Good Science Verses Flawed Science

H5N1 moves into the piggies

Before we get into today’s discussion it is necessary to go over a few basic concepts, in order to avoid confusion. The word Science in my usage refers to the scientific method: the formulation of a hypothesis about how some process works in the world, and then designing an experiment, the results of which should test whether predictions based on the hypothesis are correct. This is a paradigm which has given us all of our understanding of the natural world, and has stood the test of centuries. That’s the plan but, the design of an experiment may be flawed, measurements may be inaccurate or data recorded incorrectly, and statistical analysis of results may be performed inappropriately. Worst of all, flawed individual scientists may cheat and manufacture or corrupt data for reasons of personal advancement, or to confirm a personal prejudice. That is why it’s important not to conflate the Scientific Method with the results of a given study, even when published in the most prestigious of scientific journals, and especially not to confuse the opinion of “experts” with Science. The Scientific Method never fails to uncover the truth—but human fallibility frequently falls short of that perfection, and all too often is presented as the inviolable scientific truth.

How are people not trained in a particular area of scientific endeavor expected to know the difference between good science and something less? I can’t provide what you might feel is a satisfactory answer, but I can give some guidelines. When you read about a “retrospective, or historical case controlled study”, be prepared to take the conclusions with a grain of salt. When a study shows conclusively that the density of crows on the power lines around your house is directly related to your risk of pancreatic cancer, or that there is a correlation between the number of routine childhood vaccines and the frequency of Autism over time—it’s time to yawn and say, “Thanks for your opinion, now where is that Scientific Method thing?”

Moving on to what I think is an important scientific advance in the realm of virology, I will point you to a very recent article published in the October 30 edition of Nature.

Design of customized coronavirus receptors Peng-Liu, et al. https://www.nature.com/articles/s41586-024-08121-5

The first 20 years of this century has seen the emergence of three novel and lethal corona viruses (SARS1, MERS, SARS2). There are perhaps hundreds more viral species in this family, found in bats and other animals, and any of them could be waiting to spill over into humans with dire results. It is critical to learn as much as we can about these, and other viruses with pandemic potential. You will recall that viruses can only be grown and propagated for study inside eukaryote cells, (those with a nucleus) and for most of these corona viruses, we have no idea what receptor they use to gain entry to cells which can be maintained in the laboratory and used for experiments. The authors of the above study have very ingeniously established a method of designing “custom receptors” based on the protein sequence of the particular corona virus spike they are interested in, and expressing these custom built receptors on the surface of lab cell lines. Wait a minute, you may be thinking, aren’t they making the virus more dangerous, and hasn’t Dr. Kocher been firmly against gain of function (GOF) experiments? A valid question, but in this case they are not enhancing the function of the virus in anyway, they are simply creating an avenue through which they can more readily study the naturally occurring virus. The possibility of a lab leak remains real, but these are viruses which already occur in nature and have the distinct possibility of spilling into humans. I believe we need to study and understand them (with stringently enforced safety protocols) before we have the next chapter in the corona virus saga.

Faulty Science in neglecting the effect of cold on O-rings

And now for a taste of “bad science”. Plasmids are small circular snippets of DNA which are critical for all sorts of molecular biology research, and are used in gene therapy research, where the plasmid is assembled into a partial viral particle, which is used to transfect the target cell, and deliver the gene needed to replace the defective or missing gene. Many researchers use plasmids supplied from commercial labs or borrowed from other research laboratories —this streamlines research, reduces work duplication, and allows researchers to share their expertise. But what if a significant amount of those plasmids are defective and don’t contain the DNA sequence they are selected for? The short answer is scientific chaos: endless experiments whose results cannot be replicated in a different labs, studies with entirely misleading results, and in the arena of gene therapy more costly and either ineffective or dangerous outcomes. Recently a reference laboratory (VectorBuilder) with extensive expertise in precisely defining the DNA sequence of plasmids was concerned by the high number of errors found in samples submitted for analysis, and conducted a study where they analyzed 1,132 sequential plasmids from both commercial and academic labs, and found that an astonishing 40% of these had errors which could very likely affect the performance of the plasmid. The highest frequency of errors was found in plasmids destined for gene therapy use—not a happy scenario. In addition to the inaccurate experimental results, there is the potential for gigantic waste of scientific research dollars as labs try and fail to reproduce results, or design experiments which hinge upon accepting the validity of earlier compromised data. The study is up on BioRx preprint form, but a nice description and discussion can be found at GOLDBIO, (perhaps behind a paywall).

The Hidden Risks of Borrowed DNA; Verifying Plasmids in Research and Therapy. Simon Currie Ph.D. https://goldbio.com/articles/article/the-hidden-risks-of-borrowed-dna-verifying-plasmids-in-research-and-therapy

I sent out a brief note a few days ago regarding the finding of Avian Influenza H5N1 in a pig from a backyard farm in Oregon. This, in my opinion, is truly a sentinel event in the Zoopandemic of what I called have called, “The Most Successful Virus in History”. (Jeffrey Kocher MD. Substack May 31, 2024). The concern of course is the similarity of the cell surface receptors for influenza in humans and pigs, and the piggies’ well known reputation as an efficient mixing vessel supporting the rearrangement of human and animal influenza strains. We have a little more information now from the Oregon Department of Health and the CDC: it seems that 3 of the 5 pigs at this farm are infected, at least one “meets the case definition of influenza infection”, and the clade of H5N1 is nearly identical to the one found circulating locally in wild birds. Some experts had expressed hope that perhaps the pigs were not actually infected, but that routine samples taken from the nose of the index pig might have just contained tiny traces of the virus as a result of environmental contamination. This appears not to be the case now, and ups the ante for pigs getting some revenge for, “everything tastes better with bacon”.

It’s not hard to look at the history of modern medical science and find those individuals whose contributions saved untold lives and reduced misery: Pasteur for his work with bacteria and a practical means of safeguarding the food supply, Banting and Best with the discovery of insulin, Fleming with penicillin, and Salk’s polio vaccine. Some of these discoveries were very high tech for their era, but not all important discoveries fall into that category. This week saw the passing of Dr. Richard Cash, who as a young physician working in what is now Bangladesh, developed the most low tech of therapeutic interventions, but one that the WHO estimates has saved 50 million lives since its introduction in the late 1960s. Millions of people died every year from diarrheal illnesses, including cholera, back then. (Around one million still die each year). Primarily these people die from severe dehydration, electrolyte imbalance and circulatory collapse. Intravenous therapy, although life saving, was largely unavailable in the third world, and simply drinking water to replace the diarrhea was ineffective. Dr. Cash and his colleague discovered that adding some sugar and salt to the replacement water, and carefully keeping track of the volume lost and replaced was dramatically effective. Although low tech, Dr. Cash went about proving that the therapy worked by employing the scientific method, randomizing patients to his rehydration formula by mouth, nasogastric tube or regular water. The therapy was dramatically effective, and was so simple that it could be taught to villagers to use at home—it remains a foundational treatment today for diarrheal illness. The important point is that even given the limitations of the setting where he was working, he employed the scientific method to prove effectiveness. He did not do, as so many physicians

did during the early days of the SARS2 Pandemic, and say, “There is some remote justification for using hydroxychloroquine to treat COVID, and I just treated a lot of patients with the drug and most of them got better.” We all know the snowball of unintended consequences that decidedly unscientific approach unleashed.

I don’t want to leave you with the impression that I’m sufficiently pedantic to believe that only randomized controlled trials can give us important information. In the realm of medical science and Public Health there are natural or fortuitous experiments which, although never designed to answer a particular question, nonetheless can reveal important data. As an example I will point to an article in Science that appeared last week. As you will certainly be aware if you are of a certain age, during WWII there was strict rationing of some food items in Britain and sugar was among them. Following the end of the war and rationing, the Brits made up for lost time, and national consumption of sugar sky-rocketed, surpassing the historic pre-war levels. This research utilized the extensive data of the UK Biobank to look at the eventual health outcomes of people based on their sugar exposure during the first 1000 days from conception through later life. The natural experiment was created by the period of rationing, which controlled for the average sugar intake across the population, and allowed comparison with the period when intake more than doubled in 1953. The results are remarkable and show that early life sugar restriction reduced the lifetime risk of diabetes by 35% and hypertension risk by 20%, and also delayed the onset of these conditions by 4 and 2 years on average. In utero sugar restriction alone accounted for one third of the protective effect, and the sugar restriction occurring after 6 months was the other big contributor to protection—this makes sense since that’s when solid food is started, and between birth and 6 months of age there would be no difference in sugar intake between the groups during rationing and no rationing. Of course one can always make the claim that there may be unrecognized confounders in natural experiments like this—but when you have a clear mechanistic explanation of the relationship between say early life sugar exposure and diabetes, the likelihood that the correlation does not imply causation becomes unlikely.

https://www.science.org/content/article/britain-s-postwar-sugar-craze-confirms-harms-sweet-diets-early-life

Now that everybody in the country is 100% satisfied with the outcome of the election, I am looking forward to the return of commercials for personal injury lawyers, drugs for psoriasis and Crohn’s disease, and other comforting messages on the TV. There may be some opportunities for short term employment as all the Hollywood personalities who swore they would leave the country if they didn’t like the results of the election pack up their 10,000 sq/ft residences. Today we learned that the FBI has thwarted yet another assassination attempt on now President elect Trump. This one was bankrolled and arranged by the Iranian government—seems not everyone is completely enchanted with the whole Democracy thing. Winter has come early to the San Juans this year and we will be waxing up the skis soon. I was disappointed to find out that ski wax contains the toxic PFA “forever chemicals” and certainly finds its way into the water supply. During my weekly coffee clutch discussion with Bill Gates and Taylor Swift, I offered to give up skiing for the good of the planet if they could meet me halfway and start flying commercial. Bill said, “See you on the slopes at my private ski area”, and Taylor said, “What’s commercial”? Thanks for reading, and please pass this on to anyone who might be interested.