Long before the work of Karl Popper, the traditional scientific method relied on the doctrine of observational induction. That is, scientific theories can in some way be ‘validated’ through experimental observation, which can then be used to support some previously formed hypothesis. This can be regarded as an approach of ‘positive verification’, wherein theories are said to be true with enough experimental backing. Although at first glance this may seem to resemble the modern scientific method, the writings of Karl Popper have significantly altered the way in which the scientific community associates experimental evidence with hypotheses.
At the foundation of his work, Popper entirely rejected observational induction as a pathway to certainty. Popper believed observational induction to be a doctrine which was far too inconsistent to play a role in the natural sciences. Alternatively, Popper advocated for methods of empirical ‘falsification’, wherein scientific theories and hypotheses could only be proven to be false, rather than in any way ‘verified’ by experimental evidence. ‘Falsification’ arises when enough significant experimental data is found to confidently reject some hypothesis, thereby proving the theory from which the conclusion was deduced to be false.
Popper’s primary reason for rejecting observational induction was its reliance on the idea that singular observations can somehow be viewed to be universal. In Popper’s own words, “people who say of a universal statement that we know its truth from experience usually mean that the truth of this universal statement can somehow be reduced to the truth of singular one”. Popper argued that no scientific rule can ever absolutely be certified from a scientific observation. Regardless of the number of times the experiment is repeated with supporting data, the supported theory can never become a scientific truth.
(Note: Popper’s claim that induction only provides ‘probable assumption’ rather certain truths has notable parallels with philosopher David Hume’s argument from induction that “it is impossible to justify a law by observation or experiment, since it transcends experiment”.)
So if we can't verify scientific truths, how do we make scientific progress?
In Popper’s view, science can only progress through trial and error. Scientific conclusions can be compared with each other and experimentally tested for the “strongest” or “most withstanding” one. If a theory is compatible with experimental evidence, then the theory has, for the time being, “passed the test”. However, if the theory’s conclusion has been falsified by experimental evidence, then logically, the theory it has been deduced from has also been falsified. The scientific community hence advances to the next withstanding theory. The longer the period that a scientific model lasts without being falsified, the more likely it is to be true, even though it can never be proven as a certainty.
Popper’s work seems to shine a light on possible methodical flaws in previously established scientific theories. Psychologist Sigmund Freud, for example, was a target of Popper’s criticism, for what he labelled as “pseudoscientific” work. Freud’s theories, in the eyes of Popper, were “unfalsifiable” - they could never be disproved by new scientific evidence due to their adaptive nature. Hence, in Popper’s view, unfalsifiable theories such as those of Freud ought not to be labelled as scientific. This view can be extremely problematic for many scientific thinkers whose work cannot be conclusively falsified by experimental evidence. Crucially, this view raises the question of what we can qualify as 'science', emphasising the importance of an established and refined scientific method.
"In so far as a scientific statement speaks about reality, it must be falsifiable; and in so far as it is not falsifiable, it does not speak about reality." - Karl Popper
Popper’s work has been immensely influential in the formation of the scientific method we hold today. Whilst we may have convincing evidence for certain theories, the scientific community can never label them as absolutely “certain”. Instead, the community amends, reforms and re-tests hypotheses to the best of their ability. Theories we hold become more and more probable, but are never established with certainty. Though induction undeniably still plays a major role in the scientific method (else we could not utilise experimental evidence in our reasoning), the awareness that inductive reasoning cannot possibly establish certainty is of critical importance. Among a few other incredible thinkers (David Hume, Thomas Kuhn, etc.), we largely have Popper to thank for the advancement of the scientific method with regards to establishing certainty.
readings from -
Conjectures and Refutations by Karl Popper
The Logic of Scientific Discovery by Karl Popper
When first released in the 1950s, pharmaceutical drug thalidomide was promoted for a number of issues, including anxiety, trouble sleeping, and morning sickness. The over-the-counter medicine was initially declared “completely safe, even during pregnancy,” as its developers “could not find a dose high enough to kill a rat”. Tragically, thalidomide was found to have serious side-effects - issues such as birth defects arose in large numbers when pregnant women took the drug. The drug was quickly removed from the market in 1961, but an estimated 10,000 mothers who had already taken it experienced extreme issues in their pregnancy, and about 40% of children born died around the time of birth. Those who survived had limb, eye, urinary tract, and heart problems. This was labelled the 'Thalidomide Disaster' of the late 50s, and was a key case study used to promote stronger drug testing and regulations in the pharmaceutical industry.
The story of the Thalidomide disaster is heartbreaking, but it illustrates why a drug's stereochemistry is so crucial to investigate in pharmacology.
An obvious question which arises in relation to this disaster is how the drug could have possibly passed clinical trials when it was clearly unsafe for use in a large demographic of the population. Alongside the central factor of insufficient testing, there lies another, more intricate reason for the drug's adverse effects.
Twenty years after the disaster, Blaschke et al. reported that one of the two enantiomers of thalidomide was in fact teratogenic (causing birth defects). An enantiomer of a molecule is its optical isomer of a molecule - a non-superimposable mirror reflection. In essence, enantiomers are the "same" molecule, and can be converted into each other under certain conditions (see image below).
Thalidomide possesses a chiral carbon center, meaning it can form S- and R-enantiomers. Because the thalidomide receptor proteins are also chiral, they have different effects upon binding with the two enantiomers, hence the enantiomer which binds to the receptor makes a big difference. When the R-thalidomide enantiomer binds to the receptor, the drug's intended effects occur, whilst when the S-thalidomide enantiomer binds to the receptor, its effects are teratogenic, inhibiting new blood vessel growth in the foetus and hence causing birth defects.
A seemingly obvious answer to the problem would be would be to sell only the R-enantiomer of thalidomide on the market, thereby bypassing the teratogenic effects of its S-enantiomer. However, in vivo, the problem becomes complicated: the human liver contains an enzyme that can convert R-thalidomide to S-thalidomide, and hence even the administration of enantiomerically pure R-thalidomide results in a racemic (50/50) mixture of each enantiomer. This means that the S-enantiomer will be present in the body whether or not it was originally taken, and hence can still cause its adverse effects.
Therefore, the enantiomeric composition of pharmaceutical drugs (especially in vivo) is a critical factor to consider in drug development. Currently, regulatory guidelines do not prohibit the development of racemic mixtures of chiral drugs. Whilst appears unproblematic if neither enantiomer is hazardous, drug companies should make sure to investigate the properties of each enantiomer of a new chiral drug before they introduce it to the market. In most cases, only one of the two enantiomers is effective, and the ineffective enantiomer is quickly excreted from the body. However, bearing in mind anomalies to the trend such as s-thalidomide, it is important to never assume this harmlessness, and instead thoroughly investigate the properties of each enantiomer.
In the midst of the SARS-CoV-2 pandemic, the nation is busy stockpiling sanitisers and disinfectant sprays. Strangely enough, however, one of the most powerful weapons we have to fight the virus is also one of the most simple - ordinary household soap.
How does this staple household substance disintegrate viral particles?
To better understand how the process works, we first need to look at the virus itself.
The virus' surface is a lipid membrane, embedded with proteins seen in the diagram above (membrane proteins, spike proteins, etc.). The proteins are crucial in allowing the virus to attach to certain surfaces in our body, and hence infect our cells. The inner genetic material (viral RNA) is released into our cells after protein attachment, allowing the virus to replicate using our cells as a host.
The lipid membrane is the most crucial to the virus' integrity - without a membrane, the protein and genetic information have no structure, and hence no way of transporting themselves throughout the body and into our cells. The membrane consists of two layers (a 'bilayer') of phospholipids, which are polar molecules that line up tail-to-tail, with their hydrophilic "heads" lining the surface of the membrane and hydrophobic "tails" tucked into the middle. This bilayer essentially forms the shape of the virus, keeping its proteins on the surface and its genetic material contained.
Similarly, soap comprises of molecules called "surfactants", whose structure bears a striking resemblance to phospholipid molecules in the viral membrane. Much like phospholipids, surfactants have a hydrophilic "head" group and a hydrophobic "tail".
Due to this structural similarity, surfactants can penetrate the viral membrane, accumulating to form a complex with the membrane's phospholipids. These complexes are called micelles, and are formed by the hydrophobic tails of surfactants and phospholipids lining up against each other to form globular structures.
These micelles are then lifted from the membrane's surface, breaking away significant parts of the bilayer with each micelle. Eventually, the virus' structure falls apart and it disintegrates entirely.
Technology and Mathematics
When we measure the intake of common psychoactive substances (THC, cocaine, ketamine, etc.) we tend to make measurements in milligrams. It makes sense to us that, given the body mass to substance mass ratio, one would need a substantial amount of a psychoactive drug to significantly alter his or her behaviour.
However, a surprising outlier that we encounter here is LSD, or Lysergic Acid Diethylamide - an incredibly powerful psychedelic drug typically associated with causing strange visions or hallucinations. LSD, unlike any other typical psychoactive substances (including other psychedelics), is measured in micrograms (μg) - a thousandth of a milligram. In fact, a standard dose of LSD is anywhere from 100 - 150 μg. This may strike us as unusual: how can a drug be so potent as to have an effect on the human brain in such small quantities?
To put it shortly, the secret lies in the stereochemistry of the molecule: the orientation which certain atoms in the molecule assume in space.
Firstly, to understand this better, we must consider the receptors which the LSD molecule targets.
LSD, once in the bloodstream, binds to a multitude of receptors to produce various effects. However, most importantly, (and most relevant to the "LSD experience"), the molecule binds to the 5-HT2A receptors on cortical pyramidal cells which make up the brain's cortex. These cells are the 'key computational units' in the cortex which process sensory information, and their 5-HT2A receptors are responsible for forming a complex with "happy hormone" serotonin to bring about various changes in cortical signalling.
LSD, a significantly bigger and more rigid molecule than serotonin, binds to these receptors very differently. The specialised binding of LSD to these receptors causes the top of the receptor to cave in on itself, forming a "cap" on the molecule and securing its position in the receptor. This change in receptor shape recruits a very important biological molecule: β-arrestin, which is the cause of various changes in the perceptual system (which we may go into greater detail about in a later post). Already, we can see partially why an LSD trip is so long: the molecule is trapped in the 5HT2A receptors for hours on end, causing changes in cortical signalling for a prolonged period of time. Keep this information in mind as we explore the structure of the molecule in greater detail.
Next, let us take a look at the shape of the LSD molecule.
The molecule body is composed of 4 rings, two nitrogen atoms as well as a carboxylic acid group. Our main focus in the exploration of LSD potency, however, will be the two ethyl groups (C2H5) found at the top left of the molecule pictured.
The ethyl groups bonded to the nitrogen are free to move around in space, and hence have the freedom to bind to the 5HT2A receptor in a very specific position.
In fact, research by Professor David Nichols, PhD., has illustrated just how important these ethyl groups are to LSD potency. Nichols conducted an experiment with four stereoisomers of LSD where the ethyl groups were fixed in specific regions of space, unable to move and adapt to the shape of the receptor.
The isomers were included one LSD molecule with up,up- ethyl groups, one with up,down- ethyl groups and one with down,down- ethyl groups, as well as the original LSD molecule with flexible ethyl groups. Nichols conducted tests with each stereoisomer on the human brain, and obtained some surprising results.
Nichols found that the isomers with fixed ethyl groups recruited significantly less arrestin per microgram, with one stereoisomer recruiting as little as 100x less arrestin than the original molecule. As seen on the graph, however, one stereoisomer had a relatively similar arrestin bias to the original LSD molecule. Upon closer analysis, Nichols found that this isomer, S,S-azetidide, had a 90% similarity in ethyl group orientation to the LSD molecule when associated with the receptor.
This revealed something very valuable to Nichols: the position of the ethyl groups largely dictates how potent LSD is. If the molecule with the most similar ethyl group orientation to LSD associated with the receptor is the most potent of the isomers, then the way the ethyl groups align with the receptor's structure is key to how potent the molecule is.
If we think back to the receptor's "cap" effect on the molecule, it becomes even more clear to us why these ethyl groups determine LSD potency. The amino acid which acts as the "cap" on the receptor is leucine-229, which has a very specific, fixed R-group structure. For the cap to properly fix on top of the molecule, the ethyl groups must orient themselves in the correct position, which can be done very easily given the free movement of these groups on the original molecule. As ethyl group orientation is fixed and becomes less and less suited to the leucine molecule on the stereoisomers, the receptor can less successfully form its "cap" on the LSD molecule and hence cannot cause sufficient cortical signalling via the recruitment of β-arrestin.
It is extremely atypical to find, in chemistry, a case where ethyl groups are so important to a molecule. Ethyl groups are often viewed as rather inconsequential in the function of molecules in pharmaceutical drugs, and yet, in LSD, serve as one of the most important parts of the molecule.
Therefore, the stereochemistry of an LSD molecule may not be something that we may consider important upon first glance, however, it is greatly responsible for the incredible potency that the psychoactive drug is known for today.
the research of David Nichols, PhD
David Nichols - Psychedelic Neuroscience: LSD gives up a secret
Philosophy of Science