Catching Up With David Goodsell

It’s been nine years since I wrote a post about scientific illustrator David Goodsell. That’s too long. Russ Hobbie and I cite his wonderful book The Machinery of Life in the very first section of Intermediate Physics for Medicine and Biology. A physicist wanting to learn more about biology but not wanting to wade into all the biochemical details should simply study Goodsell’s art.

As an emeritus scientist myself, I suppose it’s unfair to complain that one year ago Goodsell retired. I hope he keeps painting on the side as he enjoys the retired life, and continues to share his work with us. Below I present a few of his more recent creations, all free via a creative commons license at the RCSB Protein Data Bank website. At the risk of sounding corny, what a true gift to mankind. And what a true gift to physics students wanting to gain insight into biological size scales and microscopic structures.

 

Influenza Virus, 2024

I’ll start with the influenza virus, since it’s still flu season here in Michigan. 

Illustration by David S. Goodsell, RCSB Protein Data Bank. doi: 10.2210/rcsb_pdb/goodsell-gallery-049 

Cross section through an influenza virion. It is surrounded by a lipid bilayer membrane (light purple) filled with hemagglutinin (purple), neuraminidase (magenta), and a few M2 proteins (small purple proteins). M1 matrix protein (blue) lines the inner side of the membrane. RNA-dependent RNA polymerase (red) is bound to the genomic RNA strands (yellow), which are protected in a helical complex with nucleoprotein (orange).

Flu viruses subtypes are often specified by nomenclature like H3N2, which means it contains type 3 hemagglutinin and type 2 neuraminidase. The flu is an RNA virus, meaning its genetic information is stored in RNA, not DNA, and in this case single-stranded RNA. The RNA-dependent RNA polymerase is an enzyme that catalyzes the replication of the RNA strands. 

The influenza virus has a diameter of about 100 nm (in other words, a tenth of a micron) 

Measles Virus Proteins, 2019

Next up is the measles virus. I show this one because measles is tragically making a comeback in the United States. Not because of some horrible mutation, but because of a hesitancy by many to get the vaccine. Fortunately, Michigan has not suffered much from the measles... yet.

Illustration by David S. Goodsell, RCSB Protein Data Bank. doi: 10.2210/rcsb_pdb/goodsell-gallery-018 

Cross section through measles virus. The virus is enveloped by a lipid membrane (light magenta) studded with many hemagglutinin and fusion proteins (outermost proteins in blue), which together bind to human cells and enter them. The viral genome is a strand of RNA (yellow) protected by nucleoproteins (green). RNA-dependent RNA polymerase (bright magenta) copies the RNA once the virus infects a cell, assisted by the largely-disordered phosphoprotein (purple strands connecting the polymerase to the nucleoprotein). Matrix protein (turquoise) helps the virus bud from infected cells. Several human proteins, such as actin and integrins, are also caught in the budding virus (shown in purple). 

This painting was created for the Molecule of the Month on Measles Virus Proteins and recognized by the 2019 FASEB BioArt Awards.

Goodsell bases these paintings on data about the virus structure. If you hang out on social media too much (as I sometimes do) you hear things like “viruses don’t exist.” Apparently people who think that believe all this data is artifact.

The measles virus is roughly two times larger than the influenza virus, having a diameter of about 200 nm. Notice how the light purple lipid bilayer, with a thickness of roughly 4 nm, appears larger in the influenza virus illustration than in the measles illustration. Goodsell strives to get it right.

 

Bacteriophage T4 Infection, 2023 

In IPMB, Russ and I write that “some viruses, called bacteriophages, infect and destroy bacteria.” They are important in the history of molecular biology and genetics, so I thought you might enjoy seeing how this infection occurs.

Illustration by David S. Goodsell, RCSB Protein Data Bank and Scripps Research. doi: 10.2210/rcsb_pdb/goodsell-gallery-048 

Snapshots from the life cycle of bacteriophage T4. At left, a bacteriophage (red) is injecting its DNA genome (white) into an Escherichia coli cell. At center, the bacteriophage has taken over the cell, destroying the cellular DNA (purple) and forcing the cell to make many new copies of itself. At right, the bacteriophage produces a channel-forming protein (magenta) that pierces the inner cell membrane, allowing lysozyme enzymes to break down the peptidoglycan sheath (fibrous molecules shown in turquoise between the two cellular membranes) that supports the cell. The cell bursts, releasing several hundred new bacteriophages.

Unlike the flu and measles viruses, T4 is a DNA virus; it injects its DNA into bacteria. Note that there is a big difference in the spatial scale of this illustration compared to the previous two. Most viruses are on the order of a tenth of a micron in size, and E. coli bacteria are about a couple microns long. Those tiny red dots are the T4's icsahedral head (capsid), and is about the same size as the influenza virus shown earlier. Remember, a human cell has a size on the order of 10 microns, which is giant compared even to those bacteria. You could fit about 2000 E. coli into a typical human cell.

SARS-CoV-2 mRNA Vaccine, 2020

Finally, I end with the Covid vaccine. In particular, it’s an mRNA Covid vaccine, as produced by Pfizer or Moderna.

Illustration by David S. Goodsell, RCSB Protein Data Bank; doi: 10.2210/rcsb_pdb/goodsell-gallery-027 

Messenger RNA (mRNA) vaccines developed for the COVID-19 pandemic are composed of long strands of RNA (magenta) that encode the SARS-CoV-2 spike surface glycoprotein enclosed in lipids (blue) that deliver the RNA into cells. Several different types of lipids are used, including familiar lipids, cholesterol, ionizable lipids that interact with RNA, and lipids connected to polyethylene glycol chains (green) that help shield the vaccine from the immune system, lengthening its lifetime following administration. In this idealized illustration, all of the lipids are arranged in a simple circular bilayer that surrounds the mRNA and the PEG strands have both extended and folded conformations. 

It is interesting how much the vaccine looks like a virus. The main difference is that it only contains mRNA that codes for the spike protein—the protein that is recognized by the immune system—and not any other proteins, so it can't make functional copies of the Covid virus. Eventually, these nanoparticles of vaccine will bind with human cells, the mRNA will enter the cell (but not the cell nucleus), and it will produce spike protein by the cell's usual translation process. The immune system will recognize the spike protein and develop defenses against it. Elegant, life-saving science at work, beautifully illustrated by David Goodsell.

The size of the nanoparticle is about 100 nm, roughly the same size as the Covid 19 virus itself. Again, you can use that lipid bilayer (whose thickness is essentially a biological constant) as a size scale.
 

I’ll end with a wonderful video about Goodsell and his art. Enjoy!

Inside the Cell: The Molecular Art of David Goodsell

https://www.youtube.com/watch?v=Gk8cNkm5NTk

The Pardee and Riley Experiment and the Discovery of mRNA

Today I want to discuss an experiment that led to the discovery of messenger RNA (mRNA). Why did I choose to focus on one specific experiment? First, because of its importance in the history of molecular biology. Second, the experiment highlights the use of radioisotopes like those Russ Hobbie and I describe in Chapter 17 of Intermediate Physics for Medicine and Biology. Third, the recent development and of mRNA vaccines for Covid and other diseases makes this a good time to review how our knowledge of mRNA was established.  

A crucial experiment was performed by Arthur Pardee and Monica Riley at the University of California, Berkeley, and published in 1960. Let me provide some context and set the stage. The structure of DNA had been discovered by Watson and Crick in 1953. By 1960, scientists knew that individual genes in DNA coded for individual proteins. The question was how the genetic information got from DNA to the protein. RNA was suspected to be involved, in part because ribosomes—the stable cellular macromolecules where DNA was produced—are made from RNA. Were the ribosomes the messenger, or was there something else? Many key experiments in biology, like the one by Pardee and Riley, are performed using a simple model system: E coli bacteria. Another important tool of early modern biology was radioisotopes, a product of modern physics from the first half of the twentieth century that was essential for biology during the second half of the century. 

Since I’m neither a molecular biologist nor a historian of science, I’ll let Horace Freeland Judson—author of one of my favorite history of science books, The Eight Day of Creation: The Makers of the Revolution in Biology—tell you about Pardee and Riley’s work.

The experiment Pardee and Riley had done in Berkeley was new, technically amusing, and persuasive. It amounted to removal of the gene from the cell after it had begun to function. They had grown… bacteria… carrying [a specific gene to produce the protein enzyme beta-galactosidase]… in a broth where the available phosphorus [an important element in DNA] was the radioactive isotope ³²P. The bacteria, with their DNA heavily labeled, were then centrifuged out... [and] resuspended in a nonradioactive broth… [Next] they added glycerol [a type of antifreeze]. Then they took one sample to test for enzyme activity [to check if beta-galactosidase was produced]. They put other samples into small glass ampules, sealed the ampules by fusing the glass at the neck, and lowered them into a vacuum-insulated flask of liquid nitrogen. The bacteria were frozen almost instantly at 196 degrees below zero centigrade. Protected from bursting by the glycerol, the bacteria were not killed, but their vital processes were arrested while the radiophosphorus in the DNA… continued to decay… From day to day, Riley raised ampules of the frozen bacterial suspension from the liquid nitrogen and thawed them… For comparison, they ran the whole [experiment] in parallel without the radioactivity [this was their control].

Before telling you the result, let me digress a bit about phosphorus-32. It’s an unstable isotope that undergoes beta decay to stable sulfur-32. This means the ³²P ejects an electron (and an antineutrino) and transforms to ³²S. In many cases (such as in sodium-24 examined in Fig. 17.9 of IPMB), beta decay occurs to an excited state that then emits gamma rays. But ³²P is “pure” meaning there are no gamma rays, or even different competing beta decay paths. The book MIRD: Radionuclide Data and Decay Schemes by Eckerman and Endo, often cited in IPMB, shows this simple process with this figure and table. 

Note the half-life of ³²P is two weeks, and the average energy of the ejected electron is 695 keV.

What happens when ³²P decays? First, the electron can damage the cells. An electron of this energy has a range of about a millimeter, so that damage would not be localized to an individual bacterium (with a size on the order of 0.001 mm). However, when the ³²P isotope decays, it will recoil, which could eject it from the DNA molecule, causing a strand break. Even if the recoil is not strong enough remove the atom from DNA, there would now be a sulfur atom where a phosphorus atom should be, and these two atoms, being in different columns of the periodic table, will have different chemical properties which surely would disrupt the DNA structure and function. As Judson says

An atom of ³²P decays by emitting a beta particle, which is a high-speed electron, whereupon it is transformed into an atom of sulphur. The transformation, and the recoil of the atom as the electron leaves, breaks the bonds of the backbone of the DNA at that point… Half of those decayed in fourteen days. The [beta-galactosidase] genes were being killed.

So, what was the result? Judson summarizes,

The nonradioactive bacteria sampled before freezing were synthesizing enzyme copiously. So were the radioactive ones before freezing… Thawed after ten days, samples of nonradioactive bacteria synthesized beta-galactosidase just as vigorously as those never frozen. But the bacteria whose [beta-galactosidase] genes had suffered ten days of radioactive decay made the enzyme at less than half the rate they had before. Inactivation of the gene… abolished protein synthesis without delay. Stable intermediates between the gene and its protein—in other words, ribosomes whose RNA carried information to specify the sequence of amino acids—were ruled out. Continual action of the gene was necessary, either directly or by way of an intermediate that was unstable and so had to be steadily renewed.

When Francis Crick and Sydney Breener learned of Pardee and Riley’s results, they combined their knowledge of this experiment with a previous one by Elliot Volkin and Lazarus Astrachan using bacteriophages [a virus that infects bacteria] to hypothesize that a new type of RNA, called messenger RNA, was the unstable intermediary connecting DNA and protein. And the rest is history.

The Pardee and Riley experiment (which made up Monica Riley’s PhD dissertation… wow, what a dissertation topic!) is beautiful and important. It is also relevant today. Why do mRNA vaccines (like the Pfizer and Moderna Covid vaccines) have to be kept so cold when being transported and stored before use? As Pardee and Riley showed, the mRNA is unstable. It will decay quickly if not kept ultra-cold. Can mRNA change the DNA in your cells? No, the mRNA is simply a messenger that transfers the stored genetic information in DNA to the proteins formed on ribosomes. Moreover, one difference between E coli bacteria and human cells is that in humans the DNA is located inside the cell nucleus (bacteria don’t have nuclei) and the ribosomes are in the cytoplasm outside the nucleus. DNA can’t leave the nucleus, and mRNA can only go out of, not into, the nucleus. So an mRNA vaccine will cause human cells to make virus proteins (for the covid vaccine, it will produce the spike protein) that will be detected by your immune system, but the mRNA will only be present a short time before it decays and will not affect your DNA. Finally, the vaccine contains mRNA for only the spike protein, not for the entire virus. So, no actual intact viruses are produced by the vaccine. The spike protein simply activates your immune system, without exposing you to an infection.

Isn’t science great?

The Age of Reason Begins

The Age of Reason Begins,
by Will and Ariel Durant.

The title of this week’s post is ironic, because with all the events of the last few months I often suspect that the Age of Reason is coming to a close. The title comes from volume seven of Will and Ariel Durant’s The Story of Civilization. After I retired from Oakland University, I set about reading the entire eleven-volume series. The subtitle of The Age of Reason Begins is: A History of European Civilization in the Period of Shakespeare, Bacon, Montaigne, Rembrandt, Galileo, and Descartes: 1558–1648.

Today I want to focus on Francis Bacon, who is probably the central figure in the Durants’ book (his picture was their choice for gracing the book’s cover). They introduce him this way.

Francis Bacon, who was destined to have more influence on European thought than any other Elizabethan, had been born (1561) in the very aura of the court, at York House, official residence of the Lord Keeper of the Great Seal, who was his father, Sir Nicholas; Elizabeth called the boy ‘the young Lord Keeper.’ His frail constitution drove him from sports to studies; his agile intellect grasped knowledge hungrily; soon his erudition was among the wonders of those ‘spacious times.’

Why bring up Bacon now? Well, the last few months have seen unprecedented attacks on science and scientists: Budget cuts to the National Institutes of Health and the National Science Foundation, climate change denial and vaccine hesitancy, conspiracy theories, political requirements for government funding, the demonization of scientists such an Anthony Fauci, and more. It seems like something horrible happens every day. This makes me wonder: what is the key feature of science that must be preserved above all else? What one thing must we save? I can think of many possibilities. Science drives our economy and prosperity. Scientific discoveries have led to amazing advances in human health. Educating and providing opportunities for our young scientists is a critical investment in our future. Yet, as important as these things are, they aren’t the central issue. They aren’t what we must save lest all be lost. It’s this key element of science, its essence, that brings me to Francis Bacon.

Bacon was an early promoter of the scientific method. The Durants write

Bacon felt that the old Organon [of Aristotle] had kept science stagnant by its stress on theoretical thought rather than practical observation. His Novum Organum proposed a new organ and system of thought—the inductive study of nature itself through experience and experiment. Though this book too was left incomplete, it is, with all its imperfections, the most brilliant production in English philosophy, the first clear call for an Age of Reason.

Let me explain (and perhaps expand on) Bacon’s idea in my own words. How do we know what is true and what is not? By evidence. By experiment. By data. By comparing our ideas to what we can measure happening in the world. By accepting as true only those hypotheses that survive our best efforts to disprove them. By submitting our conclusions to rigorous peer review from our fellow scientists. Yet the current Republican administration seems to have its own ideas of what is true, regardless of the evidence. This is the very opposite of science. It is anti-science.

For example, the reality of climate change and humanity’s impact on global warming is backed by an enormous body of data. We have records of temperature, carbon dioxide concentration, and increasingly violent storms. We have sophisticated mathematical models with which we can conduct numerical experiments to predict what will happen in the future. The evidence is truly overwhelming. Yet, many—including President Trump—don’t care about the evidence. They claim climate change is a “hoax.” They don’t back these claims with facts. They don’t approach the topic as an inductive study based on experience and experiment. They believe things for their own reasons that have nothing to do with evidence or science.

Another example is vaccines. There are so many clinical studies showing that vaccines don’t cause autism. Again, the evidence is overwhelming. Yet people like Health and Human Services Secretary Robert F. Kennedy, Jr. believe just the opposite: that autism is caused by vaccines. They don’t support such claims by presenting new evidence. While they occasionally drag up discredited studies or cherry-pick data, they don’t systematically examine all the evidence and weigh both sides. They don’t try to falsify their hypotheses. They don’t subject their ideas to peer-review. 

Still another example is the source of covid. The evidence is uncertain enough that we cannot say definitively how the covid pandemic arose. Yet, the data points strongly in one direction: Spillover from an animal to a human. Nevertheless, the government’s covid.gov website now claims that the “lab leak” hypothesis has been proven, and asserts that covid arose from sinister events in a lab in China. No, we don’t know that. While we can’t yet be certain, the evidence suggests that the cause was not a lab leak. Just because some politicians want the source of covid to be a lab leak doesn’t make it so.

One more example, of particular relevance to Intermediate Physics for Medicine and Biology, is cell phone safety. Although again there are uncertainties in the data (especially in laboratory experiments), the evidence suggests that radiofrequency electromagnetic radiation from cell phones does not cause cancer. I think that to say “suggests” is an understatement. The evidence is compelling that cell phones are safe. Yet RFK Jr. and others continue to argue otherwise, as if evidence doesn’t matter.

I would love to be proved wrong, and shown that, say, climate change is actually not happening. That would truly be wonderful, and millions of lives would be saved. But you have to prove that using evidence. You can’t just declare it. My dad was born in Kansas City and he used to say “I’m from Missouri and you have to show me!” That’s the gist of what it means to be a scientist. You have to show me, not tell me. Convince me with the data.

So, what is the feature of science that is essential? What aspect, if we lose it, means we no longer have science at all. I would say the belief that evidence matters. That experiments are how we determine what is true and what is not. If we give that up, all is lost and we’re back to the age of faith. Not religious faith necessarily, but an age where truth is determined not by evidence but by what is consistent with your personal beliefs, your friends and family, your wishful thinking, your fears, or your politics. The supremacy of evidence is where we must focus our resistance. That must be our line in the sand that we will not cross. That must be the hill from which we defend against the onslaught of the Republican War on Science, so that the Age of Reason can resume.

Francis Bacon,
From the cover of
The Age of Reason Begins.

The Durants conclude

Because he [Bacon] expressed the noblest passion of his age—for the betterment of life through the extension of knowledge—posterity raised to his memory a living monument of influence. Scientists were stirred and invigorated not by his method but by his spirit. How refreshing, after centuries of minds imprisoned in their roots or caught in webs of their own wistful weaving, to come upon a man who loved the sharp tang of fact, the vitalizing air of seeking and finding, the zest of casting lines of doubt into the deepest pools of ignorance, superstition, and fear!...

…[Bacon] repudiated the reliance upon traditions and authorities; he required rational and natural explanations instead of emotional presumptions, supernatural interventions, and popular mythology. He raised a banner for all the sciences, and drew to it the most eager minds of the succeeding centuries.

The Philosophy of Sir Francis Bacon, from Let’s Talk Philosophy.

https://www.youtube.com/watch?v=Mj4N0O7QnPY

Where Have You Gone, Physicist Bob Park? Our Nation Turns Its Lonely Eyes to You. Woo, Woo, Woo.

Voodoo Science, by Bob Park, superimposed on
Intermediate Physics for Medicine and Biology.

Bob Park died five years ago this week. He had been in poor health since suffering a stroke in 2013. Park was a physicist and the director of public information at the Washington office of the American Physical Society. He was a leading voice against pseudoscience, both in his weekly column What’s New (which, when in graduate school, I used to look forward to seeing in my email every Friday) and in his books such as Voodoo Science.

I wonder what Park would say if he were alive today? I suspect he would be horrified. But I doubt he would have said that. He was not a whine-and-fuss sort of guy. His tools were humor, irony, and sarcasm. Here is what I imagine What’s New would have looked like this week.

What’s New, by Bob Park

Friday, April 25, 2025

1. VITAMIN A FOR THE MEASLES

The Texas measles outbreak continues. Over 600 cases have now been reported, which is more than for the entire year in 2024. Health and Human Services Secretary Robert F. Kennedy, Jr. encouraged parents to treat their children suffering from measles with vitamin A, and now children are suffering from liver disease because of vitamin A overdosing. Why don’t parents simply ask their pediatrician what to do? Because pediatricians are part of the conspiracy, of course!

2. IF WE IGNORE IT, IT WILL GO AWAY

The Trump administration is trying to undo all the progress fighting climate change that has accumulated over the last few decades. His thinking is: if you ignore climate change, the problem goes away. Besides, it’s all a HOAX! King Canute tried this. He commanded the tide to stop coming in. How do you think that turned out? Physics has a way of winning in the end, whether or not it’s politically popular.  

3. LAB LEAK

The Trump administration has rewritten the covid.gov website to advocate for the lab leak hypothesis for the source of covid-19. Don't worry that the evidence is flimsy! If covid resulted from a lab leak, then it’s the scientists fault. Blame those arrogant liberal elitists like Fauci. But watch out for the next spillover event! (Can I interest anyone in some bird flu?)

4. LYSENKO

Back in the USSR, when Stalin was in charge, a crackpot named Lysenko took control of Russian science. He didn’t believe in modern genetics, regardless of the evidence. Russian agriculture collapsed and millions died. Here in the United States, we have our own version of the Lysenko affair. Trump is Stalin, RFK Jr is Lysenko, and vaccine hesitancy and climate change are genetics. I fear the outcome will be the same, which is bad for science and worse for humanity.

5. HOORAY FOR HARVARD

The NIH (remember that place that used to be the greatest biomedical research institution anywhere, ever?) has stopped funding grants to several universities, including Harvard. HARVARD! Apparently these universities will not cave in to Trump's ideological agenda. What will happen next? Who knows. Maybe Trump will be stopped by the Supreme Court. Maybe the House and Senate will decide they’ve had enough. And maybe, just maybe, it will be the end of American science.

Yesterday’s Attack on Dr. Anthony Fauci During his Testimony at the Congressional Select Subcommittee on the Coronavirus Pandemic Angers Me

Yesterday’s attack on Dr. Anthony Fauci during his testimony at the Congressional Select Subcommittee on the Coronavirus Pandemic angers me. I like Dr. Fauci and I like other vaccine scientists such as Peter Hotez and writers such as David Quammen who tell their tales. But, it isn’t really about them. What upsets me most is the attack on science itself; on the idea that evidence matters; on the idea that science is the way to determine the truth; on the idea that truth is important. I’m a scientist; it’s an attack on me. We must call it out for what it is: a war on science. #StandWithScience

The Deadly Rise of Anti-Science

The Deadly Rise of Anti-Science,
by Peter Hotez.

This week I read The Deadly Rise of Anti-Science: A Scientist’s Warning, by Peter Hotez. Every American should read this book. In his introductory chapter, Hotez writes

This is a dark and tragic story of how a significant segment of the population of the United States suddenly, defiantly, and without precedent turned against biomedical science and scientists. I detail how anti-science became a dominant force in the United States, resulting in the deaths of thousands of Americans in 2021 and into 2022, and why this situation presents a national emergency. I explain why anti-science aggression will not end with the COVID-19 pandemic. I believe we must counteract it now, before something irreparable happens to set the country on a course of inexorable decline…

The consequences are shocking: as I will detail, more than 200,000 Americans needlessly lost their lives because they refused a COVID-19 vaccine and succumbed to the virus. Their lives could have been saved had they accepted the overwhelming scientific evidence for the effectiveness and safety of COVID-19 immunization or the warnings from the community of biomedical scientists and public health experts about the dangers of remaining unvaccinated. Ultimately, this such public defiance of science became a leading killer of middle-aged and older Americans, more than gun violence, terrorism, nuclear proliferation, cyberattacks or other major societal threats.

Where did this 200,000 number come from? On page 2 of Intermediate Physics for Medicine and Biology, Russ Hobbie and I claim that

One valuable skill in physics is the ability to make order-of-magnitude estimates, meaning to calculate something approximately right.

Hotez gives a classic example of estimation when deriving the 200,000 number. First, he notes that 245,000 Americans died of covid between May 1 and December 31, 2021. Covid arrived in the United States in early 2020, but vaccines did not become widely available until mid 2021. Actually, the vaccines were ready in early 2021 (I had my first dose on March 20), but May 1 was the date when the vaccine was available to everyone. During the second half of 2021, about 80% of Americans who died of covid were unvaccinated. So, Hotez multiplies 245,000 by 0.8 to get 196,000 unvaccinated deaths. After rounding this off to one significant figure, this is where he gets the number 200,000.

There are a few caveats. On the one hand, our estimate may be too high. The vaccine is not perfect. If all of the 200,000 unvaccinated people who died would have gotten the vaccine, some of them would still have perished from covid. If we take the vaccine as being 90% effective against death, we would multiple 196,000 times 0.9 to get 176,400. On the other hand, our estimate may be too low. Covid did not end on January 1, 2022. In fact, the omicron variant swept the country that winter and at its peak over 2000 people died of covid each day. So, the total covid deaths since the vaccine became available—the starting point of our calculation—is certainly higher than 245,000.

As Hotez points out, other researchers have also estimated the number of unnecessary covid deaths, using slightly different assumptions, and all the results are roughly consistent, around 200,000. (Hotez’s book appears to have been written in mid-to-late 2022; I suspect the long tail of covid deaths since then would not make much difference to this estimation, but I’m not sure.) 

In the spirit of an order-of-magnitude estimate, one should not place too great an emphasis on the precise number. It was certainly more than twenty thousand and it was without a doubt less than two million. I doubt we’ll ever know if the “true” amount is 187,000 or 224,000 or any other specific value. But we can say with confidence that about a couple hundred thousand Americans died unnecessarily because people were not vaccinated. Hotez concludes

That 200,000 unvaccinated Americans gave up their lives needlessly through shunning COVID-19 vaccines can and should haunt our nation for a long time to come.

Infectious disease scientists such as Peter Hotez, Tony Fauci, and others are true American heroes. That far-right politicians and journalists vilify these researchers is despicable and disgusting. We all owe these scientists so much. Last Monday was “Public Health Thank You Day” and yesterday was Thanksgiving. I can think of no one more deserving of our thanks than the scientists who led the effort to vaccinate America against covid. 

Why Science Isn’t Up for Debate, with Peter Hotez.

https://www.youtube.com/watch?v=PbGfeksduGE

Breathless

Breathless,
by David Quammen.

Whenever David Quammen has a new book, I put it on my “to read” list. Recently I finished his latest: Breathless: The Scientific Race to Defeat a Deadly Virus. Here’s the opening paragraph:

To some people it wasn’t surprising, the advent of this pandemic, merely shocking in the way a grim inevitability can shock. Those unsurprised people were infectious disease scientists. They had for decades seen such an event coming, like a small, dark dot on the horizon of western Nebraska, rumbling toward us at indeterminable speed and with indeterminable force, like a runaway chicken truck or an eighteen-wheeler loaded with rolled steel. The agent of the next catastrophe, they knew, would almost certainly be a virus. Not a bacterium as with bubonic plague, not some brain-eating fungus, not an elaborate protozoan of the sort that cause malaria. No, a virus—and, more specifically, it would be a “novel” virus, meaning not new to the world but newly recognized as infecting humans.

Quammen—a national treasure—is writing about covid (or, to use its official name, SARS-CoV-2). The coronavirus pandemic did not startle him; he almost predicted it in his earlier book Spillover. Quammen’s book Breathless is to tracing the origins and variants of covid as Walter Isaacson’s book The Code Breaker is to developing a vaccine for covid: required reading to understand what we’ve all been through the last three years. (And what I went through last month with my first case of covid, but I’m healthy now and feeling fine.)

Breathless describes the scientists who developed amazing software to analyze the virus’s genome, such as Áine O’Toole’s genomic pipeline PANGOLIN. Intermediate Physics for Medicine and Biology doesn’t discuss computational genomics, but at the heart of IPMB is the idea that you can combine a hard science like computer programming with a biological science like genomics to gain more information about, and insight into, biology and medicine. Quammen interviewed O’Toole about her experience writing the PANGOLIN program (“O’Toole stayed up late one night, and the next morning, there it was.”). But he didn’t interview just her. He talked to 96 heroic scientists and medical doctors who sought to understand covid, from those I’ve never heard of such as O’Toole to those we all are familiar with such as the brilliant Anthony Fauci. These interviews give the book credibility, especially given all the covid conspiracy theories and anti-vaccine nonsense that floats around the internet these days.

For anyone who may doubt the reality of evolution, I challenge you to try making sense of covid variants without it. Quammen takes us through the list: Alpha, Beta, Gamma, and the frightening Delta.

And after Delta, we knew, would come something else. The Greek alphabet contains twenty-four letters; at that point, the WHO [World Health Organization] list of variants only went up to mu. A virus will always and continually mutate, as I’ve noted, and the more individuals it infects, the more mutations it will produce. The more mutations, the more chances to improve its Darwinian success. Natural selection will act on it, eliminating waste, eliminating ineptitude, carving variation like a block of Carrara marble at the hands of Michelangelo, finding beautiful shapes, preserving the fittest. Evolution will happen. That’s not a variable, it’s a constant.

The latest variant, Omicron, seems to have appeared just as Quammen was finishing his book.

Omicron’s panoply of mutations reflects a period of active, extensive evolution—because the mutations not only occurred but they were preserved, within the lineage, suggesting they offered adaptive value.

One of the most interesting questions addressed in Breathless is the source of covid. Was it a lab accident, a spillover from an animal host (called a zoonotic event), or a malevolent attempt at biological warfare? Quammen doesn’t provide a definitive answer, but he favors the conclusions reached in a review article written by a group of prominent virologists led by Eddie Holmes.

Yes, Holmes and his coauthors agreed, the possibility of a lab accident can’t be entirely dismissed. Furthermore, that hypothesis may be nearly impossible to disprove. But it’s “highly unlikely,” they judged, “relative to the numerous and repeated human-animal contacts that occur routinely in the wildlife trade.” Failure to investigate that zoonotic dimension, with collaborative studies, crossing borders between countries and boundaries between species, would leave this pandemic festering and the world still very vulnerable to the next one.

Run, do not walk, to your library or bookstore and get Breathless. You need to read this book. Take special heed of Quammen’s alarming, disturbing, terrifying last sentence.

There are many more fearsome viruses where SARS-CoV-2 came from, wherever that was.

 A conversation with author and journalist David Quammen.

https://www.youtube.com/watch?v=jsREp6XI0nY

I’ve Got Covid

For three years I’ve dodged the bullet, but no more; I have covid. I’m doing fine, thank you. For me the symptoms were similar to a moderate cold. My doctor put me on a five-day regimen of the antiviral drug Paxlovid plus some supplements to support my immune system (vitamin C, vitamin D3, and zinc). I’ve been isolating in our spare bedroom, which is boring but otherwise comfortable. I think I’m over the hump.

During the last few days I’ve taken several of those at-home covid rapid antigen tests. There’s some interesting physics at work in them. The figure below illustrates how they’re constructed. 

A covid rapid antigen test. From: Gupta et al. (2020) Nanotechnology-Based Approaches for the Detection of SARS-CoV-2. Frontiers in Nanotechnology, Volume 2, Article 589832.

To perform a test, you typically swab your nose, dip the swab in saline, stir, and then place a few drops of the solution onto the sample pad (A). You’re not detecting the virus itself, but instead the SARS-Cov 2 antibody. To explain what that means, I need to delve into a bit of immunology.

Our immune system produces a Y-shaped protein called an antibody, or immunoglobulin, that can selectively bind to an antigen, which is typically a protein that’s part of the coronavirus. The beauty of the antibody-antigen reaction is that it’s so specific: it lets the immune system attack a particular virus, bacteria, or other pathogen, ignoring everything else. When you get covid, your body launches an immune attack by producing SARS-Cov 2 antibodies. In the illustration above, the yellow Y is the antibody you are trying to detect. See David Goodsell’s marvelous painting of a virus being attacked by antibodies at the bottom of this post.

In the above figure, the conjugate pad (B) is where much of the physics lives. The pad contains gold nanoparticles (AuNP) that are coated with anti-human antibodies. An “anti-human antibody” is a molecule that binds selectively to a human antibody. In the figure, a red dot with a blue Y sticking out is a gold nanoparticle with an anti-human antibody bound to it.

A nitrocellulose membrane (NC membrane) is made from a mesh of nitrocellulose fibers (C). The mesh is porus and acts something like a wick, pulling the fluid from left to right by capillary action. This is why a device like that in the figure above is sometimes called a lateral flow test. The mesh also provides protected space for the nanoparticles and molecules to move around and interact in. The absorbent pad (D) acts like a sponge, soaking up the fluid as it reaches the right end of the detector, contributing to the capillary action and preventing any back flow.

As any SARS-Cov 2 antibody passes by a gold nanoparticle/anti-human antibody, it binds and the entire complex flows to the right together (in the figure, a combined red dot/blue Y/yellow Y).

Some additional molecules are bound to two spots on the nitrocellulose membrane. One, the test strip, has the SARS-cov 2 antigen. If any SARS-Cov 2 antibody passes by, it will bind to the antigen, immobilizing the gold nanoparticles. The other strip is goat anti-mouse antibody. How did a goat and mouse get involved? I don’t know. As I understand it, gold nanoparticles with antibodies that bind to the goat anti-mouse antibody are included in the conjugate pad, so regardless of if you have covid or not it serves as a control. If the nanoparticles don’t collect at the control strip, something is wrong.

Why bother with the gold nanoparticles? Their role is to transduce the signal so it becomes visible. Nanoparticles have interesting optical properties. When exposed to an electromagnetic field such as light, the electric field causes electrons to accumulate on one side of the particle creating a negative surface charge, leaving the opposite side positive from a lack of electrons. Such a distribution of charge oscillates at its own natural frequency (its plasma frequency), and when this frequency matches the driving frequency of the light there is a resonance. This “localized surface plasmon resonance” is effective at absorbing or scattering light. Scattering is particularly important because Rayleigh scattering (the scattering of light by particles with a radius much smaller than the wavelength of the light) depends on the sixth power of the particle radius. The binding of nanoparticles (which typically have a diameter of tens of nanometers) with large antibodies and antigens, and the aggregation of these complexes, can increase their effective size, accentuating scattering. In addition, the high concentration of the nanoparticles at the test and control strips enhance any optical effect. The end result is that you see a dark line if the nanoparticles are present.

So swab your nose, swish it in some saline, add a few drops to the sample pad, and wait. After about 15 minutes look at the results. If there is no control line, you’ve messed up. Throw the test away and try again. If there’s a control line but no test line, you’re negative. Be happy (but not too happy, because these tests are prone to false negatives). If there’s both a control line and a test line, you’ve got covid. The tests don’t give false positives too often, so you can be fairly confident you have the disease. Isolate yourself and talk to you doctor.

Where is the physics in all this? First, in the flow, which results from the surface tension created by the mesh of fibers, leading to capillary action. Second, in the optical properties of the nanoparticles, which provide the color that you see in the test and control strips. Unfortunately, Intermediate Physics for Medicine and Biology doesn’t discuss capillary action or surface plasmons, so you can’t learn about them there. Sorry; no book can cover everything. But there is interesting physics hidden in these tests.

Stay safe, dear reader, and may all your covid tests be negative.

This painting shows a cross section through a coronavirus surrounded by blood plasma, with neutralizing antibodies in bright yellow. The painting was commissioned for the cover of a special COVID-19 issue of Nature. From: David S. Goodsell, RCSB Protein Data Bank and Springer Nature; doi: 10.2210/rcsb_pdb/goodsell-gallery-025

 

A chemist explains how at-home covid tests work. From WIRED.

https://www.youtube.com/watch?v=2B-iZGNiPA0

See how a lateral flow immunoassay works.

https://www.youtube.com/watch?v=z07CK-4JoFo

Physics Girl has Long Covid

I’m a fan of Dianna Cowern, better known as Physics Girl, who makes Youtube videos about physics that would be helpful for readers of Intermediate Physics for Medicine and Biology. Three years ago I featured several of her videos in a blog post.

Cowern is suffering from a severe case of long Covid. I’m going to turn this week’s post over to Simone Giertz for an update on Cowern’s health.

An update on Dianna's health, by Simone Giertz.

https://www.youtube.com/watch?v=vydgkCCXbTA

 

 

The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race

The Code Breaker,
by Walter Isaacson

My favorite authors are Simon Winchester, David Quammen, and Walter Isaacson. This week I read Isaacson’s latest book: The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race. I would place it alongside The Eighth Day of Creation and The Making of the Atomic Bomb as one of the best books about the history of science. 

In his introduction, Isaacson writes

The invention of CRISPR and the plague of COVID will hasten our transition to the third great revolution of modern times. These revolutions arose from the discovery, beginning just over a century ago, of the three fundamental kernels of our existence: the atom, the bit, and the gene.

The first half of the twentieth century, beginning with Albert Einstein’s 1905 papers on relativity and quantum theory, featured a revolution driven by physics. In the five decades following his miracle year, his theories led to atom bombs and nuclear power, transistors and spaceships, lasers and radar.

The second half of the twentieth century was an information-technology era, based on the idea that all information could be encoded by binary digits—known as bits—and all logical processes could be performed by circuits with on-off switches. In the 1950s, this led to the development of the microchip, the computer, and the internet. When these three innovations were combined, the digital revolution was born.

Now we have entered a third and even more momentous era, a life-science revolution. Children who study digital coding will be joined by those who study genetic code.

Early in the book, Isaacson describes Francisco Mojica’s discovery that bacteria have “CRISPR spacer sequences”: strands of DNA that serve as an immune system protecting them from viruses.

As we humans struggle to fight off novel strains of viruses, it’s useful to note that bacteria have been doing this for about three billion years, give or take a few million centuries. Almost from the beginning of life on this planet, there’s been an intense arms race between bacteria, which developed elaborate methods of defending against viruses, and the ever-evolving viruses, which sought ways to thwart those defenses.

Mojica found that bacteria with CRISPR space sequences seems to be immune from infection by a virus that had the same sequence. But bacteria without the spacer did get infected. It was a pretty ingenious defense system, but there was something even cooler: it appeared to adapt to new threats. When new viruses came along, the bacteria that survived were able to incorporate some of that virus’s DNA and thus create, in its progeny, an acquired immunity to that new virus. Mojica recalls being so overcome by emotion at this realization that he got tears in his eyes. The beauty of nature can sometimes do that to you.

The Code Breaker focuses on the life and work of Jennifer Doudna, who won the 2020 Nobel Prize in Chemistry. However, the star of the book is not Doudna, nor Emmanuelle Charpentier (who shared the prize with Doudna), nor Mojica, nor any of the other scientific heroes. The star is RNA, the molecule that carries genetic information from DNA in the nucleus to the cytoplasm where proteins are produced.

By 2008, scientists had discovered a handful of enzymes produced by genes that are adjacent to the CRISPR sequences in a bacteria’s DNA. These CRISPR-associated (Cas) enzymes enable the system to cut and paste new memories of viruses that attack the bacteria. They also create short segments of RNA, known as CRISPR RNA (crRNA), that can guide a scissors-like enzyme to a dangerous virus and cut up its genetic material. Presto! That’s how the wily bacteria create an adaptive immune system!

Doudna and Charpentier’s Nobel Prize resulted from their developing the CRISPR-Cas9 system into a powerful technique for gene editing.

The study of CRISPR would become a vivid example of the call-and-response duet between basic science and translational medicine. At the beginning it was driven by the pure curiosity of microbe-hunters who wanted to explain an oddity they had stumbled upon when sequencing the DNA of offbeat bacteria. Then it was studied in an effort to protect the bacteria in yogurt cultures from attacking viruses. That led to a basic discovery about the fundamental workings of biology. Now a biochemical analysis was pointing the way to the invention of a tool with potential practical uses. “Once we figured out the components of the CRISPR-Cas9 assembly, we realized that we could program it on our own,” Doudna says. “In other words, we could add a different crRNA and get it to cut any different DNA sequence we chose.”

Several other themes appear throughout The Code Breaker: 

• The role of competition and collaboration in science, 
• How industry partnerships and intellectual property affect scientific discovery, 
• The ethics of gene editing, and
• The epic scientific response to the COVID-19 pandemic. 

I’m amazed that Isaacson’s book is so up-to-date. I received my second dose of the Pfizer-BioNTech vaccine last Saturday and then read The Code Breaker in a three-day marathon. My arm was still sore while reading the chapter near the end of the book about RNA Covid vaccines like Pfizer’s.

There’s a lot of biology and medicine in The Code Breaker, but not much physics. Yet, some of the topics discussed in Intermediate Physics for Medicine and Biology appear briefly. Doudna uses x-ray diffraction to decipher the structure of RNA. Electroporation helps get vaccines and drugs into cells. Electrophoresis, microfluidics, and electron microscopy are mentioned. I wonder if injecting more physics and math into this field would supercharge its progress. 

CRISPR isn’t the first gene-editing tool, but it increases the precision of the technique. As Winchester noted in The Perfectionists, precision is a hallmark of technology in the modern world. Quammen’s book Spillover suggests that humanity may be doomed by an endless flood of viral pandemics, but The Code Breaker offers hope that science will provide the tools needed to prevail over the viruses.

I will close with my favorite passage from The Code Breaker: Isaacson’s paean to curiosity-driven scientific research.

The invention of easily reprogrammable RNA vaccines was a lightning-fast triumph of human ingenuity, but it was based on decades of curiosity-driven research into one of the most fundamental aspects of life on planet earth: how genes encoded by DNA are transcribed into snippets of RNA that tell cells what proteins to assemble. Likewise, CRISPR gene-editing technology came from understanding the way that bacteria use snippets of RNA to guide enzymes to chop up dangerous viruses. Great inventions come from understanding basic science. Nature is beautiful that way.

 

.

“How CRISPR lets us edit our DNA,” a TED talk by Jennifer Doudna. 

https://www.youtube.com/watch?v=TdBAHexVYzc

Nobel Lecture, Jennifer Doudna, 2020 Nobel Prize in Chemistry.

https://www.youtube.com/watch?v=KSrSIErIxMQ

Walter Isaacson, The Code Breaker, Talks at Google.

https://www.youtube.com/watch?v=-LuAuZ09uSs

 

CRISPR-Cas9 (“Mr. Sandman” Parody), by Tim Blais at A Capella Science.

https://www.youtube.com/watch?v=k99bMtg4zRk

The SIR Model of Epidemics

In Chapter 10 of Intermediate Physics for Medicine and Biology, Russ Hobbie and I discuss models described by nonlinear differential equations. We provide several examples in the text and homework problems, but one topic we never address is epidemics.

The archetype mathematical description of an epidemic is the SIR model. A population is divided into three categories, corresponding to three dynamic variables:

    S: the number of susceptible people

    I: the number of infected people

    R: the number of recovered people.

Three differential equations govern the number of people in each category.

    dS/dt = - (β/N) I S

    dI/dt = (β/N) I S – γ I

    dR/dt = γ I

where N is the total population, and β and γ are constants. Rather than analyze these equations myself, I’ll let you do it in a new homework problem.

Section 10.8

Problem 36 ½. The SIR model describes the dynamics of an epidemic. 

(a) Add the three differential equations and determine how the total number of people (S + I + R) changes with time. Does this model include people who die from the disease? 

(b) Write the equation governing the number of infected people as dI/dt = γI (r₀ – 1). Find an expression for r₀. Initially, when S = N, what does r₀ reduce to? This value of r₀ is known as the basic reproduction number. If r₀ is less than what value will the number of infected people decay, preventing an epidemic?

(c) Suppose r₀ is greater than one, so the number of infected people grows and the epidemic spreads. How low must the ratio S/N become for I to begin decreasing? Once this value of S/N is reached, the population is said to have herd immunity and the epidemic decays away.

Results from a numerical simulation of the SIR model, using S(0) = 997, I(0) = 3, R(0) = 0, β = 0.4, and γ = 0.04. By Klaus-Dieter Keller, CC0, https://commons.wikimedia.org/w/index.php?curid=77633956

The SIR model provides insight into the COVID-19 pandemic. It’s a simple model, and many researchers have modified it to be more realistic. Yet, there is value in a toy model like SIR. It lets you to gain intuition about a dynamical system without being overwhelmed by complexity. I always encourage students to first master a toy model, and only then add additional detail.