Tagged genes

Arms Race

      “Please hear me clearly: at this level of cases with variants spreading, we stand to completely lose the hard-earned ground we have gained. Now is not the time to relax.” Dr. Rochelle Walensky, CDC Director, CNN, March 2, 2021

      “Dr. Walensky is right, and the reason she’s right is while things are way better than they were about a month and a half ago the level of infection in the country right now is the same as at the peak of the summer surge, so we’re not in great shape. And we have variants, and variants are starting to take over, and if they become dominant and we relax restrictions I think we can absolutely see a huge spike that will really lead to a lot more suffering… We have a high level of infection, we’ve got states easing restrictions, which they should not be doing at this moment, and we’ve got the variants that are circulating that are a lot more infectious. Put all that together and I can’t help but worry about where we’re going to be for the next couple months.” Dr. Ashish Jha, epidemiologist, Dean of the School of Public Health, Brown University, CNN, March 2, 2021

      “I have to congratulate this administration for what they have done…with the vaccines… But we also have to tell the story of what is still ahead of us. And at 2.9 to 3 million doses of vaccine a day, over the next 6 to 14 weeks, when this surge is likely to happen, is not really likely to take care of the problem at all… We still have a lot of high-risk people out there, and when this surge comes, they’re going to be highly vulnerable… The other thing we see right now is that every governor wants to open schools… and as a grandfather of five children I get it. But the problem is that if you look at Europe, the challenge we’re seeing right now is a lot of transmission in schools with this new variant… So we’re going to have some tough days ahead in the older population and the younger population with this new variant virus.” Dr. Michael Osterholm, Director, Center for Infectious Disease Research and Policy, University of Minnesota, on Meet the Press, March 7, 2021

      “The pandemic still remains a very serious situation.” Dr. Rochelle Walensky, Monday, March 8, 2021, Politico.

Dear Students,

The US reportedly delivered 2.9 million vaccines into arms yesterday, far ahead of what Joe Biden initially promised and almost at the 3 million per day minimum that experts have recommended. However, the UK variant (B.1.1.1) is rapidly becoming the fastest spreading strain in the US, destined to account for at least 50 percent of new cases in Americans in the next few weeks. In Britain and Europe, this has been the threshold for new and very serious burdens on health care systems.

Right now, we Americans are feeling good. The holiday surge is over, and cases, hospitalizations, and deaths have come down an astounding 70 percent since their winter peaks. However, this is primarily the result of the mess we made by our behavior on the holidays. When we’ve been banging our head against the wall harder and harder, there is only so much credit we can take for feeling better when we stop.

But now cases and hospitalizations are plateauing at levels higher than the summer peak when the virus swept the south and west and the national surges scared the living daylights out of us. We are stabilizing at that way-high level—a convenient platform for the virus to take off in a new surge—and, right on cue, we are starting to bang our heads against the wall again, with premature openings and ending mask mandates in some states and lazy complacency in many others.

These foolhardy blunders can easily take us from the high plateau we are on into a fourth wave that will once again cause scores of thousands of needless deaths.

As the photo suggests, we are in an arms race between evolutionary changes in the spike protein—the virus’s arm for prying open our cells—and the human arms getting jabbed in the vaccination campaign. The virus is flooring its Darwinian gas pedal with new variants of concern (VoCs) in South Africa and Brazil, yes, but also New York and Oregon.

Our university is among those that have seen surges in student cases—in Emory’s case an unprecedented outbreak after a year of safe performance—due to Superbowl parties, fraternity and sorority pledging, and other activities the virus loves. So many opportunities to evolve! Now spring break is coming for many colleges, and—well, here we go again.

Good news

  1. The Johnson & Johnson single-dose vaccine was given its expected Emergency Use Authorization, putting it on a par legally with the mRNA vaccines. The J&J is an adenovirus carrying viral DNA and is stable for weeks at refrigerator temperatures, a tremendous boon for rollout—as is the fact that you only need one jab. It is substantially less effective than the mRNAs at preventing cases (72 vs. ~95 percent), but, like them, close to 100 percent effective at preventing severe cases and death. Initial rollout has been slow but will ramp up fast.
  2. Not vaccines, but other preventive measures (masks, social distancing, handwashing), along with the pass-through of the holiday surge, have brought cases and hospitalizations down more than 70 percent. Nursing homes, where the most vulnerable have lived and died of COVID all along, have declined even more—in their case largely due to priority vaccinations.
  3. Total vaccinations, mainly with mRNA vaccines, have been deployed more and more effectively, with 450 vaccination centers and thousands of volunteers across the country. We are almost at 3 million a day, and if we can keep that up or, preferably, increase it, we have a chance of flattening the curve of the fourth wave. If we keep up masking and other preventive measures, we have a chance to avoid it altogether and by the end of the year bend the current high plateau way down—if the vaccines provide long-term immunity and the new variants can’t evade them.
  4. Herd immunity through widespread vaccination—up to 85 percent is needed—can be achieved and life can return to something close to normal, with tremendous positive implications for the treatment of non-COVID illnesses, education, jobs, and mental health. Healing from this dreadful national trauma will be under way.
  5. Dr. Peter Hotez has lauded the vaccine rollout in India as having the potential to save the world from the virus—even while reminding us that the US will never be safe from it until it is controlled (not necessarily eliminated) worldwide.
  6. The CDC finally came out with guidelines for people who have been fully vaccinated. They can be indoors with small numbers of fully vaccinated people without masks, or with well-known low-risk people from one other household. They should not go to gatherings, eat indoors at restaurants, and the like.

Bad News

  1. Variants of Concern now include the UK/B.1.1.7 (mutation N501Y), which spreads 50 percent faster and is sweeping the US but is susceptible to existing vaccines; the South Africa/B.1.351(N501Y+K417N+E484K), which spreads faster and is less susceptible to vaccines; the Brazil/P.1 (N501Y+K417T+E484K), same; the new New York variant/B.1.526 (S477N+E484K), same; and the Oregon variant/B.1.1.7 (N501Y+E484K), same.
  2. Lets put this bad news in English. For each of these codes, the number in the middle represents the consecutuve position of the relevant mutation on the viral spike protein. The before and after capital letters represent the one-letter code for amino acids. Thus N501Y means the amino acid in position 501 has changed from arginine to tyrosine due to an underlying mutation (replication error) in the RNA triplet that specifies 501. Since 501 is in the binding domain of the spike protein, the mutation can and does make it easier for the virus to bind with and enter cells—thus increased transmissibility.
  3. The two mutations at position 417 (K→N →or K→T) as well as the change at 477 (S→N) also affect the spike binding domain. All can enhance transmissibility and all are popping up independently in different places. Also, these Variants of Concern involve amino acid substitutions that change the shape of the folded spike protein at least a little, and are therefore able to enter our cells or resist our antibodies more easily.
  4. Most concerning to scientists appears to be the E484K mutant, (glutamic acid → lysine at position 484). This mutant, present in 5 of the 6 new strains named above, makes it easier for the virus to evade our antibodies, thus undermining both natural and vaccinated immunity. Its nickname is the “Eek” mutation, and yes, it is that scary.
  5. Mutations occur constantly, and some of them are adaptive, so the virus evolves. To paraphrase an old song, it’s a mighty restless bug in a mighty restless land. Scientists have a huge deal of trouble figuring out which of the many mutations are silent, and which, like the ones above, matter for humans. On top of that, the mutations operate synergistically, for better or worse, when they appear in the same strain.
  6. Since we still do a woefully low amount of viral sequencing, and overall testing and tracing are low and/or declining, we are fighting the new variants in the dark without a flashlight. Our friends in vaccine manufacture and development start scrambling to invent booster shots for new variants as soon as they appear, but it’s a race against time, vaccine development vs. viral evolution.
  7. There have been disappointments on the clinical side this past week. Convalescent plasma in a metaanalysis was shown to have no benefit on any standard outcome measures. Fortunately, it is being replaced with monoclonal antibodies that work better if introduced early in the illness. Dexamethasone (a steroid) increases mortality if given early in the illness but remains confirmed as effective in advanced stages. The IL-6 inhibitor tocilicumab helps if given after dexamesthasone but is harmful if given without dexamethasone. Something similar is true of other IL-6 inhibitors.
  8. Standard views about children being less likely to be infected than adults may be due to testing bias, so they may be equally vulnerable. It still seems true that they don’t get as sick, but a new study finds that as high as 13 percent of children who are infected will suffer from long COVID. Dr. Daniel Griffin, who gives the clinical updates on the This Week in Virology podcast, calls this “a disaster.” Long COVID goes up by age to peak in the age period 35-49; overall it affects at least one in five people who get infected with COVID-19.

States are opening prematurely. Governor Abbott of Texas, still reeling from accusations that his negligence caused scores of death in the recent snowstorm, has decided to cause thousands more excess deaths from COVID by boldly opening Texas “100 percent.” The governors of Mississippi, Arizona, and other states are doing the same.

This failure of leadership is a step by step repeat of the mistakes that led to last summer’s and then this winter’s surge, needlessly killing hundreds of thousands of Americans, and it will have similar consequences.

Such stupidity in leadership acts synergistically, like the evolving viral mutations, with the stupidity of ordinary Americans. If you have missed it, take a look at the photo on the left. It shows the good citizens of Boise, Idaho, ceremoniously burning masks outside the state Capitol. As with all ceremonies, this one expresses deeply held beliefs, and the adults are passing their beliefs on to their children with the ceremony.

As playwright Arthur Miller said, “The paranoia of stupidity is always the worst, since its fear of destruction by intelligence is reasonable.” These neighbors of ours have bad ideas, which they probably sense cannot hold up in the face of better ones, and since they are attached to their bad ideas, the possible loss of them makes them afraid.

Yet what can we do in the face of such stupidity except continue to meet it with the best intelligence we have? Meanwhile, as always, the stupidity of our fellow citizens, including leaders, puts us all at risk. Eek.

Stay safe. It won’t be too much longer, provided we aren’t stupid enough stretch it out again.

Dr. K

PS: Please don’t rely just on me. The best resource on what is happening specifically in the state of Georgia is Dr. Amber Schmidtke’s Daily Digest. More generally, I recommend the following: The Bill & Melinda Gates Foundation COVID-19 Update, aka The Optimist; for the science of viruses, especially the new coronavirus, This Week in Virology (TWiV) podcast; Dr. Sanjay Gupta’s podcast, Coronavirus: Fact vs. Fiction; COVID-19 UpToDate for medical professionals; and for the current numbers: Johns Hopkins University (JHU); Institute for Health Metrics and Evaluation (IHME); Our World in Data (OWiD); The New York Times Coronavirus Resource Center (NYT). For uncannily accurate warnings, follow @Laurie_Garrett on Twitter. I also recommend this COVID-19 Forecast Hub, which aggregates the data from dozens of mathematical models, and this integrative model based on machine learning. For an antidote to my gloom, check out the updates of Dr. Lucy McBride, who doesn’t see different facts but accentuates the positive.

 

 

 

New Sheriff, New Bad Guys

      “We shall fight on the beaches, we shall fight on the landing grounds, we shall fight in the fields and in the streets, we shall fight in the hills; we shall never surrender.” Prime Minister Winston Churchill, House of Commons, June 4, 1940

     “C’mon man, gimme a break!” President Joe Biden, January 21, 2021, answering a reporter who asked if a million vaccinations a day was enough

Dear Students,

Don’t get me wrong. I love Joe Biden. I supported him when most of my family and friends supported Elizabeth Warren—who by the way was the smartest person running for president, and had policy views most similar to mine—or Bernie, or others. Also, I didn’t think anyone as old as me should be president again. Yet I supported Biden because I was fairly sure that he had the best chance of winning, and because I was completely sure that he is an exceptionally good man. Although I did not say this to many people, I thought that he might be a great president.

Also, he is off to a good start. The new sheriff is laying down the law—on racism, LGBTQ rights, economic rescue, environmental protection, masking, social distancing, and vaccinations. But as far as the virus goes, he does not get a break from me, and no, it is not nearly enough.

Dr. Peter Hotez, a distinguished physician-virologist who is probably the most knowledgeable person about the pandemic after Dr. Fauci—but who can speak more freely than Fauci even now—wrote an op-ed piece in the Washington Post on January 26th in which he described the new variants of the virus as a “looming catastrophe” that will bring us to 600,000 deaths by May. We need to deliver 500 million doses of vaccines—into Americans’ arms—to end community transmission. Do we want to wait 500 days? By that time the new variants will have run all over us. We need to do it by summer. Which is why Dr. Hotez is calling for 3 million vaccinations a day.

This means that we need more than two vaccines; a vast and rapid (warp-speed?) expansion of vaccination centers beyond those already planned; unprecedented invocation of the Defense Production Act; imaginative use of the armed forces, even beyond the National Guard; and innovative use of syringes and other equipment to minimize vaccine waste. A good account of the current vaccine development situation in terms of science is here, but we need more than science, we need wartime logistics.

We also need a new level of seriousness about masks, social distancing, and handwashing. If we don’t ramp up our use of these measures, we will surely face more lockdowns, with all the associated economic, social, family, educational, and psychological pain.

If you have studied with me, you recognize that we are in an evolutionary arms race with this virus. All infectious agents adapt and evolve. They evade our defenses—both vaccines and treatments. That’s why after almost four decades we don’t have a vaccine against HIV, which evolves even within one person. That’s why we need a new flu vaccine every year. That’s why every year, thousands die of TB and malaria because they are infected by strains that resist all known treatments.

If we don’t (culturally) adapt and evolve in the face of this new virus—or should I say these new viruses?—we will lose, and as always, black, brown, and Native American people will lose most. We will not win this arms race, this by far most deadly of all our wars, by asking for “a break.” We will only win by fighting the virus every hour of every day, in every place, in every way.

Good News

  1. The new sheriff is really, really different from the old one. His deputies can shoot straight and they know how to round up bad guys—bad viruses. The heads of the CDC, FDA, HHS and many other agencies responsible for fighting disease are superb people, not third-raters and sycophants like their predecessors; they are already speaking directly and frequently to the American people, without fear of censorship for delivering scientific truth. For the first time there is a national plan, and it is a fairly good plan. With it, we are building a shield against the virus that we never had before.
  2. There has been a significant decline in the past couple of weeks in the number of US cases and hospitalizations but not yet deaths, probably related to the end of the big holiday surge.
  3. The Pfizer and Moderna mRNA vaccines are working safely, and pretty soon a few million Americans will have approximately 95 percent protection (two weeks or so after their second dose). Preliminary data suggest that protection levels could be even higher in the community than they were in clinical trials.
  4. The Janssen/Johnson & Johnson (J&J) vaccine will likely be approved (like the first two) for emergency use in the U.S., within a couple of weeks. Despite being less protective than its predecessors, it is more effective than the seasonal flu vaccine and easily passes the threshold of 50 percent protection set by health authorities. It hides the DNA—the gene—of a SARS-CoV-2 spike protein inside the Trojan horse of a cold virus disabled from reproducing. It has tremendous advantages: first, it only requires one shot; second, it does not require any specialized freezing or cooling equipment (DNA being much more stable than mRNA). These advantages will make it literally a lifesaver in rural America and in the developing world.
  5. The Oxford/AstraZeneca vaccine, despite some stumbles in the Phase III trials, is being used in the UK and was just approved by the European Union. It requires two doses but no special freezers, and will probably be added to the US vaccine arsenal in April. It is similar in principle to the J&J but uses a non-reproducing chimp adenovirus (instead of a human one) as the Trojan horse. The DNA is stable at higher temperatures, but it is still being worked out what the ideal doses would be.
  6. A monoclonal antibody drug (bamlanivimab, Eli Lilly) has shown 80 percent effectiveness in preventing infection in a randomized controlled trial in nursing home patients, and even greater effectiveness against deaths. This would have been tremendously important a few months ago, before we had vaccines, but now that we do, it’s not clear how the antibodies will be used—especially since they may interfere with vaccine effects.

Bad News

  1. The big bad news, and it is really bad, is that the virus has evolved new variants—new bad guys that will make the new sheriff’s job much harder. Of course, it has been evolving all along. A new paper, “Emergence of a Highly Fit SARS-CoV-2 Variant,” traces the first big leap the virus took last spring. As you know, “highly fit” in this context means spreading faster for more reproductive success. That first mutation was a single base change known as D614G that emerged in Southern Europe and by June was the dominant strain in the world.
  2. Viral evolution continued. In December a new “variant of concern” (B.1.1.7) was found in Southern England that contained multiple mutations and was determined to spread much faster and cause more severe disease. The mutations make it easier for a spike protein on the virus to combine with ACE2 receptors on human cells to gain entry. Hospitalizations doubled in the UK as the new variant became dominant there. More replication, more fitness, more dominance. It has been found in several US states and is predicted to be the dominant strain here by March. Fortunately, it does not evade already existing vaccines.
  3. A new South African variant (B.1.351) with different mutations of the spike protein—one of the mutations is on the presenting tip of the spike protein—is spreading rapidly and may soon threaten my old friends in Botswana. Two cases were found in South Carolina. Dr. Brannon Traxler, Interim Public Health director for the state, announced that they are independent of each other and have no travel history. She added cogently, “We know that viruses mutate to live and live to mutate.” Another independent case was found in Maryland. Given that we only sequence half of one percent of the virus samples taken in this country, it may already be everywhere. Like the English variant, it is more contagious and produces more severe cases, but unlike the English one, it also appears to be less responsive to existing vaccines.
  4. A new Brazilian variant (P.1) is worrying scientists. It is spreading explosively there and has been found in Minnesota. It may infect people who have had the disease before. It may or may not turn out to be implicated in the newly announced tragic COVID-19 deaths of nine children in the remote Amazonian villages of the indigenous Yanomami.
  5. There is no chance that one million vaccinations a day in the United States will stay ahead of the coming invasion of these new viral variants. The best, if not the only chance, is a great intensification of other preventive measures, the same that have been recommended all along. Unfortunately the behavioral trends seem to be going in the opposite direction.

On “Meet the Press” yesterday, top epidemiologist Michael Osterholm said, “The surge that is likely to occur with this new variant from England, is going to happen in the next 6 to 14 weeks. And if we see that happen—which my 45 years in the trenches tell us we will—we are going to see something like we have not seen yet in this country… Imagine where we are, Chuck, right now. You and I are sitting on this beach where it’s seventy degrees, perfectly blue skies, gentle breeze, but I see that hurricane, Category 5 or higher, 450 miles offshore. And telling people to evacuate on that nice blue-sky day is going to be hard. But I can also tell you that hurricane’s coming.”

Dr. Nahib Bhadelia of Boston University’s School of Medicine, asked to comment on Osterholm’s metaphor, said we are in  “the eye of the storm,” not sitting on the beach with the storm hundreds of miles out. She means that the worst part of the storm so far—December and January—is deceptively slacking off. As the hurricane moves over us, the lull of the eye passes, and we get slammed with another monstrous storm surge in March and April.

Dr. Osterholm went on to say that we need “an audible”—American-footballese for a last-minute yell on the field that changes the plan. He thinks we need to get as many people as possible vaccinated once right now, and forget about the second dose until later. There is controversy about this, but Osterholm is really smart.

Recall what Dr. Traxler, South Carolina surgeon-turned-health official, said when she became the first American to announce the South African strain: “We know that viruses mutate to live and live to mutate.” She continued, ““That’s why it’s critical that we all continue to do our part by taking small actions that make a big difference. These include wearing our masks, staying at least six feet apart from others, avoiding large crowds, washing our hands, getting tested often, and when we can, getting vaccinated. These are the best tools for preventing the spread of the virus, no matter the strain.”

On December 15th, when I posted “Double Down or Double Deaths,” we had just crossed 300,000, but we were having the first vaccinations and hope was in the air. I said we could go to 600,000 if we don’t change our behavior. The IHME model now projects 582 thousand by May , 600 thousand taking the new variants into account. That’s the doubling. Considering we’re at 440,000 today, it’s not a stretch.  Depending on what we do and what the variants do, we could be anywhere between 600 and 2,400 daily deaths in May. The difference would be the equivalent of two 9-11’s every two days. And of course May will not be the end.

The new shield we got on January 20th is not nearly big enough or thick enough. And the new variants teach us that unless we think about protecting the developing world, protecting the whole world, which is the virus’s continuous playground, our shield will be full of holes.

Are you tired of the precautions? I am too. I want to hug my children and grandchildren so bad it hurts (and I don’t care that it’s ungrammatical). I want to see live theater. I want to eat out with my wife in any sort of restaurant, even McDonalds. I want to smile at people and see them smile back. I am tired of restricting myself for the benefit of myself, my community, and my country. I am, to use an  expression my mother might use, bone-tired. But I am not yet dead-tired. I will be dead-tired if and when the virus kills me.

And oh, by the way. In case you get to whisper in President Biden’s ear, give him this message from me: Mr. President, Sir, with all due respect, the next time a reporter asks you if a million vaccines a day is enough, do what you always said you would do: Level with us. Don’t say, ‘Gimme a break man.’ Say, ‘No, it’s not enough. We need three million a day at least, and  I promise you I will not rest until we have that. We are at war. We will fight this virus in the clinics and in the stadiums, we will fight in the pharmacies and supermarkets, we will fight on street corners and parking lots, we will fight in convention centers and on fair grounds, we will fight in the poor dense cities and in the bucolic countryside, we will fight with syringes and tests and masks and distancing; we will never surrender.’

Stay safe,

Dr. K

The “New Biology” and “The Self”

A couple of weeks ago I posted some musings about “the self” in anticipation of being on a panel with Steven Pinker (author of The Blank Slate and The Stuff of Thought) and Noga Arikha (author of Passions and Tempers: A History of the Humours) at Tufts University. The panel, convened by Jonathan Wilson, was titled “The New Biology and the Self,” and what follows was my contribution. The graduate student referred to is Monica Chau of Emory University.

I told a very smart neurobiology graduate student named Monica yesterday that I’d been asked to speak on “The New Biology and the Self.” She said, “What’s the new biology?” I said, “I don’t know, but that’s the least of my problems. What’s the self?” Read more

What is “the Self”?

And assuming we can answer that, how is science changing it?

Big philosophical concepts bother me, but I am expected later this week at Tufts University, where I’ll be on a panel discussing “The New Biology and the Self.” So I need to get over my reluctance to talk about the self. And it’s not the only big idea that gives me trouble.

Consciousness and free will are two other notions Read more

Darwinian News, Hot Off the Press

In the Darwin bicentennial, new insights into fossils, genes, birdsong, and cancer.

google-logo-fossil1The latest issue of Nature to land in my mailbox-the May 28th one-was not a tribute to Darwin in honor of his 200th birthday and the 150th of The Origin of Species; Nature has been there, done that. But it might as well have been another celebration for him, Read more

Neuronews

Brain science's astounding pace of discovery is bringing new hope to many.

I want to take a rest from the political and religious wars and instead do a little of what I do with my students at the start of each semester. I'm teaching my course on the human brain this fall, and as usual my first lecture was called "While You Were Catching Rays-Discoveries Since the End of Last Semester."
Read more