Coronavirus Origins: Anatomy of a Scientific Inference

James Lyons-Weiler, PhD – 2/15/2020

Objective science is not about being right or wrong. It’s about positioning yourself toward maximizing your chances of learning something. Here I provide a lesson in the philosophy of Science – outlining an approach that, once abandoned, all of Science should strive to return.

THE PAST TWO WEEKS have been a fascinating exercise in Science – with many factors and forces influencing comprehension and expectation. I think it’s a fantastic opportunity for the public to have witnessed objective Science in action, and to see the definition of rigor in Science defined as operating in vacuum separated from profit motive and independent of ego.

The scientific philosopher Karl Popper urged scientists to move beyond the collection of pieces of information that confirm their favorite ideas. This type of inference-making is called positivism – and it leads to a bunch of collected facts and figures from an otherwise jumbled mess which, while appearing to be internally consistent and mutually supportive, can nevertheless be positively misleading to an incorrect inference. If we base our generalization from individual instances to the general case, a process called induction.

Since we base what we know about our world on observations, what could save us from merely agreeing with our Royal Selves with all of the confirming instances we can manage, or choose, to collect? And what do we do about the annoying contradicting observations that do not fit our induced generalized claims, since we have based our world view on all of the past confirming instances?

In other words, where does the demarcation exist between making stuff up and Science?

Enter: The Hypothesis

Popper offered a highly formalized calculus of the nature of objective scientific inference in which our goal should not be generalization via induction, but, instead, inferences more securely based on a form of deduction, specifically hypothetico-deductivism. In hypothetico-deductive science, we pose an hypothesis, or a conjecture, based on our Background Knowledge of a topic. At this time, we do not create a knowledge claim, upon which we stake our fame and glory (ego). Instead, we state the hypothesis clearly, and then imagine the most significant critical test of said hypothesis. For Popper, a Test is only truly critical if it can, in fact, potentially refute, or falsify, the stated hypothesis. If a Test does not truly place a hypothesis at the risk of being falsified, it’s not truly a critical test.

Enter: The Evidence

Once the Critical Test has been defined, and the scientific experiment or study has been executed, the information on the outcome of the Critical Test is called Evidence. We are to use, Popper says, the Evidence we have collected to re-assess the original Hypothesis, which you will recall was based on background knowledge.

If the critical test provides evidence that refutes the hypothesis, the hypothesis is considered falsified.

If the critical test provides evidence that fails to refute the hypothesis, and, importantly, the critical test was constructed and executed in such a manner that the hypothesis could actually be refuted if it were false, the hypothesis is said to be corroborated.

In either outcome, we update our background knowledge based on the evidence from the critical test, and move along secure in the hope that we have learned something.

Via H-D science, there is no role for ego; for Popper, the source of the hypothesis plays no necessary or useful role in whether the hypothesis will be falsified or not; i.e., the critical test is to be defined and constructed in a manner by which its design and execution is truly independent of whether the subjective scientist individually favors, or the current consensus favors, or dislikes, the hypothesis being tested. The only thing that matters is that the critical test is actually capable of potentially falsifying the hypothesis. That’s it.

If there was one word that should be dropped from discussions in science, it’s “prove”. Scientists don’t prove anything; as I say in discussions, proofs are for maths, logic, publications, and whiskey. Another term that I find to be extremely unscientific is “debunk”. The origin of the term has it roots in the term “bunkum”, of which the first recorded use was in 1828, when it was used to describe a “speech for Buncombe County, North Carolina” given by North Carolina representative Felix Walker during the 16th United States Congress (1819–1821). To “debunk” then means” to call someone out for bad, incorrect, or ineffectual speech, and if Science is being conducted objectively, it’s about the process, not about the speech, nor the speaker.

These terms are convenient clubs used by those who would gladly destroy the career of objective scientists whose results threaten their promise to their investors, and they play no role in the logic of Science.

Instead of these pop-culture representations of sciency-sounding things, it is importantly, that it is understood and expected that the available background knowledge, or assumptions, may not be perfect for any such enterprise in Science. In fact, the entire purpose of Evidence from a Critical Test is to determine whether the available background knowledge is to be updated, or left alone intact, unfettered by new knowledge. This is a far cry from “proving” an hypothesis. We simple either refute or fail to refute – and we only can do so if the test we use is, in fact, a critical test.

Bold vs. Weak Hypotheses

Popper did distinguish between weak hypotheses that do not go too far beyond the Background Knowledge and bold hypotheses that do go far beyond the background. These differences were important, because the further away from the background knowledge a stated hypothesis lays, the greater the degree of Corroboration – not confirmation, Corroboration – the Evidence from the Test results provide the hypothesis.

In fact, the more unexpected it is that the hypothesis survive a truly critical test, the more scientist should be impressed. Popper offered a term for this: Surprise. The higher the degree of surprise, the more improbable the outcome if the hypothesis was incorrect, and thus the higher the degree of corroboration – and the more we realize we need to update our background knowledge. Elegant.

Imagine if I come to you with a coin. I ask you: what do you think the chances are, if I flip this coin, you’d see it land on “Heads”. Most would say “50%” – a few would say “50%, if it’s ‘fair’ coin”. You watch me flip a coin, and it lands on its edge. This is so utterly improbable that you would not only be surprised: you’d be amazed. Now imagine if I give you the same coin, and you flip it – and it lands on its edge AGAIN. Clearly, you’d have found that the probability model in your head: 49.99999% chance heads, 49.99999% tails, 0.00002% edge, was wrong. You might flip it again, and again to determine how far off your 50:50:0 model was, and, for that coin, you’d say “Ok, this coin is not fair, it’s different” – if the data supported that.

Would you then generalize to all coins, and say “all coins are 10:10:80?”. No. That induction is not warranted from your observations with a single coin. That’s why independent replication is so important to Science- it determines whether an inference generalizes, and if so, how well it generalizes.

Entities that make overgeneralized claims often can get away with doing so because they carry the mantle of authority. But authority will not make a study replicate, or make a model able to predict well on new data. Biases from fraud, to hide evidence of harm from pharmaceutical and agricultural practices, are everywhere. In academia, to say so is death to one’s career. Which is why we need independent Scientists doing Objective Science in full view of the public. If it looks different, it’s because there is no agenda. I’m quite happy to be “wrong” over and over and over, as long as I am learning something about the world and the universe around us.

In the case of Coronavirus, the New Media and even some MSM picked up the idea that my statement that “at the present time, the most likely hypothesis is that novel coronavirus is lab-based” ignored the explicit caveat that Del Bigtree of The Highwire provide numerous times: it’s a ‘theory’ he said (he meant hypothesis). My infamous article actually listed multiple hypotheses, and presented the available evidenced structured as it was presented to me. I stated these hypotheses with every intent to attempt to define critical tests, old-school, in the Popperian fashion, to attempt to refute and thereby either falsify or corroborate each one. The last man standing wins.

This is only possible in a free and open society in which free and open discussions are possible. Numerous scientists from around the world have contacted me throughout the process to weigh in

It is no coincidence that Popper co-authored one of my favorite books: “The Open Society and Its Enemies” – highly recommended reading and something all who want open social media – freedom of expression – freedom of the press – freedom of Science from profit motive bias should read and give to their loved ones and friends.

Popper worked all of this out in formal calculus that, unfortunately, has all been but forgotten due to a non-sequitur “next phase” of the philosophy of science – Thomas Kuhn’s “Scientific Revolutions”, which focused on paradigm shifts, placing the power to create knowledge in the firm grasp of consensus – which of course we now know lends itself well to group think, to manipulations of perception, to propaganda, such as to claims of observational studies – weak science not capable of testing a core feature of important hypothesis of causality – as “rigorous” and sometimes even “more rigorous” than randomized prospective clinical trials with inert placebos. Under Popperian Science, the truth is reality, independent of us. It impacts us, it is something we approach asymptotically, using Science is a way of discovering knowledge. Under Kuhnian science, the loudest person in the room can define the truth; that often can mean the buyer with the largest purse.

Since entering into the domain of Coronavirus research, asking questions, posing hypotheses, defining critical tests, examining the evidence, and updating background knowledge based on the outcome of those tests, dozens of scientists from around the world have written to me in support of my efforts to address the questions we all have head-on. Some have been supportive, offering agreement; some have been supportive by challenging me. In reality, they were not challenging me, they were challenging the hypothesis. So I’m honestly grateful!

The manuscript showing the results of our study of spike protein motifs is under review, and I have asked the journal Editor to permit pre-review publication for the sake of humanity. If the publisher agrees, the results will be available to all very soon. Fingers crossed.

The conduct of independent science for the sake of knowing, in hopes it might reduce human pain and suffering, is gratifying because those who understand that it’s not about me – it’s about the 67,000 human beings with COVID-19 who may be suffering needlessly for want of a full understanding of the mechanisms of pathophysiology that SARS 2 has in it attack on humanity. It’s different from SARS – and understanding those difference draws on ecology, evolution, genetics, biochemistry, and an ability to divorce one’s ego or agenda from the outcomes of a study.

Posing incorrect hypotheses is a good, healthy and essential part of Science. Being willing to pose risky hypotheses is key to being able to make advances in knowledge.

Today, I received a card in the mail from a concerned US citizen who understands why IPAK exists, why independent Science must be made to thrive and grow in the face of a massive paradigm of science-for-the-stakeholders.

His card read:

“JLW,

If another planet offers you another position with bette(r) working conditions – free from politicized science, don’t take it!

We need you here.

MR.”

This person’s enclosed donation to IPAK will keep objective, unbiased, but imperfect hypothetico-deductive Science alive in the US.

I feel that I have a responsibility at this time in history to reverse course on the tyranny of pseudoscience and Science-like activities conducted by individuals with an agenda other than using Science as a way of knowing.

CORONAVIRUS ORIGINS HYPOTHESIS TESTING

THE HYPOTHESIS.

Step 1: Background knowledge. No one could ID the novel segment. There had been 5 coronavirus outbreaks in China in seven years; 4 from the lab, 1 from a civet (cat-like animal) as an intermediate host. Vaccines made using recombined SARS spike proteins have been made and have undergone testing since the mid-2000’s.

Step 2: Initial observations. I found it to match p-ShuttleSN, which was clearly related (somehow) to the Coronavirus Spike protein. Found a patent for a SARS vaccine that used pShuttle-SN to move a SARS spike protein into an adenovirus.

Step 3: I made the bold conjecture, given the background knowledge of a 4:1 risk of accidental vs. laboratory release of SARS coronavirus, that this was (a) likely an accidental laboratory release, and (b) most likely of laboratory origin

THE TEST: PHYLOGENETIC RELATIONSHIPS AND A SPECIAL MOTIF PATTERN.

I used phylogenetics to determine the relationship of all of the Spike protein sequences I could access, including pShuttle-SN. I sought new evidence: If pShuttle-SN turned out to be most closely related to SARS CoV 2, it may well be related causally.

It wasn’t. It clustered with SARS CoV-1, specifically, in what I call the “Cancer Center cluster”, with sequences from a Genome Center. While it was possible to replicate the alignment issue with other coronaviruses, it seemed to be related to a shorted N-terminal Domain of the S1 section of the Spike protein. Noted.

Further test: Other artificially modified spike proteins might be most closely related to SARS CoV 2.

They aren’t.

A final critical test: Since SARS CoV Spike protein is different, and different because it was from nature, but, were there any reliable sequences from a natural source from long ago that had the same type of Spike protein? If so, then we have to rule out laboratory ORIGIN – as in design, because such as finding would be highly improbable.

Result: Using motifs, I searched known B-Coronavirus Spike proteins to see if there were any older sequences from nature that also include the motif pattern that appears to be indicate (may be) indicative of a the special pathogenicity in SARS CoV 2. I found one that matched all of the known closest relatives and examples of SARS CoV 2. It was from 2005 and from a natural source: a bat. (Details to appear soon following peer-review or agreement to pre-publish).

The net result? We have updated our background knowledge, and learned something new. We have a potentially useful pathogenicity signal (shorted NTD, two missing motifs and a Gp40 motif in the C-terminal region) that anyone with a high school degree could learn to recognize with about 20 minutes training, a laptop and access to the internet. The new hypothesis – that a pathogenicity signal exists – itself is a conjecture, and needs to be tested. It falls into the realm of “Applied Science”, drawn from “Pure Science” – the act of daring to ask questions and pose hypotheses merely for the sake of knowing.

So there we have it – the Anatomy of a Scientific Inference. In my view, all of Science should return to Popperian Hypothetico-Deductivism and cast off the control of the funding masters who limit what we can study, and what we can publish. Remember that to do Objective Science means divorcing your ego from your hypothesis.

Some will complain in the comments that the Philosophy of Science has ‘moved’ on, but in reality, I’m not accepting that. Kuhn’s permission slip for induction – and that’s what it has been used for – has led biological sciences and medical sciences down a path that is making people sick. Philosophers of Science who used to enjoin Popper have abandoned all hope in the face of the juggernaut and have become Stoics – a metaphysical rising above the issues as irreconcilable. Two decades ago, I proved (using logic), using Popper’s calculus that having more scientists looking at the same problem and discussing it is more likely to yield progress in science – simple because each had their own background knowledge, meaning that the chances that someone in the room has the missing component of background knowledge to accurately and correctly interpret the evidence of a critical test of a hypothesis. The journal editor returned the manuscript with the apology that no one uses Popper’s calculus anymore. That needs to change.

Nevertheless, Vestiges of Objective Science still exist: We still use experiments with controls to test the hypothesis of interest – and the degree to which we can reject the null hypothesis is measured by a p-value. That p-value is the degree of surprise that we should express if we saw the null hypothesis rejected by chance alone. Like flipping a coin and seeing it land on its edge. We know there is a small probability, and if it were to happen again and again, we would have to surmise that our background knowledge, or expectation, needed to be updated.

But if we cannot discuss hypotheses for fear of being ‘wrong’, or cannot publish results because it may upset our funding source, or it may go against any particular political agenda, we’re going down the wrong path. We still don’t know if there is something different in China with respect to the mortality rate of the novel coronavirus. The two hypotheses that I posed

(A) the Chinese government proceeded with a large-scale coronavirus vaccination trial, or

(B) the new vaccine law (Dec 1, 2019) may be related somehow

will both soon be partly tested by the amount of of serious illness and death outside of China associated with infection. So far, there have been only four deaths outside of China, in 688 known cases, a rate of 0.005% (about what I predicted). In China, the per-case fatality rate estimate ranges from 2.1% to 2.3%, depending on whether suspected cases are included in the denominator of the total number of cases. Hopefully for the world, this hypothesis bears out.

Science is a social enterprise by which we compare our interpretations of outcomes of studies with other scientists, who can share theirs back. The age of “retraction” due to differences in interpretation, and “debunking” by shady characters with ties to Pharmaceutical companies, are over. I’ve led chants of “What do you want?” to which the crowd replies “SCIENCE!” and I have to tell you, I think we’ve reached a turning point where profitability is being given the boot out of the logical calculus of Science, and the public is learning the difference between Science, and Science-Like Activities.

I encourage every Scientist to state their bold hypotheses loudly, and clearly, and outline their reasoning. Because, as my Master’s degree mentor Paul Colinvaux shared with me, his academic advisor Dan Livingstone thought that being found to have posed an incorrect hypothesis would be “wonderful, because then we would have learned something”.

SARS CoV-2 CASES TO DATE (2/14/2020)– Update here.

Mainland China: 63,862
Thailand: 33
Japan: 29 (plus more than 200 on cruise ship off coast)
Singapore: 67
Hong Kong: 56
South Korea: 28
Taiwan: 18
Australia: 15
Malaysia: 19
Germany: 16
Vietnam: 16
Macau: 10
U.S.: 15
France: 11
United Arab Emirates: 8
Canada: 7
Italy: 3
Russia: 2
UK: 9
Philippines: 3
Cambodia: 1
India: 3
Belgium: 1
Finland: 1
Nepal: 1
Spain: 2
Sri Lanka: 1
Sweden: 1