Akiko Iwasaki talks about mucosal immunity

Akiko Iwasaki is a Professor of Immunology at Yale and a former student in my department (Dept. of Biochemistry, University of Toronto). She got her undergraduate degree in biochemistry in the mid-1990s¹ and then did her Ph.D. in the Dept. of Imunology under my friend and colleague Brian Barber.

Alex Pallazzo is a keen podcast listener and he alerted me to an interview with Akiko Iwasaki on the EMBO podcast channel: The Right Place at the Right time. There are several reasons why listening to this podcast is worthwhile if you are interested in science and immunology. The most important reason is that it gives you a good idea of the depth of knowledge in the field because the level of the interview is pitched at those who have a considerable understanding of imunology. I'm not one of those people but I recognize good science when I hear it.

Another reason is that she discusses COVID-19 and how vaccines work. As you know from earlier posts, the serum antibody levels induced by the current vaccines wane after a few months so that vaccinated people can get infected by the SARS-CoV-2 virus. The secondary response then kicks in protecting you from serious illness. In order to stop the initial infections and prevent the spread of the virus we might have to get booster shots every six months or so and that's not a satisfactory solution.

Iwasaki works on something called mucosal immunity, which is new to me but very familiar to the experts. Here's a brief description from her website and a figure from Wikipedia.

The mucosal surfaces represent major sites of entry for numerous infectious agents. Consequently, the vast mucosal surfaces are intricately lined with cells and lymphoid organs specialized in providing protective antibody and cellular immunity. One of the most fundamental issues in this field concerns how antigens in the mucosa are taken up, processed, and presented by antigen presenting cells. Our laboratory's goal is to understand how immunity is initiated and maintained at the mucosal surfaces, particularly by the dendritic cells (DCs), through natural portals of entry for pathogens that are of significant health concerns in the world.

We focus on understanding how viruses are recognized (innate immunity) and how that information is used to generate protective adaptive immunity.

I hope I understand this well enough to explain it in simple terms. Mucosal immunity means that there are IgA antibodies in the mucosa that surrounds cells in certain parts of the body. For our purposes, the cells in the respiratory tract are important in COVID-19. The memory B-cells and T-cells that respond to the antigen are located right under the mucosa. Imagine that you could produce a vaccine that induced IgA against SARS-CoV-2 in the mucosa. The antibodies would be located right where the virus enters the body and they don't disappear over time like IgG in the blood stream. Furthermore, the secondary response is induced right near the site where the virus is attacking the body.

I think you need a nasal/throat spray vaccine to make this work and such vaccines are under development. They would probably have to be given in conjunction with the intra-muscular mRNA vaccines. I wish I could get Brian Barber to explain this but I can't seem to contact him. He gave a short lesson in immunology on his daughter, Jill Barber's Instagram account last year so I know he could do it.

I learned one other thing from listening to Akiko Iwasaki. We know that SARS-CoV-2 is more virulent in cold weather, especially during the winter months. She explains that the mucosal layer needs to be kept moist but during the winter months it can dry up due to the low humidity. The outside air is cold, therefore the humidity is low, and we import that air into our homes and workplaces. This dry air promotes spread of the virus.

Maybe we should be installing extra humidifiers to keep the humidity at higher levels?

It's a bit of a stretch from Akiko Iwasaki to Jill Barber but we've known Jill since she was little and my wife and I are big fans so here's a musical interlude to take your mind off COVID-19.

---

1. She must have taken my Molecular biology course and that's probably why she knows so much!

What is the best COVID-19 vaccine?

Take any vaccine you can get whenever you can. Moderna is the probably the very best vaccine and Pfizer-BioNTech is a close second. AstraZenica is very good but Johnson & Johnson not so much.

A brief summary of the COVID-19 vaccines was published in the Dec. 23rd issue of Nature. It doesn't go into a lot of details but I think the overall impressions are valid. The most serious probem with the summary is that it doesn't take into account the Omicron variant.

Mallapaty, S., Callaway, E., Kozlov, M., Ledford, H., Pickrell, J. and Van Noorden, R. (2021) How COVID vaccines shaped 2021 in eight powerful charts. Nature 600:580-583. [PDF] The extraordinary vaccination of more than four billion people, and the lack of access for many others, were major forces this year — while Omicron’s arrival complicated things further.

The first graph shows the popularity of the major vaccines. It's significant for two reasons. First, people in North America don't realize that the AstraZeneca vaccine has made such an enormous contribution to fighting the pandemic. That's because AstraZenica wasn't approved in the United states in spite of its effectiveness and it got a bad reputation in Canada.

Second, the Chinese vaccine, CoronaVac (also known as Sinovac), has been widely distributed throughout the world. The CoronaVac vaccine is an inactivated virus vaccine that doesn't require ultracold temperatures for storage and it is relatively cheap to manufacture. China has been vaccinating people everywhere, notably in Brazil and Indonesia. The CronaVac vaccine was quite effective against the early variants but it doesn't work as well with the Omicron variant.

The distribution data also shows that the Pfizer-BioNTech vaccine, the one developed in Germany, is far more popular than the Moderna vaccine that was developed in the United States. Even Sinopharm, another Chinese vaccine, is more popular than Moderna. As far as most of the world is concerned, it's the German, British, and Chinese vaccines that are going to save them and not the one created in Boston.

Some of the vaccines are more effective than others but unfortunately the Nature article only addresses the vaccines that are widely used in Europe and North America. The data shows that the mRNA vaccines are very effective against all of the variants that arose before Omicron. The mRNA vaccines not only protected against symptoms but also against severe disease (hospitalizations). The AstraZenica vaccine was also very good but not quite as good as the mRNA vaccines. The Johnson & Johnson vaccine was much less effective.

These data do not address any possible side effects of these vaccines and that's important because it is widely believed in some countries that the AstrZenica vaccine poses a much higher risk of side effects. That's not true. There may be a slightly increased risk of side effects with AstraZenica but it's not significant.

The vaccine's ability to block symptoms depends on the antibody levels in the serum while the ability to prevent long-term infections depends on the development of robust memory B-cells and T-cells. As with all vaccines, the initial antibody levels fall after the vaccination so the ability to prevent initial infections by the virus wanes over time [The omicron variant evades vaccine immunity but boosters help] [On the effectiveness of vaccines].

You can see from the above graph that the vaccines' ability to prevent infecion by the Delta variant falls off considerably by six months after completing the vaccination schedule. It's important to note that this data is with the Delta variant and it explains why countries that rushed to vaccinate their population as quickly as possible in early 2021 suffered more in the Delta wave. It's why booster shots were promoted in Israel and the United States because both of those countries vaccinated early and waited only the minimal time between doses. (Other countries waited longer between the first and second doses so the waning of initial infection was delayed.)

The waning effect is even more pronounced with the Omicron variant because it arose later in the year when far more people were beyond the six month limit of primary infection protection. What this means, I think, is that the Omicron variant isn't special because it "escapes immunity"—that would have been true of any new variant just as it was true of Delta. In any case, the mRNA vaccines are better because they start with a higher level of protection and if the data is accurate it means that Moderna is better than Pfizer.

I was prompted to post this article because many Canadians are hesitant to get the Modern vaccine for their booster shot, especially if they had Pfizer first. That's ridiculous. Moderna is probably a bit better and, besides, there's plenty of data showing that mixing vaccines is better than sticking with the same one for all your shots.

---

Image Credit: The coronavirus figure is from Alexy Solodovnikov and Wikmedia Commons.

Ontario (Canada) hospitals are filling up with fully vaccinated patients

The Omicron wave is surpassing all records for the number of cases in Ontario. The province has given up on testing for most people so the actual case counts are far higher than the reported cases and it's unlikely that the numbers are dropping in spite of what the graph (below) might suggest. Judging by what's going on in other countries, the peak is still a week or two away.

Ontario residents have been very good about getting vaccinated. As of today, 88% of eligible people over the age of 12 have been fully vaccinated and 91% have received at least one dose. The 5-11 age group became eligible about six weeks ago and so far 45% have had one shot. This places Ontario (and the rest of Canada) among the most vaccinated places in the world.

Since the unvaccinated population is only 10% of the total, this means that most of the cases are among the fully vaccinated population and most of those cases are mild or asymptomatic. Fully vaccinated people are also getting infected in other countries but the effect is often masked by a large number of cases among the unvaccinated population. This can deceive people into believing that you don't need to worry if you are fully vaccinated.

About 30% of eligible people have received a booster shot and that group is not reporting significant numbers of infections consistent with the data showing that a recent booster will protect you from gettng even mild forms of COVID-19.

It's pretty clear that the Omicron variant is being spread by people who are fully vaccinated with no booster. They may have mild symptoms but they can infect others, including young children and the elderly, who can suffer more severe symptoms.

The number of people in hospital with COVID-19 is rising sharply but so far it's still less than the numbers in the Delta wave last Fall. That's expected to change rapidly over the next few days and there's a great danger that the health care system will be overwhelmed. The best guess so far is that we will just scrape by by cancelling all elective surgeries and restricting the number of non-COVID patients who get admitted to hospital. Other countries may not be so lucky.

Given the high levels of vaccination, you might suspect that most of the people in hospital will have been fully vaccinated and that's exactly what we see. 71% of the COVID-19 patients in the hospitals have been fully vaccinated but this number is slightly misleading since it includes patients who were admitted for other reasons and subsequently tested positive for COVID-19. Those people aren't necessarily being treated for severe COVID symptoms.

It's hard to get an accurate number for the hospitalization rate because we don't know how many cases there are but it looks like that number is below 1%. This means that, on average, fewer than one patient will end up in hospital for every 100 who get COVID-19. This rate is far below the overall rate of 3.9% since the pandemic began and about 2% for the Delta wave when a substantial percentage of the population was vaccinated. It's data like this that suggest that the Omicron variant causes a milder form of COVID-19 but the data is confounded by the fact that fully vaccinated people are now getting infected whereas they still had substantial serum antibody levels during the Delta spike. I'd like to know what the hospitalization rate (and the death rate) was for unvaccinated people last year and what it is now.

The unvaccinated group makes up only 24% of the hospitalized patients but 49% of those in the intensive care units (ICU). This is clear evidence that vaccination offers significant protection against severe forms of the disease—that's exactly what vaccines are supposed to do. However, it's worth noting that 51% of the patients in the ICUs are either fully or partially vaccinated. You can still get a serious case of COVID-19 if you are fully vaccinated. As with the case numbers, this severe outcome will not be obvious in countries with lower vaccination rates and that could be a problem if you are trying to stop the spread.

---

The effect of spike protein mutations in the Omicron variant

The Omicron variant of SARS-CoV-2 contains a large number of novel mutations in the spike protein. How did these mutations occur and what is their effect on the properties of the variant?

The origin of the novel mutations

The phylogeny of the Omicron variant is unusual—it seems to have appeared without any documented history of steady accumulation of mutations. It looks like it split from the other variants before the summer of 2020. This leads to suggestions that the virus was circulating (and mutating) long before it was first detected.

One idea is that the ancestor of the Omicron variant jumped to another species and evolved in that species for 18 months before jumping back into humans. This would account for the lack of intermediates seen in screening infected patients. Several of the key mutations in the spike protein sequence are similar to variants that have adapted to bind to the mouse version of the receptor (ACE2) (Sun et al. 2021) and the Omicron spike protein binds strongly to mouse ACE2. (The original SAR-CoV-2 variants do not infect mice.) I think it's safe to conclude (tentatively) that Omicron evolved in mice and jumped back to humans in October or November 2021.

Immune evasion

The Omicron variant infects people who have been fully vaccinated or who have been previously infected with one of the other variants (Zhang et al. 2021). This is because the low level of circulating antibodies in these individuals is not sufficient to block Omicron. The level can be boosted with a booster shot (or a recent infection) and this increase protects against infections by Omicron. Fortunately, Omicron is attacked by T-cells and memory B-cells in vaccinated individuals so the infections are mild (Redd et al. 2021).

The mRNA vaccines elicit polyclonal antibodies to the spike protein of the original (Wu) variant. Some of these antibodies will recognize surface antigens that have mutated in Omicron so that's why it requires a higher concentration of antibodies to neutralize Omicron. We're lucky that boosting the overall antibody levels with a booster shot is sufficient to protect us from infection. We're also lucky that the T-cell response is robust—it didn't have to be.

The important point to remember during the Omicron wave is that the virus infects, and is transmitted by, fully vaccinated individuals (no booster). Some of the talking heads on TV seem to forget this when they advocate for keeping the schools open as long as everybody is vaccinated. That's not going to stop the spread and, besides, some of those vaccinated children are going to end up in the hospital. What they need to be telling us is that keeping schools open is going to result in X number of hospitalizations and Y number of deaths and this is an acceptable trade-off. (Parents, teachers, school bus drivers, school administrative staff, and their elderly parents may disagree.)

Transmissibility

The Omicron variant is highly transmissible, meaning that it is more infectious than the other variants. This feature explains the enormous spikes of cases in all countries that are experiencing an Omicron wave. We've not seen anything like that in previous waves.

Some of that peak might be due to the fact that vaccinated individuals are not being as careful as they should be so they are spreading the virus in their communities. That may explain the differences between different countries, or different states within a country, but it's not the full story.

Initially, there was a lot of speculation that the spike protein mutations in Omicron made it bind more strongly to the human ACE2 receptors and that would explain why the virus was more infectious. But most of those studies were based on models and the results from different groups were contradictory. Recently the Chinese scientists who have been at the leading edge of these studies since the beginning have shown that the Omicron spike protein does not bind significantly more tightly to ACE2 than the version from other variants (Zhang et al. 2021).

It looks like the increase in infectivity is due to enhanced entry of the Omicron variant into cells once it has bound to the receptor. Some of this is probably due to a mutation that creates a more favorable furin cleavage site but additional increases in entry might be due to conformational changes in the spike protein (Zhang et al. 2021)

Milder cases?

There's a lot of speculation that the Omicron variant causes less severe forms of COVID-19 but the data is complicated by the fact that vaccinated and convalescent patients are also suffering from COVID-19 and they are partially protected. I don't think it's really known whether naive (unvaccinated and not previously infected) individuals have a milder form of the disease and I know we don't have any data on the long-term effect of Omicron infection. Please let me know of any studies that have been released.

I don't know of any logical connection between the known mutations in Omicron and the severity of COVID-19.

---

Redd, A. D., Nardin, A., Kared, H., Bloch, E. M., Abel, B., Pekosz, A., Laeyendecker, O., Fehlings, M., Quinn, T. C., and Tobian, A.A. (2021) Minimal cross-over between mutations associated with Omicron variant of SARS-CoV-2 and CD8+ T cell epitopes identified in COVID-19 convalescent individuals. bioRxiv : the preprint server for biology, 2021.12.06.471446. [doi: 10.1101/2021.12.06.471446]

Sun, Y., Lin, W., Dong, W., and Xu, J. (2021) Origin and evolutionary analysis of the SARS-CoV-2 Omicron variant. Journal of Biosafety and Biosecurity. [doi: 10.1016/j.jobb.2021.12.001]

Wei, C., Shan, K. J., Wang, W., Zhang, S., Huan, Q., and Qian, W. (2021) Evidence for a mouse origin of the SARS-CoV-2 Omicron variant. Journal of Genetics and Genomics. [doi: 10.1016/j.jgg.2021.12.003]

Zhang, X., Wu, S., Wu, B. et al. (2021) SARS-CoV-2 Omicron strain exhibits potent capabilities for immune evasion and viral entrance. Sig Transduct Target Ther 6:430. [doi: 10.1038/s41392-021-00852-5]

Omicron variant: lessons from Denmark

Danish scientists have looked at the first 785 cases of Omicron variant in Denmark. The most important lesson is that 83% of the cases were fully vaccinated. (Mostly two doses of an mRNA vaccine). This includes 7% of the total cases that had also received a booster shot. 76% of the Danish population are fully vaccinated.

Espenhain, L., Funk, T., Overvad, M., Edslev, S.M., Fonager, J., Ingham, A.C., Rasmussen, M., Madsen, S.L., Espersen, C.H. and Sieber, R.N. (2021) Epidemiological characterisation of the first 785 SARS-CoV-2 Omicron variant cases in Denmark, December 2021. Eurosurveillance 26:2101146. doi: [Eurosurveillance: Full Text]

This is similar to the results in other countries where a large percentage of the population are vaccinated. The spread of Omicron in those countries is largely driven by infection of the vaccinated group and the only way to blunt this spread is to limit contacts among vaccinated people. That means lockdowns or partial lockdowns for everybody and that seems to be working.

As usual, the United States is going to serve as a good control on these measures since the dominant message from American government, media, and health officials is that you are pretty much okay if you are vaccinated and you just have to be a bit more carefeul. No need to change your holiday travel plans.

The cases in Denmark cover all ages groups but the 20-29 age group had the highest number of infections. Quite a few of the cases could be traced to a "seasonal gathering" of 150 people and a large concert but most others seem to be due to community transmission once the variant became established. The original cases came from people who had travelled from South Africa and other countries.

Since the identification of the first Omicron case in Denmark, a steep increase in the number of cases has been observed. A major driver of this development was a large party with young adults – a population group with more social and close connections than adults and children.

We find several reasons for concern: (i) the rapid spread shortly after introduction despite extensive contact tracing efforts, (ii) the occurrence of several superspreading events with high attack rates and (iii) the high proportion of fully vaccinated Omicron cases.

So far, there haven't been many hospitalizations or deaths due to infection with the Omicron variant but that could come later.

---

The omicron variant evades vaccine immunity but boosters help

Scientists are very interested in the omicron variant and why it is so dangerous. Since vaccinated people are getting infected, it must mean that the omicron variant isn't effectively neutralized by vaccine-induced antibodies. Several preprints on this topic have been posted and they all reach the same conclusion. I'll discuss one of them.

Garcia-Beltran, W.F., St Denis, K.J., Hoelzemer, A., Lam, E.C., Nitido, A.D., Sheehan, M.L., Berrios, C., Ofoman, O., Chang, C.C. and Hauser, B.M. (2021) mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant. medRxiv. doi: 10.1101/2021.12.14.21267755

Recent surveillance has revealed the emergence of the SARS-CoV-2 Omicron variant (BA.1/B.1.1.529) harboring up to 36 mutations in spike protein, the target of vaccine-induced neutralizing antibodies. Given its potential to escape vaccine-induced humoral immunity, we measured neutralization potency of sera from 88 mRNA-1273, 111 BNT162b, and 40 Ad26.COV2.S vaccine recipients against wild type, Delta, and Omicron SARS-CoV-2 pseudoviruses. We included individuals that were vaccinated recently (<3 months), distantly (6-12 months), or recently boosted, and accounted for prior SARS-CoV-2 infection. Remarkably, neutralization of Omicron was undetectable in most vaccinated individuals. However, individuals boosted with mRNA vaccines exhibited potent neutralization of Omicron only 4-6-fold lower than wild type, suggesting that boosters enhance the cross-reactivity of neutralizing antibody responses. In addition, we find Omicron pseudovirus is more infectious than any other variant tested. Overall, this study highlights the importance of boosters to broaden neutralizing antibody responses against highly divergent SARS-CoV-2 variants.

On the effectiveness of vaccines

I've learned a bit of immunology from hanging out with immunologists so I'm going to try and explain how vaccines protect you from the worst consequences of an infection and why booster shots aren't as necessary as you think. This will be an illustration of how difficult it is for the media to keep you correctly informed about real science and why we should have more scientists explaining these things instead of doctors

Dozens of papers on this topic have been published over the past year or so and they all say the same thing. SARS-CoV-2 vaccinations induce an immediate production of antibodies in response to the spike protein antigen whether it's presented on the surface of a viral vector such as adenovirus or synthesized in your cells by mRNA. The antibodies are produced by a small number of B cells that just by chance happen to recognize the viral protein. These cells multiply rapidly so that within a few days you have enough antibodies being produced to fight off any infection.

Over time, the antibody production declines if there's no infection but some of the B cells become memory B cells that lie in wait for the next infection when they can be rapidly stimulated if you get infected months, or years, later. There's another type of cell called a T cell that also forms memory T cells that are very long-lasting and help fight off future infections.

Imagine that you encounter the virus several months after you've been vaccinated. As soon as the virus enters your body the memory cells are activated and the virus is attacked. You may have a mild case of COVID-19 for a few days but you are protected against the most severe forms of the disease. The point is that a reduction in antibody levels is perfectly normal. What's important is whether you have a robust level of memory B cells and memory T cells that can be activated. The hype in the media has convinced people that the vaccines are no longer effective after six months and you have to get a booster shot to protect you from COVID-19.

Here's a very recent paper that presents the data. It was published in Science on December 3, 2021.

Goel, R.R., Painter, M.M., Apostolidis, S.A., Mathew, D., Meng, W., Rosenfeld, A.M., Lundgreen, K.A., Reynaldi, A., Khoury, D.S. and Pattekar, A. et al. (2021) mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern. Science 374:eabm0829. doi: 10.1126/science.abm0829

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has proven highly effective at preventing severe COVID-19. However, the evolution of viral variants, and waning antibody levels over time, raise questions regarding the longevity of vaccine-induced immune protection. Goel et al. examined B and T lymphocyte responses in individuals who received SARS-CoV-2 messenger RNA vaccines. They performed a 6-month longitudinal study of individuals who never had SARS-CoV-2 infection compared with people who had recovered from SARS-CoV-2. Humoral and cellular immune memory was observed in vaccinated individuals, as were functional immune responses against the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) viral variants. Analysis of T cell activity suggested that robust cellular immune memory may prevent hospitalization by limiting the development of severe disease.

The authors looked at the immune reaction in three different groups. The first was the naive group of people who have never had COVID-19 but got the vaccine (blue). The second group was people who had already survived COVID-19 and then got vaccinated (red). The third group was composed of people who had mild cases of COVID-19 and never got vaccinated (purple).

This is a long paper with lots of experiments but the data can be summarized in the figure below. The authors looked at antibodies to the spike protein and to its specific ACE2 binding site. They also looked at neutralizing antibodies or the abiity of circulating antibodies to neutralize whole virus particles. The results are summarized in the first graph and they show that the antibody levels rise to maximum levels about one week after receiving the second dose of vaccine (administered four weeks after the first dose).

The antibody levels fall to about 10% of the maximum value over the next six months. (The x-axis is a log scale.) This is exactly what you expect for a typical vaccine. Note that the levels for people who had already been infected were higher to begin with but the rate of decline was similar to the naive group. This suggests that booster shots will have a similar effect on antibody levels.

The levels of memory B cells and memory T cells rise to a maximum at four months, right at the time of the second dose. They remain high at the end of six months.

Taken together, these data demonstrate that mRNA vaccines induced a population of memory B cells that was durable for at least six months after vaccinaton, and these cells were capable of rapidly producing functional antibodies against SARS-CoV-2, including neutralizing antibodies against VOCs [variants of concern], upon stimulation....

Taken together, these data indicate that mRNA vaccination generates durable SARS-CoV-2-specific CD4⁺ T cell memory in individuals who were not previously infected with SARS-CoV-2 and only transiently boosts these responses in SARS-CoV-2-recovered individuals.

What this means is described by the authors in the concluding remarks,

These data may also provide context for understanding potential discrepancies in vaccine efficacy at preventing infection versus severe disease, hospitalization, and death. Declining antibody titers over time likely reduce the potential that vaccination will completely prevent infection or provide near-sterilizing immunity. However, the durability of cellular immunity, here demonstrated for at least 6 months, may contribute to rapid recall responses that can limit initial viral replication and dissemination in the host, thereby preventing severe disease.

In other words, if you are fully vaccinated (two doses of mRNA vaccine) then you are well-protected against severe disease although you may suffer mild symptoms for a few days. You may be able to avoid the mild symptoms if you have gotten a recent booster shot but that effect is likely to decline in a few months.

The hype about booster shots is extremely misleading. The media is making it sound like all of your vaccine protection declines after six months and you need the boosters to have any chance at all against the omicron variant. How many times have you heard that your vaccine protection drops to 33% after six months?

You could argue that boosters aren't even necessary but that ignores the possibility that even a mild infection may be harmful to some people. It also ignores the possibility that by preventing even a mild infection you could be blocking the spread of the virus. I don't know of any data on viral loads after vaccination but I suspect that a booster offers some protection against spread.

---

Image Credit: The coronavirus figure is from Alexy Solodovnikov and Wikmedia Commons.

"Has Science Killed Philosophy?"

This is a debate sponsored by the Royal Institute of Philosophy on the question "Has science killed philosophy?" It suffers from one of the main problems of the philosphy of science and that's an unreasonable focus on theoretical physics. What's interesting is that the question even arises because that suggests to me that there's some reason to suspect that philosophy might not be as important as most philosophers think.

Watch the debate and decide for yourselves whether philosophy is still useful. Frankly, I found it very boring. I didn't learn anything that I didn't know before and I didn't find the defense of philosophy compelling. The philosopher's best answer to the challenge is that their discipline has complete control over rational thinking so every time you are thinking seriously about something you are doing philosophy. Ergo, philosophy will never be killed by science.

What do you think of Eleanor Knox's description of the differences between your right hand and your left hand? Is she on to a deep metaphysical question that science can't address? Or is this an example of why scientists are skeptical of the value of philosophy?

All three panelists were asked to identify a modern philosopher who made a significant contribution to science. Alex Rosenberg immediately identified someone named Samir Okasha whom I've never heard of. Apparently, Okasha made a significant contribution to the levels of selection question in evolution. According to Alex Rosenberg, the philosophers that he listens to tell him that if anyone has settled these question it's Okasha. Perhaps he should listen to evolutionary biologists to get their view on the subject?

---

The first review of "Viral" is out and it ain't pretty

Michael Hiltzik is first off the mark writing for the Los Angeles Times: These authors wanted to push the COVID-19 lab-leak theory. Instead they exposed its weaknesses.

Hiltzik is one of the few science writers who know what they'r talking about.¹ You should read his entire review—here are some excerpts to tempt you.

... “Viral” is a laboratory-perfect example of how not to write about a scientific issue. The authors rely less on the scientists doing the painstaking work to unearth the virus’ origin than on self-described sleuths who broadcast their dubious claims, sometimes anonymously, on social media. In the end, Chan and Ridley spotlight all the shortcomings of the hypothesis they set out to defend....

“Viral” is built on vague innuendo, dressed up with assertions that may strike laypeople as plausible but have long since been debunked by experienced virologists. An entire chapter, for example, is devoted to the “furin cleavage site,” a feature of the virus’ structure through which the enzyme furin makes the spikes on its surface — which it uses to penetrate and infect healthy cells — more effective.

The furin site was originally described by lab-leak advocates as so unusual that it could have been placed there only by humans. Virologists have since determined that the feature is not all that rare in viruses similar to SARS2, and in any case, it could have emerged through natural evolutionary processes well known to experts. Chan and Ridley place a heads-I-win-tails-you-lose gloss on these findings, writing that if the site “proves to have been inserted artificially, it confirms that the virus was in a laboratory and was altered. ... If, on the other hand, the furin cleavage site proves to be natural, it still says nothing about where the virus came from.” Why write about it at all, then?

Alina Chan's reputation is already about as low as it can get and now it looks like she's dragging Matt Ridely down with her. He was already part way there so he didn't have far to go.

The book is published by HarperCollins. Should American lawmakers look seriously at regulating the publishing industry for spreading misinformation since they're already investigating Facebook for the same crime?

---

1. See: Is the media finally realizing that they have been duped into promoting the lab leak conspiracy theory?.

Alina Chan teams up with Matt Ridley to promote the lab leak conspiracy theory

Harper is set to publish Viral: The Search for the Origin of COVID-19 in just a few days. The authors are Alina Chan, a postdoc at the Broad Institute of MIT and Harvard, and Matt Ridley, a science journalist who has written several respectable books.

The book promises to reignite discussion of the lab leak conspriracy theory with a focus on Alina Chan's role in promoting it. In preparation, you should read this article about her: They called it a conspiracy theory. But Alina Chan tweeted life into the idea that the virus came from a lab.

The origin of SARS-CoV-2 and gain-of-function research

I'm currently discussing the meaning of "function" with a small group of scientists and philosophers and it's not easy to come up with an acceptable definition. Imagine how much more difficult it is to identify research that results in a gain of function!

Gain-of-function research has been in the news recently because there are a group of conspiracy theorists who accuse the scientists at the Wuhan Institute of Virology of conducting gain-of-function research on bat caronaviruses leading to the creation of SARS-CoV-2 which then escaped from the lab to cause the pandemic. Some of these conspiracy theorists even accuse the American NIH of funding this gain-of-function research.

How do you define gain-of-function research in a meaningful manner? That's the question posed by Amber Dance in a recent Nature article. (Amber Dance is a freelance science journalist.) The first reference below is the title and subtitle of the article that was published in the magazine and the second reference is the online version.

Dance, A. (2021) The Truth About Gain-of-Function Research: Granting new abilities to pathogenic microbes sounds dangerous, but what has the research told us? Nature 598: 554-555. [doi: 10.1038/d41586-021-02903-x]

Dance, A. (2021) The shifting sands of ‘gain-of-function’ research: The mystery of COVID’s origins has reignited a contentious debate about potentially risky studies and the fuzzy terminology that describes them. Nature 598: 554-555. [Nature website]

The only relevant gain-of-function research is the type specified by NIH as "gain-of-function research of concern" (GOFROC). This is research that makes a potential pathogen more likely to cause disease in humans. This is the kind of research that would be carried out in a lab devoted to biological warfare but it could also apply to some research that was carried out in the past, as described in the article. There is no evidence to support the accusation that scientists in China, or anywhere else, were doing such research on coronaviruses.

There are other kinds of research that involve constructing chimeric viruses in order to test whether they have the potential to cause a pandemic. This is perfectly normal, even necessary, research but conspiracy theorists have claimed that this is forbidden gain-of-function research. The article does a good job of explaining this research and why it's not a problem.

---

Image Credits: The coronavirus figure is from Alexy Solodovnikov and Wikmedia Commons.

What's in your genome?: 2021

This is an updated version of what's in your genome based on the latest data. The simple version is ...

about 90% of your genome is junk

On the importance of active learning

I'm on the editorial board of an education journal so I've been following the pedagogical literature for many years. The idea of active learning, or student-centered learning, has been around for decades and there's solid evidence showing that it's way more effective than traditional lecture-style learning. If you are a teacher and you haven't adopted some form of active learning in your class then you need to change as soon as possible. There's no scientific justification for sticking with the traditional ways of teaching.

Will Ontario parents vaccinate their children?

COVID-19 vaccinations are soon going to be available for children in Ontario, Canada. Will parents vaccinate their children?

The Toronto Star recently published a poll where parents of at least one child under 12 were asked this question and 69% said yes, they were going to get their children vaccinated [Nearly 70 per cent of Ontario parents of kids 5 to 11 planning to get them vaccinated, poll says]. Only 11% said they were not going to vaccinate their children. (19% were unsure.)

It's interesting to see the reasons parents gave for not vaccinating their children. 82% of these parents say that they don't trust the vaccine because it's too new and/or not enough research has been done. That's an illogical excuse because public health officials all over the world are recommending children's vaccinations and they wouldn't be doing it if there were any serious doubts about safety. The reluctance of these parents stems from the mistrust in public health officials and science that has been fostered by the media over the past eighteen months. The Toronto Star has been one of the worst offenders.

Some of the skepticism over decisions made by public heath officials is justified but the overall effect of constant criticism and nitpicking has been to undermine the authority of the very people we rely on to get us out of the pandemic. That's unfortunate.

The other problem for Canadians is that we are inundated with news from our neighbor to the South and that country really does have a bad track record. The somewhat more justified criticism of American public health officials spills over into Canada and taints our own physicians and scientists. That's also unfortunate.

Note that only 23% of these parents can be counted as vaccine deniers and since this group only represents 11% of the total surveyed, it means that the total number of those who don't believe in vaccines is less than 3% of the parents of children under 12. This is consistent with other surveys suggesting that the hard-core vaccine deniers represent less than 5% of the population.

A substantial percentage of those who say they aren't going to vaccinate their children think that vaccinations aren't really necessary for children under 12. Some of those people are probably going to change their minds when most of their children's friends get vaccinated. They will certainly change their minds if vaccinations are required for school.

I think the survey is very encouraging. It looks like most children will be vaccinated over the next few months. There will be holdouts but most of them will eventually give in to public pressure.

---

Science writing in the age of denial

Here's an interesting presentation by Sean B. Carroll, the evolutionary biologist and author of several books on evolution. He's also written a fascinating book on Jacques Monod and he gave a talk at the University of Toronto a few years ago on the role of chance in evolution—I have a signed copy of his book (see the photo and my blog post: Biologist Sean Carroll in Toronto).

Sean likes to emphasize the importance of storytelling in science communication and education. By this he sometimes means stories about individual scientists and sometimes stories about the history of a subject. As Vice President for Science Education at the Howard Hughes Medical Institute in Washington DC (USA) he has helped craft some short videos for high school students and the presentation contains an example of one on evolution. I'm not sure I fully agree with his emphasis on storytelling—as least not to the extent that he promotes it—but some version of it can be useful as long as it doesn't get in the way of understanding important concepts.

I leave it to you to decide whether the short HHMI video is the best way to teach high school students about evolution. I personally don't like the undue emphasis on natural selection and natural history.

The reason for drawing your attention to an old 2012 presentation is to remind you about the charactieristics of science denial. Sean explains the six rules of denialism.

1. Doubt the Science
2. Question Scientist's Motives and Integrity
3. Magnify Disagreements among Scientists and Cite Gadflies as Authorities
4. Exaggerate Potential Harm
5. Appeal to Personal Freedom
6. Acceptance Would Repudiate Key Philosophy

His examples are the denial of evolution by creationists and the rejection of vaccinations by chiropractors. Today, we see how the same rules apply to those who reject COVID-19 vaccinations and to the Lab Leak Conspiracy Theory.

---