Chris von Csefalvay is a computational epidemiologist/data scientist working at the intersection of AI, epidemiology and public health.

Chris von Csefalvay

The year is 1959. Eisenhower is on his second term, Castro just kicked Batista out of the country and Ray Charles’s Let the Good Times Roll is topping the charts.

The 95% myth

Over at the work blog, I’m discussing what knowledge means for large language models (LLMs), and the ways in which we can leverage this knowledge dividend for better inference.  Read the full post here.

The knowledge dividend of large language models

The awesome thing about language is that, well, we all mostly speak it, to some extent or another. This gives us an immensely powerful tool to manipulate transformational tasks. For the purposes of this post, I consider a transformational task to be essentially anything that takes an input and is largel intended to return some version of the same thing. This is not a very precise definition, but it will have to do for now.

LAIR - Language As Intermediate Representation

As the new Omicron variant of concern of COVID-19 emerged over Thanksgiving week (of all times!), attention has been turning to Paxlovid (PF-07321332). If, like me, you torment yourself by perusing conspiracy theories, you might have heard it referred to as Pfizermectin.

Peace, love, Paxlovid and ‘Pfizermectin’

I used to be on Quora. I’m not anymore. But I used to be. And I wrote some answers. Here are some of my favourites, categorised by field… sort of.

 AI

If I wrote an AI and trained it to score 200 on a standardized IQ test, what could a human of 100 IQ still do better? Read the full answer here. Will true AI come before the ability to completely simulate a human brain? Is there a difference? Read the full answer here.

My favourite Quora answers

Tip  If you’re here for the DOI matching script, the link is here. Quarto is a great tool for reproducible research. It is also a great tool for building websites. After about a decade of Wordpress-based websites, I’ve moved to Quarto primarily for two reasons. First, most of my content is largely static.

Quarto project scripts are awesomeness

There’s a notion in artificial intelligence known as Moravec’s paradox: it’s relatively easy to teach a computer to play chess or checkers at a pretty decent level, but near impossible to teach it something as trivial as bipedal motion. (Hassabis 2017) The sensorimotor tasks that our truly wonderful brains have mastered by our second birthday are much harder to teach a computer than something arguably as ‘complex’ as beating a chess grandmaster.

The hardest AI problem you’ve never heard of.

It appears that in what is clearly a wonderful little PR stunt, a Polish rum company managed to do a Sophia and appoint an ‘AI-driven’ ‘robot’ as its ‘CEO’.  The other guilty party to this pile of steaming bovine excrement is Hanson Robotics, famous for giving us Sophia, the “world’s first robot citizen”. Most of what I’m saying here goes just as well for Sophia.

The skeuomorphic fallacy

Yesterday, I completed a marathon on the SkiErg, with a pretty respectable time (see results here). I know I can do better, and I know I

 will

do better. On the other hand, this was a marathon where I pretty much did everything wrong. And that was sort of an instructive experience in its own right. The title is somewhat misleading. Not much went wrong – the marathon itself was smooth sailing.

How to do a SkiErg marathon entirely the wrong way (but still finish)

There’s something special about language. It is ‘our own’, it is ‘us’, in a profound way, and quite surprisingly, more so than art. I was deeply struck by this when I first saw reactions to large generative language models that created realistic, human-ish prose.

Beyond Broca

In my latest post for the Starschema blog, I discuss the end of dashboards, and what comes next:  Read the full post here.

As we may see: the world after dashboards

There might be valid concerns about the mRNA vaccines. Then there are the clearly insane ones, such as the claims that it involves the injection of a microchip. The argument that mRNA vaccines are a form of ‘gene therapy’ are somewhere in the middle, and that makes responding to it somewhat difficult.

Why the COVID-19 vaccines are not gene therapy

The temple of Asclepios, the Greek god of healing arts and medicine, at Epidaurus was pretty much the ancient Greek world’s equivalent of the Mayo Clinic. It then tells us a lot about the Greek worldview of healing that one of the things the temple complex prominently featured was a theatre. The Greeks believed in drama therapy, but in perhaps a slightly different way of how we think of it today.

The Moral Pulse of the Machine

Every year, the Commandant of the Marine Corps publishes a reading list of books that often only bear on warfighting tangentially at best. The idea behind this is that those entrusted with the lives of servicemembers should have an understanding of the world that goes beyond the profession of arms. In much the same way, I have been advising data scientists to go beyond professional literature.

Five non-data-science books for data scientists

In the middle of the green and pleasant countryside of England lies a small piece of commons –– land, that is, over which a number of people share certain rights. In this hypothetical scenario, it’s six farmers,  to . Each of them has a hypothetical cow, which differs from ordinary cows in that it grazes a fixed unit, and produces a fixed amount of milk (unlike real cows, which vary wildly in their input and output parameters, or so I’m told).

Ransomware attacks as n-person prisoner’s dilemmas

Say you’re busing tables and you’re trying to pass someone in a wheelchair. What do you do? Do you say “excuse me” and wait for them to move? Do you say “excuse me” and then try to pass them? Do you just try to pass them? Do you say nothing and just try to pass them? All of these are, actually, pretty legitimate answers. Now, say you’re a robot.

What I learned from getting bodied by a robot.

Asemantic Induction of Hallucinations in LLMs

There’s a style of visual design I’m inordinately fond of called Raygun Gothic. It’s hard to describe what the hell exactly one needs to be on to enjoy it, but think of it like the aesthetic from the latter Fallout games with a more optimistic outlook on the future. Gibson described it as “the future that never was”, and I think that’s a pretty apt description. We get these competing futures in technology all the time.

Prompt Engineering: The Art of Yesterday

It’s not every day that you find out you have climbed the exalted heights of another discipline. My work is pretty interdisciplinary, but it shocked me, too, that I’m apparently holding forth on neoliberalism and the epistemic question in African universities (archive link):  This, of course, came at some surprise to me, as I have never written anything on the topic.

Stochastic parrots, cap and gown edition

In the first four entries (1 2 3 4) of this sequence, I have focused primarily on what LLMs aren’t, can’t, won’t, wouldn’t and shouldn’t. It’s probably time to conclude this series by that much awaited moment in all stories, where the darkest night finally turns into a glorious dawn, where we finally arrive at the promised land, where we finally get to talk about what LLMs

 could

be. What I see as the most successful potential model of

Teams of Rivals

My recent post on the Starschema blog discusses the need for better data products to tackle future pandemic challenges:  Read the full post here.

Data for the next pandemic

I have probably spent more time looking at Poussin’s

 Dance to the Music of Time

than any other work of art. Sneaking off to the Wallace Collection in London and just looking at the

 Dance

was my comfort activity while living in London – a time that was not exactly devoid of its trials. It’s not, by any measure,

 great

art, insofar as such judgments can be made with any objectivity.

The Lyre of Hephaestus

In a recent paper that has attracted the interest of popular media as well, Fabio Urbina and colleagues examined the use (or rather, the abuse) of computational chemistry models of toxicity for generating toxic compounds and potential chemical agent candidates.(Urbina et al. 2022) Urbina and colleagues conclude that Urbina, Fabio, Filippa Lentzos, Cédric Invernizzi, and Sean Ekins. 2022.

A different shade of grey

I love posts that allow me to merge some of my addictions.

Auto-DOI for Quarto posts via Rogue Scholar

As the new Omicron variant of concern of COVID-19 emerged over
Thanksgiving week (of all times!), attention has been turning to
Paxlovid (PF-07321332). If, like me, you torment yourself by perusing
conspiracy theories, you might have heard it referred to as
Pfizermectin. Behind that is the idea that the "COVID pill" Paxlovid is,
basically, a re-packaging of ivermectin, a disproven treatment for
COVID-19. [(Popp et al. 2021)]{.citation cites="popp2021ivermectin"}

::: {.no-row-height .column-margin .column-container}
::: {#ref-popp2021ivermectin .csl-entry}
Popp, Maria, Miriam Stegemann, Maria-Inti Metzendorf, Susan Gould, Peter
Kranke, Patrick Meybohm, Nicole Skoetz, and Stephanie Weibel. 2021.
'Ivermectin for Preventing and Treating COVID-19'. *Cochrane Database of
Systematic Reviews*, no. 7.
:::
:::

::: {#the-pfizermectin-gambit .section .level1}
# The Pfizermectin Gambit

The Pfizermectin argument rests on the fact that Paxlovid, an oral
treatment for COVID-19 (colloquially known as a "Covid pill") is a
protease inhibitor, and so is ivermectin. Consequently, so the reasoning
goes, ivermectin is just as good --- except it is no longer an
economically viable drug, vis-a-vis Paxlovid. So, it is claimed,
ivermectin was repackaged, and now sold at a premium.

So suggests, for instance, paleo-libertarian Lew Rockwell:

> Biden Admin Plans 'Imminent' Booster Expansion; Orders 10M Courses of
> 'Pfizermectin' 
> By Tyler Durden<https://t.co/IMckQeK541>
>
> --- Lew Rockwell ([(**lewrockwell?**)]{.citation cites="lewrockwell"})
> [November 19,
> 2021](https://twitter.com/lewrockwell/status/1461791639224164354?ref_src=twsrc%5Etfw)

The problem is... Paxlovid is not ivermectin. It is not even similar,
and the difference is crucially important to why Paxlovid is likely to
be an effective medication, and ivermectin won't.
:::

::: {#whats-different-about-paxlovid .section .level1 .page-columns .page-full}
# What's different about Paxlovid

As always, there's a kernel of truth in the overall lie. It is true that
both Paxlovid and ivermectin are inhibitors of the 3-chymotrypsin like
protease (3CLPro). 3CLPro is the principal protease of coronaviruses. It
belongs to a wider class called mixed-nucleophile proteases superfamily
A. Their main function is to find peptide bonds in proteins between
glutamine on one hand and serine, glycine or alanine on the other.

To understand what's going on here, we need to look at protein synthesis
by viruses. A lot of the time, viral proteins are produced as one big,
long protein called a polyprotein. Then, viral proteases break these at
pre-determined cleavage sites into the constituent parts of what
eventually becomes a viral particle. As far as the virus is concerned,
interference with that cleavage is bad, bad news, essentially inhibiting
the ability of the virus to create copies of itself that are effective
infectious agents.

::: {.quarto-figure .quarto-figure-center}
<figure class="figure">
<img
src="https://chrisvoncsefalvay.com/posts/paxlovid/paxlovid.png.webp"
class="img-fluid figure-img" />
<figcaption>Paxlovid (PF-07321332, in blue) bound to 3CLPro (volume
model). Author’s own work, based on PDB:7SI9.</figcaption>
</figure>
:::

This 'molecular scissor' in coronaviruses is 3CLPro, and as such, it's
clearly a target of interest. Mody et al., in a paper that has earned
its spot on my list of top 10 papers of 2021, looked at 3CLPro
inhibitors, and found that around 50 µM (micromoles) of ivermectin were
sufficient to achieve a 75% or so reduction in the activity of 3CLPro.
[(Mody et al. 2021)]{.citation cites="mody2021identification"}

::: {.no-row-height .column-margin .column-container}
::: {#ref-mody2021identification .csl-entry}
Mody, Vicky, Joanna Ho, Savannah Wills, Ahmed Mawri, Latasha Lawson,
Maximilian CCJC Ebert, Guillaume M Fortin, Srujana Rayalam, and
Shashidharamurthy Taval. 2021. 'Identification of 3-Chymotrypsin Like
Protease (3CLPro) Inhibitors as Potential Anti-SARS-CoV-2 Agents'.
*Communications Biology* 4 (1): 93.
:::
:::

However, that's actually bad news --- because 50 µM is, actually, a lot.
And therein lies the problem.
:::

::: {#the-pharmacokinetic-difference .section .level1 .page-columns .page-full}
# The (pharmaco)kinetic difference

The problem with ivermectin is very simple. In order for an enzyme
inhibitor to be effective, it needs to reach a concentration where it
inhibits the target enzyme enough to make a dent in the underlying
process. The standard metric for this is known as
![](https://latex.codecogs.com/png.latex?IC_%7B50%7D) --- the
concentration of the inhibitor required to inhibit enzyme activity by
50%. This value for ivermectin is somewhere in the realm of tens of µM
for 3CLPro.

One µM of ivermectin weighs around 0.0875mg, so a 1 µM solution of
ivermectin would have a concentration of around 87.5 nanograms per
millilitre (ng/mL). To reach even a very conservative 5µM, you would
need blood levels of 437.5ng/mL.

And that's a problem, because above 80 or so ng/mL, ivermectin is pretty
toxic. [(González Canga et al. 2008)]{.citation
cites="gonzalez2008pharmacokinetics"} To reach the lowest conceivable
limit of inhibitory action on 3CLPro would require doses that are
incompatible with... well, life.

::: {.no-row-height .column-margin .column-container}
::: {#ref-gonzalez2008pharmacokinetics .csl-entry}
González Canga, Aránzazu, Ana M Sahagún Prieto, M José Diez Liébana,
Nélida Fernández Martı́nez, Matilde Sierra Vega, and Juan J Garcı́a
Vieitez. 2008. 'The Pharmacokinetics and Interactions of Ivermectin in
Humans---a Mini-Review'. *The AAPS Journal* 10: 42--46.
:::

::: {#ref-owen2021oral .csl-entry}
Owen, Dafydd R, Charlotte MN Allerton, Annaliesa S Anderson, Lisa
Aschenbrenner, Melissa Avery, Simon Berritt, Britton Boras, et al. 2021.
'An Oral SARS-CoV-2 Mpro Inhibitor Clinical Candidate for the Treatment
of COVID-19'. *Science* 374 (6575): 1586--93.
:::
:::

The alleged 'Pfizermectin' achieves this efficacy at a nanomolar level
-- at a concentration roughly ten thousand times lower. [(Owen et al.
2021)]{.citation cites="owen2021oral"} At that concentration, Paxlovid
is still well within its margin of safety.

This is not by accident, by the way. Paxlovid is the product of rational
drug design, using computer models to identify a small molecule drug
that is not only effective against an enzyme target but also has
favourable pharmacokinetics. Far from merely 'repackaging' ivermectin,
as the Pfizermectin theory alleges, this is an entirely new drug. It is
structurally novel, and bears little resemblance, if any, to ivermectin.
It was designed from the ground up to be orally effective, and be so at
doses that are safe.
:::

::: {#conclusion .section .level1 .page-columns .page-full}
# Conclusion

In the end, action happens in vivo --- in real, living beings.
Ivermectin might be a workable drug in vitro, where the model does not
have to account for the inconvenience of actually keeping the host
organism alive and breathing. To many of us who have looked at the maths
of it, it has been clear that with the inhibitory concentrations
required by ivermectin, it is never going to transition from the bench
to bedside. Ivermectin does have a mechanism that counteracts
SARS-CoV-2, the virus responsible for COVID-19. It's just that it is way
too weak to be of any practical use.

Pfizer's drug developers have solved this through molecular dynamics
simulations and rational drug design (and, in fact, have released a
paper on just how they did it, which is very, very cool).[(Zhang et al.
2021)]{.citation cites="zhang2021structure"}. Paxlovid is the result of
this development --- and it is far from being 'Pfizermectin' or
repackaged ivermectin.

::: {.no-row-height .column-margin .column-container}
::: {#ref-zhang2021structure .csl-entry}
Zhang, Sheng, Maj Krumberger, Michael A Morris, Chelsea Marie T
Parrocha, Adam G Kreutzer, and James S Nowick. 2021. 'Structure-Based
Drug Design of an Inhibitor of the SARS-CoV-2 (COVID-19) Main Protease
Using Free Software: A Tutorial for Students and Scientists'. *European
Journal of Medicinal Chemistry* 218: 113390.
:::
:::

Until now, much of the activity has been focusing on debunking
misconceptions about the COVID-19 vaccine and sensationalistic tripe
about the pandemic. As curative non-vaccine treatments are entering the
market, it will be important to provide the public with the proof they
need to dispel dishonest notions about the "Covid pill". First and
foremost among these is that the "Covid pill", whether molnipiravir or
Pfizer's Paxlovid, is not a repackaging of ivermectin in any conceivable
sense.

And the strongest proof of that is the simplest, too: it works, in ways
ivermectin is mathematically incapable of working.
:::

::: {#quarto-appendix .default}
::: {.section .quarto-appendix-contents}
## Citation {#citation .anchored .quarto-appendix-heading}

<div>

::: {.quarto-appendix-secondary-label}
BibTeX citation:
:::

``` {.sourceCode .code-with-copy .quarto-appendix-bibtex}
@misc{csefalvay2021,
 author = {Chris von Csefalvay},
 title = {Peace, Love, {Paxlovid} and “{Pfizermectin}”},
 date = {2021-11-27},
 url = {https://chrisvoncsefalvay.com/posts/paxlovid},
 doi = {10.59350/576dr-vbd49},
 langid = {en-GB}
}
```

::: {.quarto-appendix-secondary-label}
For attribution, please cite this work as:
:::

::: {#ref-csefalvay2021 .csl-entry .quarto-appendix-citeas}
Chris von Csefalvay. 2021. "Peace, Love, Paxlovid and 'Pfizermectin'."
<https://doi.org/10.59350/576dr-vbd49>.
:::

</div>
:::
:::