Irving Langmuir and pathological science: A warning for our times

It's American chemist Irving Langmuir's birthday today, so it's a good time to remind ourselves of his very illuminating and timeless warning about "pathological science". Langmuir was the first industrial scientist to win the Nobel Prize. The prize was awarded to him for pioneering contributions to surface chemistry, although he also did important research in electronics and solution chemistry. He did most of his work during the early part of the 20th century when science - especially physics and chemistry - was advancing at breakneck speed. Not surprisingly, when science advances at breakneck speed, so do its quacks. 

Langmuir took note of the many cases of fraudulent science published during the previous decades and in 1953 gave a talk about the misuses of science which he titled "pathological science". His basic definition of pathological science was "science" which tricked people into believing false results by "subjective effects, wishful thinking and threshold interactions." Not all pathological science is willfully fraudulent, but all of it suffers from a common set of pitfalls that distinguish it from solid science. One can recognize how prescient Langmuir's talk was by the fact that many of the criteria we use today for evaluating scientific results or progress and identifying scientific misconduct are elaborations of his theses.

Among the cases of pathological science that Langmuir cited were N-rays, Martian canals, UFOs and extrasensory phenomena. The list has only grown since then, and to it we can today add homeopathy, polywater, cold fusion, "arsenic bacteria", faster-than-light neutrinos and evidence of cosmic inflation. There are many causes of pathological science. Some of them are simply the result of working at the frontier of science where little is known and mistakes are easy to make, others are the result of cognitive, social and emotional biases which scientists suffer from as much as anyone else, and yet others can be the result of active fabrication.

Langmuir listed many tell-tale signs for identifying pathological science. Among these were the following:

1. The maximum effect that is observed is produced by a causative agent of barely detectable intensity, and the magnitude of the effect is substantially independent of the intensity of the cause.

Homeopathy is a classic manifestation of this particular feature of pathological science. It rests on the potent medical effects of barely detectable (and in many cases non-existent) substances dissolved in water. However, the example of "arsenic" bacteria looks at this feature from a different vantage point. In that case what the authors (who claimed that they had discovered bacteria growing on arsenic instead of phosphorus) failed to test for was traces of phosphorus that could have actually invalidated their hypothesis. 

Sometimes a causative agent of "barely detectable intensity" could in fact be valid, but even in that case its effects need to be consistent and reproducible, and there also needs to be a good theory which can support its causal connection to the phenomenon under investigation; that connection can validate the dependence of the effect on the intensity of the cause. The arsenic bacteria case failed on both counts.

1. The effect is of a magnitude that remains close to the limit of detectability; or, many measurements are necessary because of the very low statistical significance of the results.

This is a straightforward caveat against statistical insignificance. When Langmuir was lecturing the science of statistics was just coming into its own. Since then and especially in the last decade or so, mountains of material have been published on key statistical concepts and pitfalls like p-hacking, effect size, sampling bias and cherry-picking. Pioneering psychologists like Daniel Kahneman and Amos Tversky have showed how humans can be fundamentally incapable of thinking statistically. Failure to pay attention to any one of the myriad important statistical measures can deceive scientists into seeing a result where none exists. In my own field of molecular modeling, due attention to statistics has become a rallying cry for many scientists. The reproducibility crisis has turned into one of the biggest challenges to contemporary science.

That being said, one has to appreciate that scientists in some areas like particle physics are working at the very edges of statistical meaning; particles like the Higgs boson are discovered by looking at three or four sigma levels of statistical significance. In that case Langmuir's second caveat is important; you have to make many more measurements than what would be ordinarily necessary - or feasible for that matter - to confirm the effect. That is why data at the LHC comes from billions or even trillions of collisions between particles. The same goes for testing subtle effects of drugs across diverse populations.

1. Claims of great accuracy.

Solid science never tries to make claims that are bigger than what its edifice would sustain. I would think that most pathological science actually tries to keep away from proclamations of great accuracy, instead trying to skirt falsification by keeping its claims as vague and generic as possible. Astrology is a notorious example, keeping its "predictions" so vague that almost any event will "confirm" them. And yet I can also imagine practitioners of pathological science trying to dazzle credulous believers with the false veneer of accuracy. In this category I would probably place any number of health fads that allow you to lose 20 pounds in exactly 13 days, or guarantee immunity against a remarkably accurate and comprehensive list of maladies. So Langmuir is right in this regard; if it sounds too accurate, it probably is.

1. Fantastic theories contrary to experience.

This particular caveat was Langmuir's way of saying that "extraordinary claims require extraordinary evidence", about twenty five years before Carl Sagan said it. Any number of pseudoscientific phenomena will fall into this category: alien abduction, psychokinesis, the afterlife, reincarnation...the list goes on. More challenging claims are those like the ones about "arsenic" bacteria. These are at least plausible enough in principle and don't seem to violate any known laws of physics and chemistry, but given the number of conditions that need to be simultaneously satisfied in order for them to be true, they are extremely unlikely except in the face of convincing evidence.

At this point it's worth pointing out that there have been a number of theories in science, most notably in physics, that are in fact quite fantastic. Time dilation, spacetime curvature and quantum entanglement are only three of them. Yet what made these amazing creations of the mind plausible was the mathematical rigor behind them and their agreement with previous theories (relativity for instance arose from a desire to make Newton's laws of motion and Maxwell's laws of electromagnetism consistent with each other). And even then, they were regarded as hypotheses before experiment overwhelmingly confirmed them; that is why even today, in spite of the fact that they run completely "contrary to experience", we still believe these theories.

1. Criticisms are met by ad hoc excuses thought up on the spur of the moment.

I can think of no better example of this feature of pathological science than creationism and intelligent design. Come up with an objection to a creationist idea and the creationist will have an answer for it. In almost every case the answer will be non-falsifiable and so general that it will either be impossible to disprove it or it would be possible to always "prove" it because of its hollow generality. At some point your theory then becomes so wide as to accommodate every single objection and fact, and a theory that explains everything then ends up explaining nothing.

1. Ratio of supporters to critics rises up to somewhere near 50% and then falls gradually to oblivion.

This is an especially amusing and true aspect of pathological science. Usually when an improbable discovery is announced there's always enough number of believers to push hard for its plausibility and significance. Part of the reason is psychological; we actually want new, groundbreaking discoveries in science. The discovery of cosmic inflation and that of arsenic bacteria both fall in this category. I don't know how many of those who read about these believed in them, but Langmuir's estimate sounds rather reasonable. It did not take much longer then for this number to rapidly dwindle and fall to oblivion.

The political environment in the near future is almost certainly going to push its own brand of "science" on the public, even as it revels in its own version of "facts". In addition, the deluge of big data has already made it hard to separate the wheat from the chaff. All this has lowered the bar for deception and outright fraud. Only scientists can police each other and make sure that chicanery, both willful and accidental, don't become part of established scientific fact. Irving Langmuir's warning about pathological science shines as brightly as ever.

Einstein's wonderful letter to David Hilbert: A message for our times

David Hilbert (born today in 1862) was one of the greatest mathematicians of the 20th century. He made incisive contributions to a remarkable range of mathematical fields, published a best selling textbook on mathematical methods in physics, laid out a famous list of twenty-three unsolved problems which still challenge the field's practitioners and was a kind of philosophical godfather to at least two generations of mathematicians. Under his influence German mathematics reached its zenith before it was scattered apart by the rise of totalitarianism.

Perhaps less known is Hilbert's friendly and sometimes not-so-friendly rivalry with Einstein. Einstein's two most serious mathematical competitors were Hilbert and Henri Poincare. Poincare came close to discovering special relativity. Hilbert came close to discovering the equations of general relativity. Unlike Einstein, both were men of prodigious mathematical talent. Einstein's own mathematical shortcomings are well known; he had to learn most of the mathematics he needed for cracking open general relativity from friends and colleagues, most notably Marcel Grossmann.

In 1915 Hilbert came very close to publishing the equations of general relativity before Einstein did. Einstein had given a lecture in Berlin on his tentative attempts at formulating the equations. Hilbert was in the audience and doubled his efforts to find the right formulas. In the end Einstein ended up finding the correct form of the equations just a few days before Hilbert. It's quite likely that Hilbert would have gotten there first had Einstein gotten stalled for some reason.

However this story may paint a false picture of why it was Einstein and not Hilbert who ended up inventing general relativity. The short answer is that it was not mathematics but physics that was at the heart of relativity theory. Hilbert was the greater mathematician among the two, but Einstein's physical insights and visualization of thought experiments were unparalleled in the history of physics. Like a select few scientists - Feynman, Faraday and Fermi come to mind - he saw the physics first and then dragged the math behind him later. He had already viewed gravity as a field of spacetime which could be deformed and pulled by the time he started thinking about the equations. Hilbert, like more traditional physicists, tried to solve the equations first and get to the physical picture later. 

Generally speaking, truly great and successful physicists are ones who see the physical picture first, and Einstein was in the front rank of this group. Thus even if Hilbert had gotten to the equations first, Einstein would still have won the day. His 1915 paper on relativity contains not only the equations but all kinds of amazing physical insights that would lead to observations on the bending of spacetime and the expansion of the universe.

The last word belongs to Einstein, not because he was a great scientist but because he was a great human being. After the whole nail-biting race was over, he wrote a sensitive letter to Hilbert that exuded generosity, acknowledged his own flaws and sought reconciliation and friendship. 

The letter is a role model for competition and disagreement, and should be a must read in this era of political disagreement and conflict. Ultimately Einstein showed that while physics is important, being good human beings is even more important.

Gertrude Elion: Nobel Laureate, inventor of lifesaving drugs, woman in science

It's Gertrude Elion's birthday today. Below is one of hundreds of typical letters of gratitude that she received when she was awarded the Nobel Prize for Physiology or Medicine in 1988.

The prize - one of a select few recognizing drug discovery - was awarded to her, George Hitchings and James Black for the discovery of life-saving medicines for cancer, organ transplantation, viral diseases and stomach ulcers. She was only the fifth women to get it.

Elion repeatedly used to say that such letters and the saved lives of their recipients had long since made up for any formal honors or degrees that she might have lacked. One such degree was the PhD. When Elion applied to PhD programs after graduating with high honors from Hunter College in New York City in 1938, in the middle of the Great Depression, fifteen colleges refused her scholarships or fellowships because she was a woman. Until then Elion, who had been raised in a strongly egalitarian household by a generous-minded father, never thought that her being a woman would make a difference. But in 1938 in did, and Elion persisted and succeeded against such odds.

If some men held her back, others like her father, her fiancé and George Hitchings pushed her ahead. Her fiancé was a young man with a promising career in statistics whom she fell in love with as a student at Hunter College. His death due to a bacterial infection that could be completely cured just a few years later by penicillin cemented two desires in Elion: to stay married to her work and to devote her life to curing human disease and misery. Throughout her life, when she was approached by men either with proposals of marriage or bewilderment that she was a female scientist, she cheerfully dismissed such overtures and simply moved on without holding grudges; her work would speak for itself.

Elion found a job at the company Burroughs Welcome (which later became Glaxo Smithkline) by sheer chance, when her father who had seen an ad in the paper asked her to reach out to them. She asked if she could interview there on a Saturday since she was attending classes for graduate school on weekdays. Fortunately the company said yes, and fortunately George Hitchings was also working there on a Saturday.

Hitchings was interested in the application of chemistry to medicine. At that point in history, all medicines had been discovered by trial and error, with the latest example being sulfa drugs. Scientists typically sifted through thousands of molecules like dyes and petrochemicals with the hope that one of them would show interesting activity against diseased cells. Antibiotics hadn't been invented yet. Hitchings wanted to make drug discovery more rational, and his hypothesis was that one should do this by looking at the difference between normal cells and abnormal cells such as cancer cells. He had worked on nucleic acids before and he knew that cancer cells used much more nucleic acid for growth and metabolism. Why not try to look at the structures of nucleotides and modify their chemical structures in order to "trick" cancer cells into using the wrong material?

Hitchings's idea gripped Elion and she spent the rest of her life exploring its manifestations in a spectacular manner. Hitchings never held her back from going out on her own and made sure she was always listed as an author on all the important papers. There was another woman in the lab named Elvira Falcon; she was both Elion's scientific partner and opera partner, and the two enjoyed regularly watching leading operas at the Met. For some time Elion kept on working part time on her PhD, but she finally decided to forgo an official degree because the dean would no longer let her work part time; he dismissed her by saying that surely she must not be serious about becoming a scientist if she was interested in only working on her degree part time. Elion's lack of a PhD shows both the burdens of the PhD system as well as the prejudice against scientists without PhDs.

Among half a dozen others, Elion discovered at least three breakthrough drugs which were the first of their kind and which are still used in diverse areas of medicine. She was a pioneer in both chemotherapy and antiviral therapy. In 1950 she made 6-mercaptopurine which cut the rate of death from acute childhood leukemia in half. Although it brought temporary remission, it could be combined with other drugs to increase lifespan. Elion was only thirty two when she discovered 6-mercaptopurine. Much more important than the specific drug was the new paradigm she unveiled; cancer could now be attacked by looking at chemical differences between molecules used by normal and cancerous cells. It's an approach that is at the heart of cancer drug discovery even today.

Another compound made by Elion was azathioprine. Azathioprine dramatically reduced the immune response and became the first immunosuppressant. Until then organ transplantation had been a nightmare, with violent rejection of kidneys, livers and other organs dooming patients to early deaths. Azathioprine made organ transplantation possible. Doctors who used it were heralded as miracle workers and received Nobel Prizes. The icing on the cake for Elion and Hitchings was being able to see and talk to patients whose lives they had played a direct role in saving, a rewarding experience that organizations really should confer on their scientists. The third important drug which Elion discovered was acyclovir, used against the herpes virus. This drug was discovered on the same basis as the anticancer drugs, by assuming that a compound similar to that used by the virus in its own metabolism would thwart its growth. Acyclovir is still used at the frontline when it comes to fighting viral diseases, not just for herpes but also against chickenpox, shingles and other infections. I quickly benefited from it myself when I came down with chickenpox.

Elion kept on working until the end of her life and died in 1999. It is difficult to overestimate how many lives she saved with her discoveries, and the steady stream of letters of gratitude she received were the best testaments to her work. She was working in a golden age of drug discovery where relatively cheap research would yield important medicines, FDA regulations were slim and drugs could be easily tested on patients. But the powerful paradigm she unearthed will always be a model for drug discovery. Today the pharmaceutical industry has largely supplanted the logic used by Elion with random screening of synthetic and natural molecules. Perhaps it's time to again refocus on Elion's paradigm and look for molecules that are similar to those used by diseased cells and tissues. Fortunately the field of cancer metabolism and cancer immunology are partly based on such thinking. The flame that Elion and Hitchings lit is still alive and seems to be aglow with new hopes and promises.

Physics Nobel Prize winners and second acts: A rare pairing