In the current poisoned social climate of public discourse where scientists have been accused of siding with liberal policies and ideas, one thing has been forgotten: science is a very conservative enterprise. What I mean by this is that in science the established theories or accepted ideas are given preeminence over new theories and ideas. Why this is the case is not clear, and to my knowledge this premise has not been formally written into the scientific method. Science may be conservative because new theories that seek to upend the established wisdom have to clear a higher bar, as they have to explain the facts better than stablished theories. Alternatively, science may be conservative because once scientists have settled into working with a set of models and understating phenomena in a certain way, they may not be eager to introduce chaos into their world view. Whatever the reason, most scientists that seek to topple scientific orthodoxy must get ready to face a lot of opposition from their peers.
The geneticist Piotr Slonimski faced this prospect when in 1947 he made a discovery. At the time it was established wisdom that living things require a group of enzymes called cytochromes, which are involved in energy metabolism. Slonimski discovered a yeast mutant that, according to his measurements, did not have any cytochromes. The implications were clear: cytochromes are not necessary for life. Slonimski encapsulated the fear he felt at the moment in his autobiography where he wrote.
“Whenever one finds himself at odds with the “conventional wisdom”, as we have called it for a long time, or a “paradigm” as it was renamed by Thomas Kuhn …,there is nothing to expect other than hell from the great unknown presences, and adverse and chilling responses from the people you thought were your friends. There is something profane about upsetting the conventional wisdom… The dispelling of a paradigm is tantamount to being asked to be ostracized, and one can expect to be flayed publicly.”
How a scientist will or should handle the introduction of new ideas into the scientific discourse depends on the dynamic of the particular field in which they operate. However, as Piotr Slonimski also wrote, there is only one thing to do and that is to “confront the arbiters of the conventional wisdom”.
In his particular case, Slonimski took a sample of his yeast cultures to one of the leading cytochrome experts in the world, David Keilin. He showed up at Keilin’s office and explained he had a yeast mutant that grew normally in the absence of cytochromes. Keilin accepted the sample and went to his lab while Slonimski paced outside. After a while Keilin came out and said “You are right!” Eventually Slonimski and others figured out what was going on. The yeast cells he discovered have a mutation in the DNA of an organelle called mitochondria. Mitochondria are the powerhouses of the cell. This mutation eliminates the cytochromes residing in the mitochondria and renders these organelles unable to function. The yeast cells Slonimski discovered derived their energy by other means. This was a significant discovery that shed light on important aspects of the bioenergetics of cells.
However, it is not always so straightforward to confront the arbiters of the conventional wisdom. In 1972 the American neurologist and biochemist Stanley Prusiner became interested in a type of diseases that caused dementia and death and were thought to be caused by what were presumed to be “slow viruses”. Among these diseases were those like Creutzfeldt-Jakob disease and kuru that infected humans, and those like scrapie that infected sheep. Prusiner decided to figure out what was the causative agent of these diseases, which at the time was a daunting problem as the available assays were slow and expensive.
Over the next decade he produced many preparations of the infectious agent only to find that these preparations contained protein but not nucleic acids. Moreover, the infectiveness of these preparations was eliminated by agents that destroyed proteins but not nucleic acids. This was a noteworthy observation because viruses (and in fact all living things) require nucleic acids to make more copies of themselves. Eventually he came to the conclusion that the infectious agent was exclusively composed of protein which was a concept that ran contrary to the prevailing wisdom that an infectious agent must contain nucleic acids. In an article published in 1982 he officially made this heretical claim christening the infectious agent “prion” (derived from protein and infectious).
The reaction of the scientific establishment was swift and vitriolic. The concept of the prion was ridiculed in public and private, and at every scientific meeting he attended Prusiner was lambasted with a barrage of criticism. An anonymous satirical limerick was even circulated among the laboratories in the field and quoted by journalists:
There was a young turk named Stan
Who embarked on a devious plan.
"If I simply rename it,
I'm sure I can claim it,"
Said Stan as he pondered his scam.
"Eureka!" Cried Stan, "I have found it.
Well...maybe not actually found it.
But I talked to the press
Of the slow virus mess,
And invented a name to confound it!"
Through all this Prusiner persevered. He discovered the Prion protein and the gene that coded for it and found that the difference between the infectious protein and the normal protein was the way it was folded. More significantly, Prusiner found that the infectious protein can alter the folding of the normal protein making it infectious. This represented a truly novel mechanism of disease causation. During this time not only did other scientists fail to discover any nucleic acids associated with the putative slow viruses or with prions for that matter, but scientists that tried to replicate Prusiner’s work obtained the same results. Eventually the scientific establishment gravitated towards Prusiner’s ideas and he received one prize after another culminating in the Nobel Prize in 1997.
Despite the above stories, the plight of the lone visionary scientist fighting the system to get a radical idea accepted should not be romanticized. As Prusiner himself declared: "Most radical ideas turn out to be incorrect. It is very important that the people who propose new ideas be given a tough time." For each scientist that upends the established wisdom in their fields there are dozens of others whose ideas never gain traction among their peers because they don’t explain the facts well or because the experimental results on which they are based cannot be replicated by others.
So next time you read in the press about the latest liberal-related slur levied against scientists remember that in its essence (to paraphrase what Stephen King wrote in his book Danse Macabre, albeit in a completely different context) science “is really as conservative as an Illinois Republican in a three-piece pinstriped suit”.
The pictures of Piotr Slonimski and Stanley Prusiner are in the public domain
Of Sizes Large and SmallRead Now
The physical abilities of fleas are often compared with those of humans to highlight how remarkable these insects are. For example, a website took the record distance jumped by a flea which is 13 inches and reasoned that since a flea is 1/8 inch in length that means this flea jumped 110 times its length. The claim was then made that if a 5 foot tall human being were to try to equal this feat, such person would have to jump 550 feet, which is nearly the length of 2 football fields!
The above type of reasoning is probably to be expected when most people (including yours truly) have grown up reading books and watching movies where people, animals, or insects are resized by some fiat to very small or very large body dimensions. Just to name a few: Ant Man, Honey I shrunk the Kids, Them!, Fantastic Voyage, and the inhabitants of the nations of Lilliput and Brobdingnag in Gulliver’s Travels. The truth is that using this form of linear thinking when extrapolating from one body size to another is comparing apples to oranges.
The mechanical strength of body structures and the physiology and biochemistry that living things rely on to move and survive at a certain body size are very different from those of living things that have vastly different body sizes. A 200 pound human needs to have a certain bone structure as well as the muscles to go along with it to be able to support such large weight. By comparison, a flea weighs 0.0000022 pounds and has a body designed to support this tiny weight. This is part of the reason why it can make those seemingly amazing jumps. A 200 pound flea would collapse and die unable to support its body weight and unable to breathe. If it could muster the strength to jump with a force proportional to when its size was small, it would tear itself to pieces. On the other hand, a human being the size of a flea would lose heat so fast that it would die from hypothermia if other problems don’t kill it first. A viable human the size of a flea would not look like a human being anymore, but it would probably be able to compete with fleas in several feats of strength.
The above is not merely a curiosity. Scaling body sizes is an important and very complex discipline in pharmacology. For example, if the only information available regarding the dose of a drug to be administered comes from experiments performed with small animals, then based on that information what should be the starting dose to be administered to humans in a clinical trial? Or if the only information regarding dose comes from adults, what should be the starting dose to be administered to infants? The answer has to take into account several physical and biochemical parameters and is seldom straightforward. However, the linear thinking involved in the scaling of the flea to the human is out of the question. An example with tragic consequences of this thinking involved the sad case of Tusko the elephant.
Tusko was an Asian elephant at the Lincoln Park Zoo in Oklahoma City. In 1962 researchers decided to administer LSD to this elephant to see if they could reproduce a physiological state related to rutting that makes male elephants very aggressive. To calculate the dose they used a reference dose employed in a cat and extrapolated it linearly on a milligram per kilogram basis to the weight of the elephant. When the elephant was administered the drug, it went into convulsions and died. The issue that the researchers did not recognize is that one pound of cat has a much higher metabolism than one pound of elephant. When metabolic rate is taken into account it can be worked out that this poor elephant received a dose that was ten times higher than the effective dose on cats!
Issues of scaling do not pertain only to biological systems. For example, a chemist may use a certain synthetic procedure in the laboratory to make small amounts of a chemical to be used in research. However, if large quantities of this chemical are required, scaling up the procedure in an industrial setting is a very complex issue, especially if the procedure involves reactions that generate heat. In a previous post I mentioned how the large volume of an elephant related to its surface area causes heat to exit its body very slowly, whereas the opposite occurs in a mouse. Similarly the flow of heat out of a small reaction vessel in a research lab is much faster compared to that which takes place in the large volume of an industrial reactor. If heat production and flow in an industrial reactor are not controlled, something called a “runaway reaction” can occur which generates heat faster than can be removed. The buildup of heat from a runaway reaction can lead to explosions and fires like the one that happened at the Morton International plant in Paterson, New Jersey, in 1998.
So by all means admire the feats of strength of tiny living things, and enjoy the next movie where some oversized critter terrorizes the city, but remember that in reality what works for the small will not work for the large and vice versa.