cholesterol cause heart disease? And then, formulate a prediction based on this observation – if cholesterol is lowered then the risk of developing heart disease will be reduced. In the scientific method the approach is to set up the question as a negative statement ‘Lowering cholesterol will NOT lower heart disease rates’ the null hypothesis. A test (experiment) is then undertaken to disprove or ‘falsify’ the statement. Sometimes we can say, based on the result of the test, that the statement is highly unlikely to be true – we reject the null hypothesis with an acceptable degree of certainty (a greater than 1 in 20 chance in biology, three-sigma in physics) and this provides a measure of the likelihood that our original prediction is correct. That is, in science we are careful not to declare a truth, only to prove that the opposite is false. (For the record, there is now a high degree of certainty that lowering cholesterol does prevent heart disease). We can then set up the next question based on this finding and so proceed to build an evidence chain and an expanded framework of understanding. It is the ability in repeated cycles of ever-increasing sophistication to construct a question and then test it that is the basis of modern science. If we had not adopted this rigorous evidence-based approach we would still be in the era of the ancient Greeks. This refinement can take time; the study of ‘gravity waves’ postulated to exist by the theoretical work of Einstein had to wait 100 years before we could build the tools to detect them – patience is an essential virtue in science.

Some of the most important concepts for students of science to grasp are: -

First, that the outcome from an experiment, even the most convincing result, is not a just a destination but must be a launchpad to further work.

Second, that the chain of evidence going from one experiment to the next is only as strong as the level of (un)certainty at each step. This is reflected in the language that you will see used in all major scientific journals; published papers are peppered with phrase such as ‘highly likely’, ‘suggests’, ‘indicates’. Scientists are trained to be cautious in their conclusions and editors of journals enforce this with vigour! The best experiments are those where only one factor is changed so that you can be reasonably certain that the outcome is due to that variable alone (in the example above cholesterol is lowered but blood pressure etc. are kept the same), even then the language is circumspect.

Third, as much attention must be paid to the assumptions being made going into the research study as to the perceived outcome. Changing only one factor minimises the assumptions but this is not always possible in complicated studies. Scientists, therefore, will record the initial assumptions and, where known, their uncertainty and relate the outcome to this. Where there is a large degree of uncertainty about the mechanism or system under investigation, this has to be reflected in the level of confidence in the conclusion.

Challenges in understanding the natural world.

There is beauty and complexity in the natural world that evokes rightly a sense of wonder and aesthetic appreciation. In the curious, it engenders a desire to know how it comes about, especially when the focus of attention is ourselves and how we came to be the most successful species on the planet.

Biology has uncovered many complex systems that though initially challenging and seemingly difficult to understand in terms of their origins have slowly yielded their secrets with the result that we now comprehend how they might have developed. Examples from the world of mammals include the blood clotting system on which we depend when faced with injury, and the eye which as a working organ requires multiple structures to be in place to function correctly. In the case of the eye, it now clear that these light-sensing and visualisation organs have developed many times in the animal kingdom. In fact, it is a prime example of convergent evolution and a new understanding has emerged that the functional units making up these complex structures are derived by mutation (possibly following gene duplication) from components of other, existing systems. (Most proteins are made up of sub-structures (coded by multiple exons in a gene) that can often be re-used and re-purposed, and with time a derivative protein can deliver a change in function). In the microbial world, the bacterial flagellum (spinning tail) was identified as a complex structure whose evolution was hard to understand but again plausible pathways of re-purposing of protein sub-units and development from more primitive structures have been described.

For the practising scientist, the declaration that a system is so complex that it cannot have evolved presents a challenge and a conundrum. How should he or she respond to this assertion? What questions now arise that can be tested in further hypotheses – as explained above, this is the nature of scientific discovery. Can the scientific method of cycles of question setting, experimental observation, and rejection or non-rejection of hypothesis be undertaken to build a better understanding of the biological processes under study? The consequence of making a declaration such as that stated above is that it terminates further enquiry, and presents a final conclusion that virtually all scientists (regardless of their faith beliefs) would regard as unhelpful in progressing understanding. As stated above, science is the body of knowledge that has accrued by the continued and continuing application of the scientific method.

In line with the cautious approach taught to students and exercised by all professional scientists in their daily work, a statement that a mechanism (evolution) could not possibly have given the observed outcome requires that the mechanism is understood with a high degree of certainty, or the conclusion must be expressed with uncertainty limits that are a function of the aggregate uncertainties inherent in the initial assumptions. The evidence chain for biological evolution is very strong. It integrates observations and experiments from geology, comparative biology, genetics, and palaeontology. The remarkable cross-referencing studies of the fossil record and molecular genetics in particular give a high degree of certainty that our current understanding of the framework of evolution is well-founded. However, the detailed molecular mechanisms (for example of how protein sub-units can be re-used and re-purposed) are a work in progress. Given this level of uncertainty, it is arguably premature to rule out a decipherable mechanistic explanation for any of the features we see in living organisms. The examples above of convergent evolution (for more on this topic see the excellent book by Denis Alexander “Is there purpose in biology”) are illustrative of the fact that there is now a track record of the ‘improbable’, once investigated with the expanding tool set at our disposal, becoming with time comprehensible.

In this vein, it is worth making a note on the fast-moving field of genetics and the origins of the processes that facilitate the production of proteins and other cell structures. For sure, the DNA-based coding system for protein production via the intermediate agency of RNA is a complex operation within cells, and many sub-structures, proteins, and nucleic acid polymers need to be in place at the same time for it to work. Moreover, following the revelations from the human genome sequencing project, we now know the situation is even more complex than first thought with structural and regulatory features in the DNA strands, and a plethora of small RNA forms that control gene expression. We are only just scratching the surface in our understanding of these mechanisms. A wide range of hypotheses has been generated regarding the origin of these systems and their component parts, and these are being tested in labs around the world. For example, was the protein coding process originally based on RNA only and DNA was a later development? Do short RNA sequences have a natural affinity for specific amino acids and on and on ? Exploration of this new frontier is expected to yield eventually important insights into the causes of cancer and hopefully novel means of defeating diseases based on RNA viruses (to bring the discussion up to date). What is clear is that many of the basic molecular processes that are key to our understanding of the way in which the cell operates are yet to be discovered. We need patience.

Professor Chris Packard