Written by my boss
MARCH 21, 2020: 287,329 Cases In:
WARNING: material below are my personal observations, opinions and dark humor (not subjected to peer review) -and thus only intended for close friends and family only. There are some positive things to look towards on the clinical horizon I am really excited about over the coming weeks, but we are all going to have to hunker down a little in the meantime to flatten the curve while we get these near term solutions in order. It is easy to get worried about this thing and what could happen. The good news at a high level is that this is a virus that we can get our hands around, it is not mutating very fast and we will be able to knock out in the long term with medicine if it does not burn itself out. It is hurting us right now in a number of ways, but the zombie apocalypse isn’t going to happen.
Scientifically speaking, one of my big biotech projects for the last 5 years has involved engineering viruses for cancer and gene therapy applications. No, this is not my runaway virus, but virology is something I do study like cancer and immunology very closely. So COVID-19 is genetically most closely related to its cousins, SARS and MERS. The family tree of COVID-19 makes it pretty clear that its origin is from viruses that are spread through bats. There is also a high probability that it got to humans via another animal called pangolins (strange pokemon looking creatures that are killed for their large scales as supplements or eaten as delicacy). Their trade is illegal in China and most parts of Asia and Africa but it seems there may have been some black market activity where COVID-19 made the jump to humans just like SARS did through civet cats. At this point, however, most of you won’t be having pokemon for dinner tonight, so it is really not relevant except to say that bats are likely the main pool of these types of viruses (turns out bats are quite resistant to coronavirus because of an interferon pathway- this also plays in to some thoughts about beta-interferons we use for multiple sclerosis in humans as a possible therapy for the side effects of COVID-19). Those bioweapon conspiracy theories may be fun to talk about over drinks, but if you want to start a conspiracy, tell people Batman made COVID-19 and you will be at least telling a half-truth!
So for coronavirus outbreaks in humans, SARS came first. The mortality rate of it was high, about 10%. MERS came later and had an even higher rate of mortality (some reports as high as 30%). So far, COVID-19 across the population has a significantly lower rate of mortality than SARS (broadly 15-20 times worse than the flu), but it can be very dangerous in some populations. Fortunately for the very young, the mortality rate has been much lower, but kids can certainly get it, and most likely spread it. Some data from intensive testing in Korea and Italy suggest they are something to watch carefully as a source of spread. For those who are older this gets much more dangerous as it does for people with diabetes, high blood pressure, and lung problems (basically enough people that we should all really care about this). So COVID-19 is not the zombie apocalypse, but it is getting around better than the common cold (of which about one quarter are from other coronavirus strains), and it requires that we be diligent to not overload our hospitals while other efforts for a first line mitigation mature in clinical trials to allow implementation (repurposed anti-viral drugs and anti-inflammatories vs vaccines).
Viruses are not like bacteria, they need to grow in a host (like us), so they don’t replicate on their own. Some viruses like COVID 19, SARS and MERS (of the Nidovirales order for those that care) and influenza exist with their genetic information that never becomes DNA. It’s an intermediate called RNA (which humans also use, but unlike these viruses, we store our data in DNA and deploy instructions with RNA). RNA viruses never bother making DNA, they just make more copies of their RNA for efficiency. So later below you get a sense of how we can go after this RNA source with some types of medicine. From a stability perspective, some viruses come enveloped (their outside packaging has stuff from human cells and virus material) whereas other types of viruses have a harder protein shell of all virus material (adenovirus is an example). Most enveloped viruses are sensitive to being outside the body, but it seems that COVID-19 is a bit more of an outlier here. As an example, HIV viruses (i.e. lentivirus) is enveloped but does not survive well outside the body at all. More on the stability of COVID-19 later when it comes to spread and protection.
Map Reading – The Big Picture
So I may work on viruses scientifically, but I am NOT an epidemiologist (they are the scientific accountants that like to count things much more than I do, but plot them out to build predictive models so they are very important).
Below is a snapshot in time of where ‘coronavirus’ (COVID-19 specifically) is in the global pandemic process right now. I follow the Hopkins Tracker for my own benefit (link below) -I assure you that all of the different trackers have errors and deficits well beyond how much testing inputs there are, but Johns Hopkins has been monitoring this longer than others that have popped up recently so I just stick with it. On a global scale, COVID19 is now definitely a pandemic (simply stated-you have a better chance finding a country on the map where it is present right now than where it is not). The peak initially in Asia is now in Europe and starting to grow in the US (but note state vs country bias in bubble size). New York, Washington State and California are growing faster than others but testing bias is a challenge. Some advanced modeling independent of testing suggests that all things being equal for every patient death recorded there may be 700-900 cases out there based upon the time to mortality and virus spread rate during that time. So 10 deaths reported would basically mean there are 8000 present with the virus at the time (it’s a very inaccurate approach but can help for those wondering about testing).
Red bubble size below shows the number of patients that have tested positive so far. Big bubbles in China, big bubbles in Europe, smaller bubbles in US. However the coffee colored bubbles below that show you how many of those cases that are red have not yet recovered. Here, you can see that Europe is where the peak is of patients are that have not recovered yet, and the hospitals are working the hardest. China on the other hand is on the back nine of this thing, while the US is just teeing at the first hole (most of you know how bad a golfer I am, and hence why I might relate viral outbreaks to having to play a round of golf! no offense to others). I am personally of the opinion that the best way to navigate is seeing how others have played the course and learning what to do and not to do – that said different countries have their own systems. I won’t ever play golf like Tiger Woods and the US won’t be able to wall off certain cities from the rest of the US just because they have more cases of COVID-19.


Reference
https://gisanddata.maps.arcgis.com/apps ... 7b48e9ecf6 The X/Y plot perspective –Houston… we have a problem
Right now the yellow line below is the US and the rest of the world minus China. We are in what biologists like to call ‘log phase growth’. It scary and it looks like a rocket taking off when you graph it and it’s hard to see when it will ever stop. This is the point where it is easy to panic. For most people we just want to know when it will end.
Well, on a positive note, the orange lines below are from China on the other side now where things really started to take off in Jan but then started leveling off in mid Feb. The little pop you see in early Feb is actually a recount that was a result of using additional methods for diagnosis (a CT scan of the lungs) in addition to the COVID-19 genetic test to diagnose the virus infection. I spent most of the beginning of this year on video conferences with scientists and engineers in China all on lockdown and nothing happening business wise. Near the beginning of February, there were some dark feelings once and a while where sympathy for the health and wellness of others started to bump into fears about whether business was going to survive. But when those rocket launch log curves start to run out of fuel and level off it’s a really great feeling. It will do that for Europe next and then US.
Today China is still being very careful, but are back to work having moved from first splitting the company into shifts of an A team and a B team after several weeks of home isolation. The theory goes that after the home isolation and a check for symptoms, if anyone from A team developed COVID-19 then all of A would go home for 14 days of quarantine again while B could continue. After a few weeks of A and B not showing symptoms then then you go to A+B. Some of the clinicians we work with are from Shanghai Public Health Clinical Center used this model after the SARS outbreak years back and its good practice when you move to the next step.
COVID Stability -Myths and Data

Many people have been trying to keep their 6 feet of social distance but the key is to ask where is the virus mostly likely to be? To help answer these questions a recent New England Journal Publication looked at this below.
What they basically did was to compare the stability of COVID-19 to the other coronaviruses in the air and on surfaces. This is virus half-life at room temperature. Red curves are COVID-19. What you can see is that on things like carboard, steel and plastic, COVID-19 survives REALLY WELL. In fact it can be 80 plus hours to bring viral loads on these surfaces down.
So when things come in your house, look at surfaces like this. COVID-19 is killed by heat, by UV light but can live for 2 years in your freezer. So think about how you make something before you heat it up (and kill any COVID-19).
Wiping packaged plastic things down with hot soapy water is not a bad idea. I had some fun hitting lemons from the store the other day with scalding hot water before putting them away - I think the rinds are still good for martinis (or Quarantinis as they are now called).
If you get take out, if it is in aluminum tray, put it in the over for a second bake, probably all good. BBQ, no problem.
Salad – I haven’t solved that one yet personally. We are on a steamed spinach kick for greens now.
Cardboard arrivals at home ala prime delivery? Maybe a good idea over the next few weeks to remove the contents outside and wipe down and just take the carboard to the trash. Just look at the half-lives below when you think about it and you can get creative.
https://www.nejm.org/doi/10.1056/NEJMc2004973 Medicine On The Horizon
Many (many) years ago I remember chasing the rotavirus season (a common stomach virus, mostly affecting young children) around the world trying to enroll a randomized trial in children’s hospitals for a new medicine for kids presenting with gastroenteritis and dehydration. Frightened parents in the Emergency Room trying to decide whether to give their vomiting, dehydrated baby a new medicine over other approaches is one of those things that sticks with you about how hard clinical trials are in critical care situations. So even when lots of people are sick in the hospital, it is difficult to get the data you need to know if things are working better or not than just doing what you would normally do. Clinical trials and medical research is something we usually spend months in preparation planning the protocol and working through the details. When the hospitals are getting overrun by cases, it is really hard to do good clinical medicine to test whether something is safe and effective. So I am impressed that many studies have been able to get up and running quickly without the time we would normally use to figure out the right dose the timing and the readout that matters to test a medicine.
Practically speaking, there is no vaccine coming your way next month. The cavalry won’t arrive this year for some basic reasons. First is that we can’t give PERFECTLY healthy people an experimental vaccine that has not been tested first in smaller groups for safety. Anyone that has ever seen someone crash from a bad anaphylactic reaction to a vaccine and go into multi-organ failure knows you don’t want that to happen to large numbers of perfectly healthy people. So we start in small numbers, we watch them carefully and then proceed to larger numbers with enough follow up to know it’s safe for healthy people. This is the long term solution and its very doable but think 2022 for that.
However, if someone in a high risk group is hospitalized with low oxygen levels with COVID-19 and could die, there is a good reason to try and help that person with an experimental medicine. And this is where you start. Below are a number of targets on COVID-19 that people have been looking at. This is usually how we think about anti-viral medicines. In our case though we had a head start from knowing the genetic sequence of the virus for nearly 3 months and people have been able to get a head start in both China and Europe.
So The first place to start of course is to look on the shelf and see what might work.
Reference ACS 2020
https://dx.doi.org/10.1021/acscentsci.0c00272
So as for using what’s in the cupboard, recent data below from the French looked at a combination of a malaria drug (chloroquine) and an antibiotic (azithromycin) in a small number of patients. So you ask, well COVID-19 isn’t malaria and it’s not bacteria. BUT….hydroxychloroquine and chloroquine work to stop malaria in a way that may also make it hard for the virus to enter the body. There are small parts of our cells called endosomes that naturally acidify that COVID-19 seems to use to unlock a door to enter the cell- chloroquine acts as a door chain and may make it harder for the virus to open that door to the cells in our body by raising the pH and making it hard for the viruses to break in.
The azithromycin part has to do with a curious (almost a myth) of the anti-inflammatory effects of the anti-bacterial. So the data below are from a really small number of patients, and there are some issues about who dropped out of the trial but this is something that we can get to people really fast. It’s an oral generic drug you take when you go traveling to the tropics (it can make you sick if you don’t use it properly so its not like aspirin) but we can certainly make a lot of this and it is safe enough to go to large numbers of people. This is the type of thing you might give to family members if someone in the family comes down with COVID-19.
The other thing is managing what happens when patients progress to a more challenging stage of disease- with COVID and SARS the cells lining the lung get attacked (the cilia and the alveolar cells). This causes the lungs fill with fluid and then the immune system goes bonkers trying to get rid of the virus to the point that they actually start killing more normal tissue-
One way to stop this late stage damage is an antibody I used to work on called Actemra (tocilizumab) and is now tentatively approved in some countries for the treatment of cytokine storm in patients with advanced COVID-19 - we use this antibody as well in patients receiving CAR-T immunotherapy if the immune system goes out of control when trying to attack cancer. The other therapy people are trying is beta-interferons. This is used to calm the immune system as it does for the well kno0wn use in the treatment of multiple sclerosis. Funny as this links back to bats that seem to be resistant to the toxicity of coronaviruses due to differences in their interferon pathway. Data are pending there but medicine that can help get patients out of the ICU faster will be good for us all. If we reduce patient time in the ICU time or on ventilators then we will all get through this easier from having more medical resources.

Early French Data on Chloroquine/Azithromycin combo
Finally there is a more specific anti-viral which is called remdesivir- this is a drug that I personally think may be the best near term solution if proven effective in certain groups before vaccines or other therapies come online. Gilead developed this a long time ago, and it was tried in late stage patients with Ebola virus (if used too late it will not help). Remdesivir is an RNA polymerase inhibitor, meaning it damages the virus while it is trying to replicate making faulty copies of the virus. There is are two large trials underway in China that may read out in a few weeks and a second set of trials going on in the US. It is most likely effective to hit the virus in cases that are advanced but it has to be used before the lungs are so damaged and the immune system is taking patients into organ failure. It’s an IV drug right now so it would only be used in the hospital but could be something very important for the hospitals to use if safe and effective. This is something that if effective could get to hospitals in a matter of weeks and could be scaled up relatively well (China has also scaled up production). It can also get moved into an oral formulation later which would be the Tamiflu equivalent you would take for COVID-19.
So all these data are all going to become available over the next few weeks and between the existing medicines in the pipeline and those being deployed I think we are going to be OK. My personal hope is that by May we are all out of the log phase of this and have gotten a good handle on this and will be back online with either split teams with the needed precautions.
Stay well Everyone