John Mattick presents his view of genomes

John Mattick has a new book coming out in August where he defends the notion that most of our genome is full of genes for functonal noncoding RNAs. We have a pretty good idea what he's going to say. This is a talk he gave at Oxford on May 17, 2019.

Here are a few statements that should pique your interest.

• (0:57) He says that his upcoming book is tentatively titled "the misunderstandings of molecular biology."
• (1:11) He says that "the assumption has been very deeply embedded from the time of the lac operon on that genes equated to proteins."
• (2:30) There have been three "surprises" in molecuular biology: (1) introns, (2) eukaryotic genomes are full of 'selfish' DNA, and (3) "gene number does not scale with developmental complexity."
• (4:30) It is an unjustified assumption to assume that transposon-related seqences are junk and that leads to misinterpretation of neutral evolution.
• (6:00) The view that evolution of regulatory sequences is mostly responsible for developmental complexity (Evo-Devo) has never been justified.
• (8:45) A lot of obtuse theoretical discussion about how the number of regulatory protein-coding genes increases quadratically as the total number of protein-coding genes increase in a bacterial genome but at some point there has to be more protein-coding regulatory genes than total protein-coding genes so that limits the evolution of bacteria.
• (13:40) The proportion of noncoding DNA increases with developmental complexity, topping out at humans.

• (14:00) The vast majority of the genome in complex organisms is differentially transcribed in different cells and different tissues.
• (14:15) The whole genome is alive on both strands.
• (14:20) There are two possibilities: junk RNA or abundant functional transcripts and that explains complex organisms.
• Mattick then takes several minutes to document the fact that there are abundant transcripts— a fact that has been known for the better part of sixty years but he does not mention that. All of his statements carry the implicit assumption that these transcripts are functional.
• (20:20) He makes the boring, and largely irelevant, point that most disease-associated loci are located in noncoding regions (GWAS). He's responding to a critic who asked why, if these things (transcripts) are real, don't we see genetic evidence of it.
• (24:00) Noncoding RNAs have all of the characteristics of functional RNAs with an emphasis on the fact that their expression is often only detected in specific cell types.
• (31:50) It has now been shown that everything that protein transcription factors can do can be done by noncoding RNA.
• (32:15) "I want to say to you that conservation is totally misunderstood." Apparently, lack of conservation imputes nothing about function.
• (41:00) RNAs control phase separation. There's a whole other level of cell organization that we never dreamed of. (Ironically, he gives nucleoli as an example of something we never dreamed of.)
• (42:36) "This is called soft metaphysics, and it's just come into biology, and it's spectacular in its implications."

• (46:25) Almost every lncRNA is alternatively spliced in mice and humans.
• (46:30) There's more alternative splicing in human protein-coding genes than in mice protein-coding genes but the extra splicing in humans is mostly in the 5' untranslated region. (I'm sure it has nothing to do with the fact that tons more RNA-Seq experiments have been done on human tissues.) "We think this is due to the increased sophistication of the regulation of these genes for the evolution of cognition."
• (48:00) At least 20% of the human genome is evolutionarily conserved at the level of RNA structure and this does not require any assumptions.
• (55:00) The talk ends at 55 minutes. That's too bad because I'm sure Mattick had a dozen more slides explaining why all of those transcripts are functional, as opposed to the few selected examples he picked. I'm sure he also had a lot of data refuting all of the evidence in favor of junk DNA but he just ran out of time.

I don't know if there were questions but, if there were, I bet that none of them challenged Mattick's main thesis.

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Science communication in the modern world

Science editors asked young scientists to imagine what kind of course they would have created if they could go back to a time before the pandemic [A pandemic education]. Three of the courses were about science communication.

COM 145: Identification, analysis, and communication of scientific evidence

This course focuses on developing the skills required to translate scientific evidence into accessible information for the general public, especially under circumstances that lead to the intensification of fear and misinformation. Discussions will cover the principles of the scientific method, as well as its theoretical and practical relevance in counteracting the dissemination of pseudoscience, particularly on social media. This course discusses chapters from Carl Sagan’s book The Demon-Haunted World, certain peer-reviewed and retracted papers, and materials related to key science issues, such as the anti-vaccine movement. For the final project, students will comprehensibly communicate a scientific topic to the public.

Camila Fonseca Amorim da Silva University of Sao Paulo, Sao Paulo, Brazil

COM 198: Everyday science communication

As scientific discoveries become increasingly specialized, the lack of understanding by the general public undermines trust in scientists and causes the spread of misinformation. This course will be taught by scientists and communication specialists who will provide students with a toolset to explain scientific concepts, as well as their own research projects, to the general public. Upon completion of this course, students will be able to explain to their grandparents that viruses exist even though they can’t see them, convince their neighbors that vaccines don’t contain tracking devices, and explain the concept of exponential growth to governmental officials.

Anna Uzonyi Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

COM 232: Introduction to talking to regular people

Communicating science is difficult. Many scientists, having immersed themselves in the language of their field, have completely forgotten how to talk to regular people. This course hones introductory science communication skills, such as how to talk about scary things without generating mass panic, how to calmly discourage the hoarding of paper hygiene products, and how to explain why scientific knowledge changes over time. The final project will include cross examination from law school faculty, who are otherwise completely uninvolved with the course and possess minimal scientific training. Recommended for science majors who are unable to discuss impactful scientific findings without citing a P value.

Joseph Michael Cusimano Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, VA, USA.

They sound like interesting courses but my own take on science communication is somewhat different. I think it's very difficult for practicing scientists to communicate effectively with the general public so I tend to view science communication at several different levels. My goal is to communicate with an audience of scientists, science journalists, and people who are already familiar with science. The idea is to make sure that this intermediate group understands the scientific facts in my field and to make sure they are familiar with the major controversies.

My hope is that this intermediate group will disseminate this information to their less-informed friends and relatives and, more importantly, stop the spread of misinformation whenever they hear it.

Take junk DNA for example. It's very difficult to convince the average person that 90% of our genome is junk because the idea is so counter-intuitive and contrary to the popular counter-narratives. However, I have a chance of convincing the intermediate group, including science journalists and other scientists, who can follow the scientific arguments. If I succeed, they will at least stop spreading misinformation and false narratives and start presenting alternatives to their sudiences.

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Junk DNA

My book manuscript has been reviewed by some outside experts and they seem to have convinced my editor that my book is worth publishing. I hope we can get it finished soon. It would be nice to publish in in September on the 10th anniversary of the ENCODE disaster.

Meanwhile, I keep scanning the literature for mentions of junk DNA to see if scientists are finally coming to their senses. Apparently not, and that's a good thing because it means that my book is still needed. Here's the opening paragraph from a recent review of lncRNAs. The authors are in the Department of Medicine at the Medical College of Gerogia, in Augusta, Georgia (USA).

Ghanam, A.R., Bryant, W.B. and Miano, J.M. (2022) Of mice and human-specific long noncoding RNAs. Mammalian Genome:1-12. [doi: 10.1007/s00335-022-09943-2]

Approximately ninety-eight percent of our genome is noncoding. Contrary to initial descriptions of this vast sea of sequence comprising “junk DNA” (Ohno 1972), comparative genomics and various next-generation sequencing studies have revealed millions of transcription factor binding sites (TFBS) (Vierstra et al. 2020) and tens of thousands of noncoding genes, most notably the class of long noncoding RNAs (LncRNAs), defined currently as processed transcripts of length > 200 base pairs with no protein-coding capacity (Rinn and Chang 2020; Statello et al. 2021). The widespread transcription of LncRNAs and abundance of regulatory sequences such as enhancers support the concept of a genome that is largely functional (ENCODE Project Consortium 2012). Such a dynamic genome should not be surprising given the complex nature of gene expression and gene function necessary for embryonic and postnatal development as well as disease processes.

• No reasonable scientist, especially Susumu Ohno, ever said that all noncoding DNA was junk.
• There are millions of transcription factor binding sites but most of them are spurious binding sites that have nothing to do with regulation. They simply reflect the expected behavior of typical DNA binding proteins in a large genome full of junk DNA.
• Nobody has demonstrated that there are tens of thousand of noncoding genes. There may be tens of thousands of transcripts but that's not the same thing since you have to prove that those transcripts are functional before you can say that they come from genes.
• There is currently no evidence to support the concept of a genome that is largely functional in spite of what the ENCODE researchers might have said ten years ago.
• Such a genome would be very surprising, if it were true, given what we know about genomes, evolution, and basic biochemistry.

Except for those few minor details—I hope I'm not being too picky—that's a pretty good way to start a review of lncRNAs. :-)

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Jacques Fresco (1928-2021)

Jacques Fresco died last December. I am kind of a scientific grandson of Jacques Fresco since he mentored my Ph.D. supervisor, Bruce Alberts when he (Bruce) was an undergraduate at Harvard.

While at Harvard, Jacques mentored then-undergraduate Bruce Alberts, who taught at Princeton from 1966 to 1976, served as president of the National Academy of Sciences and wrote the seminal textbook, “The Molecular Biology of the Cell.”

In addition to reassuring Alberts’ parents that they shouldn’t worry about their son’s choice to pursue science instead of medical school — a story Fresco enjoyed telling — he also played a key role in bringing the young scientist to Princeton. “Before I had even completed my Ph.D., he convinced Princeton to offer me an assistant professorship that I did not deserve,” Alberts recalled. “And at Princeton for 10 years, we of course spent an enormous amount of time together. So Jacques was very central to my life as a scientist and a close friend.”

The Fresco lab was right above the Alberts lab when I started graduate school at Princeton in 1968. The main focus of the Fresco lab was the structure of tRNA and in order to isolate different tRNA molecules they needed a very large gel filtration column that was about 4m tall and about as big around as a dinner plate. The column was too tall for their lab so they had to drill a hole through the concrete floor and drop it down into the lab below!

One of my graduate student friends worked in the Fresco lab on hydrogen exchange in tRNA. The idea was to measure the number of hydrogen bonds in the structure by looking at the exchange bewtween hydrogens in the medium and in tRNA. The experiment used a radioactive isotope of hydrogen (tritium) in the medium and each experiment required about one curie of radioactive hydrogen and that's a lot. After a few years my friend decided to become a plastic surgeon instead of a scientist!

I knew Jacques Fresco quite well when I was a graduate student and I always thought he was an excellent scientist.

Many of his students mentioned what an enormous role Fresco played in shaping their careers, in large and small ways. “Jacques treated everybody with the same respect, irreverence and love of life,” said Steven Broitman, a professor of biology at West Chester University in Pennsylvania who completed his Ph.D. with Fresco in 1988. “In addition to all he taught me about science, he also modeled the simple enjoyment in doing science that I have always tried to keep with me and pass on to my own students. He was larger than life, a major figure in the birth of modern molecular biology. He was deeply loved, and he will be missed.”

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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.

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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 AstraZenica 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 CoronaVac 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 Moderna 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.

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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.

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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.

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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.

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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.

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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?

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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?

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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.

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