Category: health

The Lancet goes woke

February 9, 2021 • 1:30 pm

A long time ago, when I was naive (that would be about a year!), I thought that academics who succumbed to Wokeness would reside more often in the humanities and arts rather than the sciences. I’m not sure why, except that I thought that those in STEM would not succumb as easily to irrational or incoherent ideas, and had better things to do than to spout untested theories and demonize ideological opponents. After all, postmodernism came from the humanities, not the sciences.

I was wrong. The sciences were a little late getting started, but now they’ve bought a first-class ticket on the train to Wokesville. After all, scientists, like everybody else, have a big fear of being called racists or bigots.  Now many prestigious science journals, like Science, Nature, and Cell, are publishing woke pieces like an elephant with the trots. And so the editors of the journals go along to get along, and to show the world their concern and virtue.

The latest victim, and one that’s fallen hard, is The Lancet, Britain’s premier medical journal and one of the best medical journals in the world.  I about keeled over when I saw this article (click on screenshot, pdf here).

Actually, the authors don’t seem to be medical doctors, though I might be wrong, but rather work on health policy, social justice, anti-racism or international affairs. That may explain both their use of Critical Race Theory (CRT) jargon and their recommendations, which don’t seem to have much to do with global health organizations except to indict them for racial and gender inequities. This may reflect racism, but may not. Yet why bother with the power-dynamic bits of Critical Race Theory (the authors are really big on “intersectionality”) instead of just suggesting the possibility of racism in the field—something that the authors insinuate but fail to substantiate? That is because they automatically assume that unequal representation of those in power implies current racism: the “Equity/Bias Fallacy”.

But never mind. Just reading this thing makes your head hurt, and, at the end, you have no idea what the authors want to happen except to have more diversity at upper levels of health policy. How this will help the people of the world (and it well may) is not even touched on. Instead, we are blanketed with layer after layer of CRT jargon and prods about the importance of intersectionality, which isn’t really the main issue for the kind of inequities they mention. Read it for yourself.

A few mind-numbing bits of prose (fortunately, the piece is only two pages long):

As women of colour scholars, practitioners, and educators whose work addresses race, gender, and class inequity, we recognise that it is vitally important to take a gender lens to addressing health inequities. But this gendered perspective must not be unidimensional. We now call upon our colleagues, particularly influencers in high-income countries, to meaningfully engage with critical race theory, a transdisciplinary intellectual movement to understand and disrupt systemic racism. Of particular relevance to these efforts is the concept of intersectionality, a central tenet of critical race theory coined by Kimberlé Crenshaw to describe how multiple social categorisations—such as race and gender—interact and confer interlocking oppressions and privileges.

This intentional centring of race in global health will help to achieve the mutually reinforcing goals of eradicating both racial and gender inequity. As a point of departure, we articulate the multiple racial contexts of the global health sector, with the aim of moving beyond a colour-blind gender lens.

And here’s what’s new: the authors have simply taken CRT and pasted it onto of global health organizations—as you could do with any organization:

We are pleased that scholars and advocates of global health and gender now acknowledge the importance of explicating the interlocking oppressions of gender inequity and racism, among other “-isms. For decades, the concept of intersectionality has been foundational to scholarship addressing systemic racism, most prominently in the USA with respect to simultaneous oppressions due to race and gender. Nowadays, concepts such as intersectionality are also applied to other social categories, such as religion, nationality, and socioeconomic status. However, the concept of intersectionality is a relatively new addition to the global health gender lexicon. 

They did something new! But they have to deal with an annoying observation: some countries don’t need to use CRT in this endeavor because they’re either racially homogeneous or aren’t obsessed with racial issues and “diversity”. Yam et al have an answer for them, lining up their jargon like bullets in a weapon’s magazine:

Like gender’s problematic binary of male versus female, race is a complex social construct with biological implications, the classifications of which vary across history and geography.  Globally, many societies—particularly racially homogeneous ones—do not regard race as the predominant societal fault line along which health disparities fall. But it bears reminding that global health research and practice take place in multiple, interlocking racial contexts.

So even if you don’t need to use CRT in your area, remember that it’s not the same in other places! So learn your CRT! (Note as well the authors’ gratuitous claim that the “male versus female binary” is “problematic.”) And if race is a social construct, then what are its “biological implications” for today’s health organizations?

They then present their figure, which adds nothing to the piece:

(Caption from paper): Multilayered and intersecting racial contexts in global health

Does that figure enlighten you?

The piece goes on and on and on, ending with their call to arms, which is simply “Use CRT”:

Current impassioned conversations about systemic racism present an opportunity to embrace race as an omnipresent factor influencing global health practice, research, and outcomes. This racial consciousness needs to be part and parcel of our efforts to address gender inequity worldwide. Now, more than ever, we must centre our work on people at the racial margins, in each of the intersecting racial contexts of the global health sector. Only then will we develop an essential sense of humility and self-awareness to be antiracist in our work.

Humility? That word doesn’t belong in the same article with Critical Race Theory, which is about as un-humble a theory as one can imagine. (For one thing, its advocates won’t accept anything that falsifies it, including income disparities among different ethnic groups.)

The article is completely useless, except to let the readers know that the editors of Lancet, by publishing it, show themselves to be Concerned. It will amount to nothing, change nothing, and says almost nothing. If the authors are trying to argue that racism exists at the higher levels of global health, let them say that clearly, deep-six the CRT, and then tell us how to efface this racism. More important, they should also tell us how greater equity at these levels will actually help the suffering people of the planet.

Sadly, this kind of stuff is being sent to me by readers with increasing frequency, and when it appears in one of the world’s best journals, I’m afraid I have to say something.

I’m done for today. Let’s move on to a cop and an owl.

The coronavirus and some basic evolutionary genetics

February 7, 2021 • 9:15 am

by Greg Mayer

Jerry and I were both working independently on posts about the coronavirus. When we realized this, we conferred and decided to continue our efforts, but with some coordination and cross-fertilization. Jerry’s piece was posted on Friday. 

[JAC: Greg has a “technical notes” section at the end which clarifies terms in the text that might confuse nonbiologists.]

1). Getting people vaccinated will impede the origin of new variants, because adaptive evolution is faster in larger populations. Widespread vaccination, by reducing the number of cases, will reduce the population size of the virus. Adaptive evolution is faster in large populations because selection is more effective in large populations; this is a well-known population-genetical result. And it’s also faster because large populations, by having a greater total number of mutations, explore more of the total mutational space—including the possibility of favorable double (or more) mutations in which the component single mutations are not favored but the combinations are. This is, in part, the principle behind the AIDS “cocktail” treatments: by attacking HIV in multiple ways at once, no single resistance-conferring mutation will allow the virus to escape, because if one drug doesn’t get it, another one will. Only having multiple mutations will confer resistance to the whole “cocktail”, but this is very improbable because the individual mutations, not being favored, will not accumulate. But in a very large sample (i.e., a large population), improbable things can happen.

There are also interesting issues of components of fitness or levels of selection in the evolution of viruses (or any disease-causing micro-organism, for that matter). Jerry discussed this in his piece, contrasting the evolution of virulence within an infected host versus transmissibility between hosts. These can be viewed as two components of reproductive fitness: competition to reproduce within the host, and competition to move to new hosts. Or it can be viewed as different levels of selection—individual selection among virus particles within hosts, and group selection between the populations of viruses between the hosts—they all get sneezed out to the next host as a group. The evolution of myxoma virus in rabbits in Australia, which Jerry discusses, has been interpreted from both points of view. The interest comes from the potential conflict between what’s “good” within the host (reproducing very rapidly), and getting to the next host. If you are too good at “taking over” the host, you might kill off the host before you can spread to the next host. And if you don’t spread, you go extinct. So, what’s good in the host may not be good for getting to the next host.

There’s also an interesting issue of what is the proper estimate of population size for the virus. Is it the number of viral particles? The number of hosts? For within-host selection, it would be the number of viral particles in that host. For selection between host populations, it might be nearer to the number of hosts. (I would guess that the theory for this has already been developed in the context of group selection theory.) Either way, fewer hosts, with lower viral loads within hosts, lowers the rate of adaptive evolution of the virus.

2.)  By a *very* crude analysis, the UK variant does not show evidence of selection on its protein sequences. The ratio of Nonsynonymous (N) to Synonymous (S) mutations is 13/6 = 2.17, which is very close to the expected ratio of 2.66 for neutral (i.e., unselected) mutation in a completely *random* genome. The defect of this analysis is that the virus’s genome is of course not random. I would expect that someone with the genomic sequence and the right software is already carrying out a proper analysis using the actual nucleotide and codon distribution of the virus. (In fact, I wouldn’t be surprised if it’s already been done; not being a virologist, I don’t follow that literature.) A second, and perhaps more important defect, which would apply even to a proper analysis, is that nonsynonymous/synonmymous ratios average over sites for a whole protein or genomic sequence, so even strong selection at one or a few sites in a protein can be lost in a sea of neutral change in the rest of the protein. (See Technical note below for more details.)

There are other ways of inferring selection, and Jerry stressed one of those: if the virus evolves in parallel in multiple locations, that suggests the action of selection. We seem to be seeing that, independently, in several different locations, the same variant is spreading widely and increasing in frequency. If the variants were neutral, their frequencies would change only due to chances of sampling and which variant happened to get somewhere first, so we wouldn’t expect the same variant to “get lucky” and take over all the time.

Another hint of selection would be if substitutions affecting function (such as nonsynonymous mutations and deletions) are concentrated in a part of the genome known to be of adaptive significance, such as the spike protein. That protein is a highly functional part of the virus, for it’s the part it uses to stick to host cells. The UK variant shows at least two nonsynonymous mutations and one deletion in the spike protein, but without full data, I can’t say if this is a greater than expected number for the spike protein (which forms ca. 10% of the genome).

3). The variants are differentiated strains, not “mutations”. The identified variants differ by multiple substitutions, and thus are not a mutation, but the accumulation of multiple mutations. Some substitutions in a strain may be subject to selection, but others will not be. If we think of the virus as a “species” (which, being a collection of asexual lineages, is not quite what the virus is), then the variants or strains are like “subspecies”: differentiated descendants of a common ancestor, differing in a number of ways, some of which may be adaptive, while others may not be. (In biological species, subspecies interbreed, and thus are a form of geographical variation; in viruses, however, the variants can exist without interbreeding in the same geographic area, including inside the same host, so the analogy to subspecies is inexact.)

4).  Some of the media, or at least reporter Apoorva Mandavilli of the NY Times, are grasping that virus evolution is key to the course of the pandemic. Words and phrases in her article include: “selection pressure”, “evolve” (4 times!), “evolving”, “evolutionary biologist”, “adaptation”, and “coronavirus can evolve to avoid recognition”. And here’s a statement in the article of the distinction between genetic drift and selection:

Some variants become more common in a population simply by luck, not because the changes somehow supercharge the virus. But as it becomes more difficult for the pathogen to survive — because of vaccinations and growing immunity in human populations — researchers also expect the virus to gain useful mutations enabling it to spread more easily or to escape detection by the immune system.

This article is a pretty direct affirmation of the importance of understanding how evolution works when dealing with viral diseases.

5).  After the AIDS epidemic, we all should have learned the importance of evolutionary biology for transmissible diseases. The lessons learned during the spread, evolution, and control of HIV and other viruses are so clear that they have become textbook examples of evolutionary principles, from elementary grades to college texts. Epidemics are all about evolution.

6.)  You should call it the “UK variant”. The article at Ars Technica from which I got the (limited) genomic data I used above, falls over itself trying not to use geographic terms because they cause “stigma”. This is stupid. One of the oldest practices in taxonomy is to name species after the place they are found. The native anole of the southern United States is named Anolis carolinensis, because the description was based on lizards supposed to be from Carolina. It was later found to occur all over the southeastern United States, with closely related forms (sometimes considered conspecific) on a number of West Indian islands. It has also been introduced all over the world, from California to Hawaii to Japan. It is still Anolis carolinensis. Stability of names is important, and names related to place are a useful mnemonic, since they require no knowledge of Latin or an arcane numbering system. (The article refers to the UK variant as “B.1.1.7”. If there’s only one variant this might do, but with multiple ones it becomes an exercise in memorization.) 

Technical note. “Nonsynonymous” mutations are mutations of the DNA sequence which change the amino acid structure of the resulting protein. Because the genetic code is redundant (DNA codes for the same amino acid in more than one way), some mutations are “synonymous”, resulting in an unchanged protein. There are 549 possible mutations of the 61 amino acid coding codons (61 codons X 3 nucleotides per codon X 3 possible nucleotides to change into). Of these possible mutations, 399 are nonsynonymous and 150 are synonymous. (I couldn’t find these numbers anywhere, so I counted them up myself from the table in Muse and Gaut (1994); my count could be off, but, I hope, not by much.) If a protein coding DNA sequence has a completely random sequence (i.e. all 61 protein coding codons are equally represented), then mutations occurring at random will occur with a nonsynonymous to synoymous ratio of

N/S = 399/150 = 2.66

and, if the mutations are neutral, will be fixed (i.e. will reach a frequency of 100%) in the same ratio, which is where I got the expected N/S ratio of 2.66 for evolution by neutral mutation.

However, the DNA sequence is not random, so we usually express the nonsynonymous/synonymous ratio by looking at the rate of substitution per site. Thus, we divide the the number of nonsynonymous mutations by the number of nonsynonymous sites (i.e. the number of nucleotide positions which would give rise to a nonsynonymous amino acid if mutated), and similarly for synonymous mutations. This gives us the dN/dS ratio, which is expected to be 1 under neutrality, because we have normalized by the expected rates of each type of mutation. It is greater than 1 when there is positive selection in favor of new mutations. In calculating dN/dS, adjustments can be made for known biases in the process of mutation (e.g. the different rates at which mutations which change the ring structure of the nucleotides occur).

dN/dS ratios are subject to some of the same limitations as raw N/S ratios, including the averaging effect noted above. Yang and Bielawski (2000) is a modestly readable introduction to using rates of nonsynonymous versus synonymous substitution to detect selection.

Charlesworth, B. and D. Charlesworth. 2010. Elements of Evolutionary Genetics. Roberts, Greenwood Village Colorado. An upper level text, but not as daunting as some. Amazon

Diamond, J., ed. Virus and the Whale: Exploring Evolution in Creatures Small and Large. NSTA Press, Arlington, Va. Uses HIV as an example of viral evolution. Amazon

Emlen, D. J. and C. Zimmer. 2020. Evolution: Making Sense of Life. 3rd ed. Macmillan, New York. Uses influenza as an example of viral evolution. Amazon

Herron, J.C. and S. Freeman. 2014. Evolutionary Analysis. 5th ed. Pearson. Uses HIV as an example of viral evolution. publisher

Muse, S.V. and B.S. Gaut. 1994. A likelihood approach for comparing synonymous and nonsynonymous nucleotide substitution rates, with application to the chloroplast genome. Molecular Biology and Evolution 11:715-724. pdf

Yang, Z. and J.P. Bielawski. 2000. Statistical methods for detecting molecular adaptation. Trends in Ecology and Evolution 15:496-503. pdf

h/t Brian Leiter for the Ars Technica piece.

My Pfizer jabs

January 27, 2021 • 10:45 am

As I’ve mentioned in passing, I’ve had two coronavirus shots; these used the Pfizer vaccine. The university hospital has been vaccinating a gazillion people, starting with healthcare workers on the front line, hospital employees, local oldsters (like me) and then residents of the South Side, mostly black, as well as healthcare workers who aren’t affiliated with the hospital but work on the South Side. It was heartening to go to the Covid clinic, an efficient and dedicated facility in the hospital, and wait in line with a cross-section of Chicago, including healthcare workers in their scrubs, all of us “in it together.” I have nothing but praise for that organization and its efficiency, and everyone was uber-friendly. I even got a “congratulations” after my second shot.

And as I stood in line, I realized what a fantastic thing these vaccines are, and, indeed, what all vaccines are.  If our immune system had no memory, if scientists hadn’t figured out that you could stave off disease by tweaking that memory, and if they hadn’t figured out how to do it without causing the disease, humanity would have been driven down over and over again.

The Pfizer vaccine is even more marvelous: a vaccine made by injecting into your arm a liquid solution of RNA “code” for the virus’s spike protein, with that code encapsulated in little fat bubbles. Once in your arm, the specially designed code makes its way to your cells, which then use the code to make many copies of the virus’s spike protein. Those free-floating copies are themselves harmless, but are the parts of the virus that adhere to cells when you get Covid-19. The immune system then recognizes the spike proteins as foreign, goes to work destroying them, and then the memory of those proteins is stored in our immune system (this is the way that all vaccines work). When you get a second shot, the immune system recognizes the spike proteins that it’s seen before, and mounts a huge defense against them, creating not only greater memory but often producing some side effects for the second jab. When you’ve mounted two defenses, your immune system is ready to go when it sees the spike protein on a virus that infects you.

In late December I wrote a post about how scientists had tweaked the spike protein’s RNA code to get it into our cells intact and make it produce many copies of the protein. That tweaking itself rested on years of molecular-genetic work done without the goal of making a vaccine. It’s a testament to the power of pure research and human curiosity.

All in all, I consider the mRNA vaccines, like the Pfizer and Moderna ones, as “miracles”—except I don’t like the word because it smacks of religion. But they do show what our evolved neurons are capable of doing when faced with a medical problem. I don’t know a secular word for “miracle”, but if there is one then it should be used with these vaccines. And remember, jabs went into arms less than a year after the virus first began its depredations in China. Further, the vaccine was designed within just a few days after the genome of the virus was decoded, which itself took less than a week.

But people want to know what the shots were like.  The first one was a piece of cake: it was a simple jab (they manage to get six doses out of a vial at the hospital, increasing the number of jabs by 20%), and I didn’t even have a sore arm. The only side effect was a very slight soreness at the injection site, but a soreness that could be detected only by pressing on the site.

It was 18 days between jab 1 and jab 2, though the usual period is 21 days. I took the shorter period because it was within CDC and Pfizer recommendations, and I was eager to become immune. I’m not sure how they know that 13-21 days is the right interval, and I don’t think they really did a lot of tests about that.

The second jab went into my arm on Monday. I was informed in great detail, and given an instruction sheet, that this jab was likely to cause more side effects, including chills, fever, muscle aches, and even vomiting. I was prepared for that: it’s better to suffer for a day or so than to get infected! I felt fine throughout Monday, but my arm was a little bit more sore than after the first jab. On Tuesday morning I also felt pretty good, and, because they said symptoms may begin within 12-24 hours, I thought I was home free.

That was not to be. At about noon yesterday (28 hours after my second jab), I begin feeling muscle aches, overall tiredness, and a general malaise, as if I were getting the flu. I recognized this as side effects and went home, dosing myself with Tylenol. My temperature, which is normally low (about 97.3° F, went up a bit, to 99.5°F). I did not lose either my appetite or sense of taste or smell, and I had a decent dinner but abjured the vino. I went to bed still feeling out of it.

But I woke up this morning feeling right as rain. As the instructions said, the side effects pass within 48 hours.  One has to wait two weeks, I understand, to acquire the vaunted 95% immunity that comes with this vaccine. From this my advice would be “when you get your injection, schedule it for late in the afternoon, go home, and then be prepared to not go to work the next day.” A Friday afternoon would be ideal for that second shot.

I asked the nurse who gave me the second jab if there was any correlation between the severity of one’s side effects and the effectiveness of the immunization. One would think that a vigorous immune response to the second dose, indicating that your immune response was quite active against the protein, would mean that you’d be better protected against the real virus. In other words, the worse the side effects, the better off you are. She said there was no correlation, as did the instruction sheet I got. I still am a bit dubious, but if there is a correlation, that I’m good to go against the virus.

Of course I urge everyone to get their jab. I asked a staff member on campus with whom I’m friends if she got the jab. I was surprised when she said “no.” When I asked why, she said because “people had died from the vaccine.” She was afraid of it, which I think is a fairly common feeling. But I looked up the deaths associated with the Pfizer vaccine, and, as we know, it’s not risky. There were six deaths during the phase 3 trials, but four of those were in the control group. Two died in the vaccine (experimental) group, one from arteriosclerosis and the other from a heart attack. Those deaths were probably the results not of the vaccine, but of underlying conditions. Of course some people will die after being vaccinated: as the control group shows, that will happen in any large group of people! On balance, though, all the experts say it’s better for your own welfare to get vaccinated than to risk Covid-19. And it’s better for society as well, since the more people who get vaccinated, the quicker we’ll attain herd immunity.

I went back to my friend and told her the statistics, but she was unmoved, and clearly didn’t want to discuss the point. Although I was concerned with her health, I realized that there was no point in arguing, as vaccination avoidance is almost a form of religion, and certainly a type of faith. I won’t bring up the subject again.

I’m sure all readers here are eager to get their shots, and it’s frustrating to watch while others get them but you can’t get an appointment. Biden and his administration are working hard on the issue. But we should be cognizant of the vaccine shortages in other countries, which are far more severe than in America or Europe. The news last night reported that America will have five times the number of doses necessary to vaccinate the entire population, and Canada six times. Couldn’t the excess be used in places like Latin America, where the Covid rate is high but vaccines rare?  I know that Bill Gates and others are donating lots of dosh to buy vaccines for poor countries, but we will need about 18 billion dollars to do that job. This is not a U.S. or European issue, but a world issue, and with the vaccine we should be far more concerned about other countries than we usually are. Even from a selfish point of view, if you don’t go after Covid everywhere, the whole world remains in danger.

I didn’t take a “vaccine selfie”; here’s the best I can do:

The mRNA coronavirus vaccine: a testament to human ingenuity and the power of science

December 27, 2020 • 9:45 am

The Pfizer and Moderna vaccines are a triumph of both technology and of drug testing and distribution. But to me, the most amazing thing about them is how they were designed. Unlike most vaccines, which are based on either weakened or killed viruses or bacteria, these use the naked genetic material itself—specifically, messenger RNA (mRNA). Viral mRNA serves normally to make more viruses using the host’s own protein-making machinery, and the virus’s genome codes for the most dangerous (and vulnerable) part of the virus: its spike protein. This is the protein that, sticking out all over the virus, recognizes and binds to the host cell—our cells. That allows the virus to inject its entire genome into our cells, commandeering our metabolic processes to make more viruses, which then burst out of the cell and start the cycle all over again.

The spike protein is the dangerous bit of the virus; without it, the virus is harmless. If we could somehow get our immune system to recognize the spike protein, it could then glom onto and destroy the viruses before they start reproducing in our cells. And that’s what the Pfizer and Moderna vaccines do.

The vaccine is in fact composed not of spike protein itself, but of artificially synthesized instructions for making the spike protein. Those instructions, coded in mRNA, are packed in lipid nanoparticles and injected into our arms.  The mRNA, engineered to evade our body’s many defenses against foreign genetic material, goes into our cells and instructs our own protein-synthesizing material to make many copies of the spike protein itself.  Since these copies aren’t attached to a virus, they aren’t dangerous, but they prime the immune system to destroy any later-attacking viruses by zeroing in on the spike proteins on the viral surface.

Thus the vaccine uses our own bodies in several ways: to make copies of just the spike protein, and then to provoke our immune system to recognize them, which the body “remembers” by storing the instructions to fabricate antibodies against real viral spike proteins.  The part of this story that amazes me is the years of molecular-genetic studies that went into our ability to design an injectable mRNA, studies that weren’t done to help make vaccines, but simply to understand how the genetic material makes proteins. In other words, pure research undergirded this whole enterprise.

You can read a longish but fascinating account of how the mRNA vaccine was made at the link below at science maven and engineer Bert Hubert’s website (click on the screenshot). Hubert doesn’t go into the details about packaging the engineered mRNA into lipid nanoparticles, which is a tale in itself, so there’s a lot more to learn. At the end, I’ll link to a story about how quickly this vaccine was made—less than a week to both sequence the virus’s RNA, including the spike protein, and then use that sequence to design a vaccine based on the spike protein.  What I’ll do here is try to condense Hubert’s narrative even more. 

Before China even admitted that the viral infection was dangerous and spreading, Yong-Zhen Zhang, a professor in Shanghai, had already sequenced its RNA (the genetic material of this virus is RNA, not DNA), and then deposited the sequence on a public website (a dangerous thing to do in China). The entire viral genome is about 29,000 bases long (four “bases”, G, A, C, and U, are the components of RNA), and makes 6-10 proteins, including the spike protein.

Within only two days after that sequence was published, researchers already knew which bit coded for the spike protein (this was known from previous work on coronaviruses) and then, tweaking that sequence, designed mRNA that could serve as the basis of a vaccine. Once you’ve designed a sequence, it’s child’s play these days to turn it into actual RNA.

The final mRNA used in the Pfizer vaccine is 4282 bases long (if you remember your biology, each three bases code for a single amino acid, and a string of amino acids is known as a protein). But the vaccine mRNA does a lot more than just code for a protein. Here are the first 500 bases of the Pfizer mRNA as given by Bert Hubert, and below you’ll see a diagram of the whole mRNA used in the vaccine:


If you remember your genetics, this sequence looks odd, for mRNA sequences usually contain the bases A, G, C, and U (uracil). Where are the Us? In this vaccine, the Us have been changed into a slightly different base denoted by Ψ (psi), which stands for 1-methyl-3′-pseudouridylyl. I’ll give the reason they did this in a second.

But what you see above is less than one-eighth of the whole mRNA used in the vaccine. I won’t give the whole sequence, as it’s not important here, but the structure of the mRNA is. Remember, this was engineered by people using previous knowledge and their brains, and then entering the sequence into a “DNA printer” that can fabricate DNA that itself can be turned into virus-like RNA. Isn’t that cool? Here’s a picture of the Codex DNA BioXp3200 DNA printer used to make the DNA corresponding to the vaccine’s RNA (photo from Hubert’s site):

And here’s the heart of this post: the structure of the 4282-nucleotide string of RNA that is the nuts and bolts of the vaccine (also from Hubert):

You can see that it’s complicated. The heart of this is the “S protein__mut”, which is the engineered code for the spike protein. But all that other stuff is needed to get that bit into the cell without it being destroyed by the body, get it to start making lots of spike protein to act as a stimulus (antigen) to our immune system, and to get the spike protein made quickly and copiously. The more innocuous spike protein we can get into our body, the greater the subsequent immune response when the virus attacks. Each bit of the mRNA shown in the diagram above has been engineered to optimize the vaccine. I’ll take it bit by bit:

Cap: Underlined in the diagram above, this is a two nucleotide sequence (GA) that tells the cell that the mRNA comes from the nucleus, where it’s normally made as a transcript from our DNA. These bases protect the engineered RNA from being attacked and destroyed by our body, as it makes it look like “normal” RNA.

Five prime (5′) untranslated region (“5′-UTR”) in the diagram.  This 51-base bit isn’t made into spike protein, but is essential in helping the mRNA attach to the small bodies called ribosomes where it is turned into proteins—three-base “codon” by three-base “codon”—with the help of smaller RNA molecules called “transfer RNAs” (tRNAs). Without the 5′-UTR, the protein won’t get made. Besides helping get the engineered mRNA to the ribosomes, this region has been further engineered. First, the Us have been engineered into Ψs, which keeps the immune system from attacking the mRNA without impairing its ability to attach to the ribosomes and make protein. And the sequence has been further tweaked to give it information for making a LOT of protein. To do this, the designers used sequence from our alpha-globin gene’s UTR, for that region makes a lot of protein. (Alpha globin is one half of our hemoglobin molecules, one of the most copious and quickly made proteins in the body.)

S glycoprotein signal peptide (“sig”) in the diagram. This 48-base bit, which does become part of the protein, is crucial in telling the cell where to send the protein after it’s made. In this case, it tells it to leave the cell via the “endoplasmic reticulum”, a network of small tubules that pervades the cell. Even this short bit was engineered by the vaccine designers, who changed 13 of the 48 bases. Why did they do this? Well, they changed the bases that don’t make a difference in the sequence of the protein (these are usually bases in the third position, whose nature isn’t important in protein sequence). But these bases do affect the speed at which a protein is made. Hubert doesn’t explain why this happens, but I suspect that the engineered changes were designed to fit with more common transfer-RNA molecules (tRNAs), which are the small bits of RNA that attach to amino acids in the cytoplasm and then carry them to the mRNA to be assembled into proteins. While there are 64 three-base sequences (4³), there are only 20 amino acids that normally go into proteins. That means that some tRNAs code for the same amino acids. Since these “redundant” tRNAs are not present in equal quantities in the cell, you can make proteins faster if you design an mRNA sequence that matches with the most common tRNAs. I’m guessing that this is what these 13 changes were about.

Spike protein (“S protein__mut”) in the diagram. This is the heart of the mRNA, containing 3777 bases that code for the spike protein. In this code, too, they’ve “optimized” it by changing the “redundant” bases to allow protein to be made faster. The Ψs are now gone, as they’re not needed to evade the body’s defenses.  But there’s one bit that puzzled me until I read Hubert’s explanation. The spike protein made by the body after vaccination differs from the viral spike protein in just two of the 1259 amino acids. The engineered sequence substitutes two amino acids—both prolines—for amino acids in the viral spikes. Why? Because it was known from previous work that these prolines stabilize the spike protein, keeping it from folding up. It thus retains the same shape it has in the native virus. A folded-up spike protein may induce antibodies, but they won’t readily go after the virus’s own spike proteins because their shape is different.  This is just one of the many bits of prior knowledge that came to bear on the vaccine’s design.

The 3′ untranslated region (“3′-UTR”) in the diagram: mRNA’s have these, but we’re not quite sure what they do, except, as Hubert says, the region is “very successful at promoting protein expression.” How this happens is as yet unclear. This bit, too, was engineered by the vaccine designers to make the mRNA more stable and boost protein expression.

The poly-A tail (“poly[A]” in the diagram). This is the 140-base end of the message. All mRNAs made into proteins contain a repeat of the adenine base at the butt (3′) end, so we get an AAAAAAAAAAAAA. . . sequence. It turns out that these A’s are used up when an mRNA molecule makes protein over and over again (they’re like telomeres that get shorter as we age!). When all the As are gone, the mRNA is useless and falls off the ribosomes. Again, previous knowledge told the designers how many As to put at the end of the sequence.  It was known that around 120 As gave the best result in terms of protein production; the designers used 100 As split up with a 10-base “linker” sequence. Hubert doesn’t explain the linker, and I don’t know why it’s there.

Nevertheless, you can see the complexity of this vaccine, whose design rests on an exact knowledge of the spike protein’s sequence (recent mutations in the sequence don’t seem to affect the efficacy of the vaccine, as they probably don’t affect the spike’s shape), as well as on previous research about stuff like the Ψ bases helping evade mRNA destruction, the optimum sequences for high production of protein, the number of As at the end that are most efficacious, and then those two proline substitutions in the vaccine’s spike protein. It’s all marvelous, a combination of new and old, and a testament to the value of pure research, which sometimes comes in mighty handy.

This prior knowledge, combined with fast sequencing of RNA and the development of machines to turn code into RNA, help explain why the vaccine was designed so quickly. Of course it had to be tested and distributed as well, and this Guardian article tells you ten additional reasons why it took only ten months to go from the onset of the pandemic to a usable vaccine.

Finally, a bit of history of science is recounted by “zeynep” at Substack, showing additional reasons why the vaccine came out so quickly (click on screenshot). It’s largely about Yong-Zhen Zhang, the Chinese scientist who published the genetic code of the Covid-19 virus. Zeynep sees him as a hero who took risks with that publication. What’s clear is that without that code (and of course sequencing of DNA and RNA has been done for a long time—another benefit of pure research), we wouldn’t be near as far along as we are in battling the pandemic.

When you think about all this, and realize that only one species has both the brains and the means to make a designer vaccine to battle a devastating virus, and then think about the many scientists whose work contributed over many years to the knowledge involved in designing these vaccines, it should make you proud of humanity—and of the human enterprise of science. Yeah, we screw up all the time, and are xenophobic and selfish, but this time we overcame all that and used the best in us to help all of us.

Thanks to Bert Hubert for helping me understand the complexity of these vaccines.

Guest post: The New Yorker suggests that “other ways of knowing” can cure Covid-19

December 17, 2020 • 9:15 am

A few years ago I got an email from a colleague who was disturbed about the anti-science attitudes of the New Yorker, which include an emphasis on “other ways of knowing” —often through the arts and literature. But first I’ll repeat my colleague’s analysis:

The New Yorker is fine with science that either serves a literary purpose (doctors’ portraits of interesting patients) or a political purpose (environmental writing with its implicit critique of modern technology and capitalism). But the subtext of most of its coverage (there are exceptions) is that scientists are just a self-interested tribe with their own narrative and no claim to finding the truth, and that science must concede the supremacy of literary culture when it comes to anything human, and never try to submit human affairs to quantification or consilience with biology. Because the magazine is undoubtedly sophisticated in its writing and editing they don’t flaunt their postmodernism or their literary-intellectual proprietariness, but once you notice it you can make sense of a lot of their material.

. . . Obviously there are exceptions – Atul Gawande is consistently superb – but as soon as you notice it, their guild war on behalf of cultural critics and literary intellectuals against scientists, technologists, and analytic scholars becomes apparent.

Today’s topic, though, is “other ways of knowing through folk wisdom“. In particular: ways of healing used by indigenous people. Now this shouldn’t be rejected out of hand; after all, many modern remedies, like quinine, derive from plants used by locals. But that doesn’t imply a wholesale endorsement of “the collective lived experience” touted in this video about plant-based healing. For the “collective lived experience”, after all, sometimes includes shamanism and, in the example below, “spiritual elements” as a way of curing disease. And here the disease that “lived experience” tackles is something the Siekipai of Ecuador have never experienced: Covid-19.

Reader Jeff Gawthorpe saw a New Yorker video at the link below; I’m not sure whether you’ll have free access, but you will using the yahoo! finance link at the bottom, where the video was republished.

Jeff is about as distressed as I by the fulminating wokeness of the magazine and delivered his critical “review” of the video, which I asked if I could put up in full, including his name. (I don’t like paraphrasing other people’s words, especially when they’re as good as the analysis below). Jeff said that was fine, and so here is his take, indented. I have to say that I agree with it, and have a few comments of my own at the bottom.

Around 30 minutes ago I happened across a dreadful video on the New Yorker‘s website, which drove my temptation to meet head with keyboard through the roof. This piece of ‘journalism’ was entitled: “Fighting COVID-19 with Ancestral Wisdom in the Amazon”. And yes, It’s as bad as it sounds: unscientific, irresponsible nonsense. Complete tosh.

The message which the piece attempts to convey is that COVID-19 can be dealt with by ‘lived experience’, ancient ‘ways of knowing’, and a few bits of boiled tree bark. Then, if you hadn’t had enough already, Just before the end, a caption pops up saying: “With a new stock of plants, the Siekopai are prepared to address future outbreaks of the virus according to their traditions.” Urrrhhgg.

You’ll notice that they are canny enough to maintain a degree of plausible deniability by making no definite claims. To me this demonstrates the very worst of journalism:

  • Conveying mistruths to support an ideology
  • Lacking the courage to commit to claims by asserting them as supportable facts

That’s bottom of the barrel journalism at the best of times, but now it’s irresponsible, reckless even. It presents a clear message that indigenous knowledge and ancient wisdom are perfectly acceptable ways of dealing with the pandemic. At no point is it mentioned that these ‘remedies’ are not backed by evidence, clinical or otherwise.

As you know, many western societies have huge anti-vax movements which often distrust and denounce mainstream medicine. Unfortunately, this video just adds fuel to the anti-vaxers fire. By failing to mention that these plant ‘remedies’ have zero efficacy, they are providing implicit support to the anti-science, anti-vax groups. Worse still, they are acting like digital snake oil salesmen, imbuing members of the public with false confidence that that they can avoid or fight off this virus with a couple of well chosen tree bark specimens. It’s dangerous, irresponsible nonsense.

Click below to see the video:

My own comments are few. First, it looks like the “remedy” includes cinchona bark, the source of quinine, as a palliative (the remedy seems directed at symptomatic relief rather than a cure).

Second, even “lived experience”, while useful, is no substitute for double-blind clinical trials. Granted, the Siekipai can’t do that, but they sure as hell should take the vaccination when it gets to them.  And, like Jeff, I think it’s totally irresponsible of The New Yorker to present this video without any kind of caveat. After all, when Trump skirts the truth, they don’t hesitate to correct him.  I guess “lived experience of indigenous people” is a different matter—it’s not as if they’re recommending drinking bleach or anything.

My doctor’s new post about the Pfizer vaccine: your questions answered (and you can ask the doc if you have others)

December 14, 2020 • 10:15 am

My GP, Dr. Alex Lickerman, has once again put up a coronavirus post on his practice’s website, and allowed me to reference it here. It’s timely because it’s all about the new Pfizer vaccine. (A ICU nurse in New York may have been the first to get the shot.) How effective is it, and how do we know that? Is it safe? What about kids under 16, who weren’t part of the clinical trials? And pregnant women, who also weren’t tested? Since this is a mRNA rather than a killed-virus vaccine, should we have extra concerns about safety? What adverse reactions have been reported? If you were already infected, does the vaccination also reduce your risk of getting reinfected?  When will “normal” people who aren’t healthcare workers or nursing-home patients be able to get their jabs?

Alex has kindly agreed, as he has before, to answer readers’ questions about the new vaccine, so put your questions in the comments section below and he’ll address them as he has time. Alex has read all the relevant scientific literature, as well as the data from the vaccine trials, so ask away! But do read his 4-page summary beforehand, as it has a lot of information.

I’m not going to put up his whole post; you can go to his site to see it,  which you can do by clicking on the screenshot below:

I’ll just post Alex’s recommendations, followed by his list of “unanswered questions” (indented). The short message: GET THE SHOT AS SOON AS YOU CAN!

CONCLUSIONS

  1. The vaccine is highly effective in preventing symptomatic COVID-19 infection.
  2. The vaccine is safe. Adverse reactions, both local and systemic, are mostly minor. Though the study hasn’t yet gone on long enough to prove there are no serious long-term adverse affects, such adverse affects, if they exist, are likely to be rare and non-life-threatening based on other Phase I and II studies of other RNA vaccines.
  3. We recommend everyone who is eligible to receive the vaccine should receive it when it becomes available to them.
  4. It very well may take all of 2021 to get everyone who’s willing to be vaccinated to receive the shots, which means it likely won’t be until early 2022 that life returns to pre-pandemic normal. In the meantime, continue to wear a mask when indoors with anyone you don’t live with, wash your hands frequently, and refrain from dining indoors at restaurants.

UNANSWERED QUESTIONS

  1. While suggested by the study, still left unproven is whether BNT162b2 [Pfizer’s name for the vaccine] prevents severe COVID-19 infection, whether it prevents COVID-19 infection after just one dose, and whether it prevents COVID-19 infection in subjects who’ve already had COVID-19.
  2. The study didn’t look to see if the vaccine prevents asymptomatic infection. Nor did it assess whether subjects who developed COVID-19 despite vaccination are less likely to transmit the virus. Thus, it’s not yet clear how effective the vaccine will be in containing the spread of the infection.
  3. The study hasn’t gone on long enough to tell if subjects who were vaccinated yet still contracted COVID-19 have a lower risk of long-term effects of COVID-19.
  4. We don’t yet know if the vaccine reduces the risk of dying from COVID-19.
  5. There was insufficient data to draw conclusions about safety and efficacy of the vaccine in children younger than 16, pregnant or lactating women, and patients who are immunocompromised.
  6. We don’t yet know how long immunity lasts and whether or not booster shots will be necessary.

Britain’s High Court restricts medical treatment of teenagers who identify as transsexual

December 2, 2020 • 11:00 am

Lately we’ve been talking about several issues related to transsexual people, in particular the senses in which they can or should be distinguished from people of their biological sex, including their participation in sports; possible effects (or lack thereof) of hormone treatment; and recent books that call for caution in supporting and medically treating gender-dysphoric teenagers who may later regret actions taken when they weren’t capable of informed consent. While I think the discussion has been rational and certainly not “transphobic”, I’ve nevertheless been the recipient of a spate of emails, often nasty ones, excoriating me for promoting an “anti-trans” agenda. I’ve resisted the temptation to respond with recommendations for self-copulation.

The last issue, treatment of young children (mostly girls), is the subject of today’s post. It turns out that yesterday Britain’s High Court ruled that children under 16—and perhaps those between 16 and 18—might have to have a court ruling before they’re allowed to take “puberty blockers”, a somewhat reversible treatment that stops puberty in its tracks. Taking these blockers is usually the first step in further transitioning involving irreversible treatments like cross-sex hormone treatment or surgery. The court ruled that under-16s are largely incapable of giving “informed consent.” You can read about this case in the three article below from the BBC, The Guardian, and The Times of London (click on screenshots to access articles).

From the BBC:

From The Guardian:

From the Times (paywalled):

The High Court decision came in a case brought by two people against the Tavistock and Portman National Heath Service Trust, the clinic in England that counsels and treats those who consider themselves transsexual. One of the cases was brought by Keira Bell, 23, shown in the pictures above. She was treated with puberty blockers at Tavistock after she was referred there at 16, and regrets it. (I’m not implying that most teenagers later regret such treatment, as I have no data on that, but I suspect most of them have no regrets. Nevertheless, if an appreciable number do, that’s a reason for caution.)

The other person bringing the case was “Mrs. A”, the mother of a 15-year-old autistic girl who is awaiting treatment at Tavistock “Mrs. A.” is worried that her daughter will “get it wrong” before she can make a mature decision.

There are a fair number of young girls who have sought and received treatment at Tavistock: the paper reports that, in the last year, 161 children were referred to the Gender Identity Development Services (GIDS), and of these three were 10 or 11 years old and 95—nearly 60%—were under 16. The Times notes that those seeking treatment involve “a disproportionate amount of girls and young women.”  These numbers have been growing rapidly, from 97 children and young people referred to the clinic compared to 2,591 in 2018. Here’s a plot I showed recently:

Here’s a plot from a paper in the Archives of Sexual Behavior showing the number of people referred each year to the UK’s Gender Identity Development Service. It shows the strong rise in referrals of adolescent females compared to males, and some rise in children as well. In the last 7 years it seems to have gone from fewer then 40 to over 1700 in adolescent females—a roughly 43-fold increase!

We don’t know the reason for this rapid increase: among suggested causes are a freer climate that allows children to express their gender identities, or a faddishness that turns troubled or confused children to a form of treatment that is heavily supported and often makes them into a type of hero.

Regardless, here’s the papers’ summary of the High Court ruling (you can read the full ruling here); this is from The Guardian:

In their decision, Dame Victoria Sharp, president of the Queen’s bench division, Lord Justice Lewis and Mrs Justice Lieven, said a child under the age of 16 may only consent to the use of medication intended to suppress puberty “where he or she is competent to understand the nature of the treatment”.

Such an understanding must include “the immediate and long-term consequences of the treatment, the limited evidence available as to its efficacy or purpose, the fact that the vast majority of patients proceed to the use of cross-sex hormones, and its potential life-changing consequences for a child”.

The judges said there would be enormous difficulties for young children weighing up this information and deciding whether to consent to the use of puberty blocking medication.

“It is highly unlikely that a child aged 13 or under would be competent to give consent to the administration of puberty blockers,” the judges added. “It is doubtful that a child aged 14 or 15 could understand and weigh the long-term risks and consequences of the administration of puberty blockers.”

For treatment of those over 16 it is normally presumed that they have the ability to give consent. But in gender reassignment cases where puberty blockers may lead to subsequent surgical operations, the judges said: “Given the long-term consequences of the clinical interventions at issue in this case, and given that the treatment is as yet innovative and experimental, we recognise that clinicians may well regard these as cases where the authorisation of the court should be sought prior to commencing the clinical treatment.”

The NHS, which is appealing the judgement, has immediately stopped the inception of puberty-blocking as well as cross-sex hormone treatment, and issued some statements. From the BBC:

An NHS spokesperson said: “We welcome the clarity which the court’s decision brings. The Tavistock have immediately suspended new referrals for puberty blockers and cross-sex hormones for the under-16s, which in future will only be permitted where a court specifically authorises it.”

In September, the NHS announced an independent review into gender identity services for children and young people.

The Tavistock and Portman NHS Trust said it was “disappointed by today’s judgment and we understand that the outcome is likely to cause anxiety for patients and their families”.

It added: “Our first duty is to our patients, particularly those currently receiving hormone blocking treatment, and we are working with our partners, University College London Hospitals NHS Foundation Trust and Leeds Teaching Hospitals NHS Trust, to provide support for patients concerned about the impact on their care.”

In contrast, groups like the “trans children’s charity Mermaids” decried the decision:

Lui Asquith, from trans children’s charity Mermaids, said the ruling was a “devastating blow” and “a potential catastrophe for trans young people across the country”.

The charity said: “We believe very strongly that every young person has the right to make their own decisions about their body and that should not differ because somebody is trans.”

You can see more about Mermaids’ reaction here. But their last statement skirts the question that the Court was asked to decide: How old must you be before you are capable of making a medical decision that may be irreversible?  And it’s not just trans people to whom this applies: what if a 13-year-old boy wanted his penis removed because he didn’t like it? Should he be able to make “his own decision about his body”?

I think that reasonable people should agree that there is an age below which a child isn’t deemed capable of making a medical decision like this one, even if they feel strongly that they are transsexual.  Surely 6 is too young and 20 sufficiently old to make a “mature” judgement. But it’s also clear that children differ in the level of “maturity”, so there might be some flexibility (though there isn’t in things like drinking ages). The court, in ruling that 16 is a cut-off point, was surely being subjective, and they realized it, for they affirmed that even older teenagers might require a court judgment to begin puberty blockers. For those younger than 16, it seems reasonable to me to wait until they turn 16 until they can give “informed consent,” or be able to bring their case to legal judgement.

Those who think that 10-year-olds should be able to make their own decisions, and take puberty blockers or cross-sex hormone treatment at will (counseling is surely required), seem to me unreasonable. After all, courts have set age limits for other decisions that require “informed consent”, like age limits for statutory rape (in Illinois, 17 is the legal age of consent for sexual acts. If you’re 16, are you too young to consent to sex but old enough to have your sex transformed to another?) It’s a sign of the valorization of all desires to be transsexual that a charity like Mermaids wants anyone, no matter how old, to have their own decisions not just respected, but acted upon.