_{“If some areas, cities, states, or what have you…prematurely open up…my concern is that we will start to see little spikes that might turn into outbreaks.” Dr. Anthony Fauci, answering Sen. Patty Murray, May 12, 2020}

_{“When the outbreak started, sir, we had an aggressive contact tracing program, but unfortunately as the cases rose, it went beyond the capacity…so we lost the containment edge.” CDC Director Dr. Robert Redfield, answering Sen. Tim Kaine, May 12, 2020}

_{“The purpose of science is not to open the door to infinite wisdom but to set some limit on infinite error.” Bertold Brecht, Life of Galileo}

_{Dear Students,}

_{Les jeux son faits. Or in English, the die is cast. Or in plain American, the dice have been rolled. Think of a slow motion video with a close-up of a hand releasing the small dotted cubes. We watch them seem to float through the air, then one, then the other touch the table surface ever so gently, then they bounce and float again, and then…}

_{Never have I hoped so much that I would lose a roll of the dice, because I (among others) have hypothesized disaster. I want to come up “snake eyes” and slink away from the game. I want the majority of states opening up to come up with sevens and elevens. I want the American people to win this great gamble. We know so little about this virus that there’s a chance for an unlikely outcome, on either side.}

_{No matter now though. Les jeux son faits. The video is so slow that it may take two weeks for the rolling dice to come to rest.}

_{I am not going to repeat what I said in my previous updates about patience and precautions. My news this week is about what in our course we always called “Nuts & Bolts.” The slogging may be a little heavy in places. After all, I’m the professor. Knowledge is news. Knowing what you know is good news.}

_{Good (Science) News}

1. _{We have known the sequence of this virus, SARS-CoV-2—causing the illness COVID-19—since early January. It is a single strand of RNA of a strain new to humans, with a wide adaptability, causing disease in many mammals. There is a bat coronavirus that is 93% identical to it, but other human SARS-CoVs are only 80% identical. It has a large genome for an RNA virus, with multiple “hot spots” for mutations, although it mutates slowly compared to flu.}
2. _{Corona, meaning crown, refers to the club-shaped surface proteins (aka “spikes”) that cover the surface created by the RNA with the help of human cells’ machinery. It has to get into our cells, and we have known since March that it does that because the spikes recognize an enzyme on cell surfaces called ACE2, normally part of a complex sequence controlling blood flow and blood pressure. Spike proteins use ACE2 to (sort of) pry open the cell. Once in, the RNA replicates itself and makes spike and other proteins protecting it and countering our immune system. It can do this (I’m estimating) a gazillion times.}
3. _{The first and still most accurate test for active cases of the virus uses a version of PCR (the polymerase chain reaction) to amplify the virus’s RNA enough to measure it accurately. Last month a device from Abbott called ID Now that amplifies viral RNA much more rapidly was approved for emergency use. Last Friday (5/8) the FDA approved for emergency use a first-in-class test for viral antigens, meaning fragments of viral proteins. It is also possible to infer the presence of the virus indirectly from very high levels of IgG antibodies (Abs, pronounced “ay-bees”). At-home testing is partly approved; DIY sample collection, send in the sample.}
4. _{With regard to establishing who has had the virus and recovered (or never showed symptoms), there are up to 12 approved antibody tests and 200 more in development. Most of these are qualitative, especially the rapid-diagnostic ones (RDT; 10-30 min) using finger pricks, saliva, or nasal swabs. They tell you you either do or don’t have IgG or IgM antibodies to the virus. ELISA assays (2-5 hr), showing how your antibodies combine with viral proteins in a dish, can be quantitative. Neutralization assays (3-5 days) put your cells and Abs in a dish with the virus and quantify the amount of Abs needed to block the virus from entering the cell.}
5. _{Treatments under study include antivirals (Remdesivir and others developed for older viruses), immunotherapies (which, like interferon beta, strengthen the immune system), convalescent plasma (from recovered patients), immune globulins (Abs purified from same), monoclonal antibodies (Abs specific to viral proteins, mass-produced from cloned cells), and others. Remdesivir shortens hospital stays in very sick COVID-19 patients from 15 to 11 days. (For true nerds, Remdesivir mimics the RNA base adenine; it slips into adenine’s place in viral RNA replication, dashing the virus’s reproductive dreams, partly.)}
6. _{Roughly 100 labs around the world are developing COVID-19 vaccines by varying methods to increase the chances of success. This includes DNA and RNA vaccines matching part of the viral genome, proteins mimicking part of the spike, and other strategies. The first clinical trials were begun 62 days after the virus sequence was published, by far the fastest time ever, around 10 more were added by late April, and more will begin soon. Dr. Fauci said today that, “this is a virus that induces an immune response, that people recover, the overwhelming majority of people recover from this virus… The very fact that the body is capable of spontaneously clearing the virus tells me that, at least from a conceptual standpoint, we can stimulate the body with a vaccine that would induce a similar response.” So he considers it “much more likely than not that somewhere within that time frame [12-18 months] we will get a vaccine.”}

_{Bad News}

1. _{The supply chain is not robust for any of the above, and will not be for many months. Remdesivir, the only proven (in an unpublished study), partially effective treatment is being rationed to states and hospitals, forcing doctors to play God. There is not yet a serious plan to ramp up new pharma factory building to meet the coming demand for treatments or vaccines, if and when they are proven.}
2. _{We continue to have a poor grasp of the nature of this virus. It behaves differently in different countries, perhaps more so than be explained by the varying quality of social hygiene. No one knows how many asymptomatic cases there have been, why there is so much variation in the length of presymptomatic infectiousness (~2-14 days, average around 5), why young adults have mild or no illness, why children are usually asymptomatic carriers but (rarely) develop a just-discovered life-threatening illness (viral? post-viral?), why it attacks the lungs in most patients but in some attacks the heart or other organs while sparing the lungs. One thing we do know: it is very contagious. In evolutionary terms, it’s very clever: “I’ll infect the active young without (usually) killing them, because they’ll carry me around the globe.”}
3. _{Testing for active infection is currently around 250,000 a day nationally. Even the Federal government says we will probably need to get to 1.5 million a day, and other public health authorities and economists say will need 20 million a day or more to safely get the economy, including education, back up to speed. Our government brags that we have more testing per capita than South Korea. Yes. Now. After that country has beaten down the first wave of the pandemic because it had scores or hundreds of times more testing than we did in February and March. Contact tracing is practically non-existent so far, and hundreds of thousands of tracers may ultimately be needed. See what other countries have done here.}
4. _{Testing is less sensitive (does it pick up everyone who has the virus?) and specific (does it identify accurately those who don’t) as it becomes more rapid. Antibody testing is far behind active virus testing, which is far behind that in other countries. Ab testing is also less accurate. Regulation of antibody (serological, post-illness) testing is chaotic; companies governed by profit motive abound.}
5. _{Only one treatment (Remdesivir) is proven effective in COVID-19 illness, and Dr. Fauci (who almost leapt out of his seat with excitement when he first announced it) today called the effect “modest.” There are no meaningful treatments yet. Remdesivir helps (we think) but as mentioned is being rationed to a fraction of the patients who need it. This rationing will be repeated with any future proven treatments. The treatment ultimately will likely be a cocktail of different drugs, as with HIV, but that took years to develop. A smart friend of mine, Cynthia Fox (author of Cell of Cells) says her motto is CCC—Cocktails, Cocktails, Cocktails!}
6. _{The bottleneck for vaccine deployment has nothing to do with lab science, it has to do with three phases of clinical trials. That’s what will take 10 to 16 of the 12 to 18 months (minimum) needed. Why? because some vaccines have triggered devastating immune responses, sometimes deadly. I remember 1977, when the swine flu vaccine caused hundreds of cases of a nervous system disease, and the 1990s, when early rotavirus vaccines caused very serious intestinal complications requiring surgery. I want you to trust vaccines, but only vaccines that have been properly studied for safety and efficacy. Unlike the lab development phase, that can’t be rushed.}

_{Also in today’s Senate hearing, Dr. Fauci said, “The idea of having treatments available, or a vaccine, to facilitate the reentry of students into the fall term, would be something that would be a bit of a bridge too far.” I hope he is being too pessimistic, but hope doesn’t make things happen. Sometimes, if we’re lucky, science does. And science needs patience.}

_{Stay safe, Dr. K}