Learn about the Science of COVID-19 with Dr. John SantaLucia (Part 1)

Rev. Susan Mozena:

Today, we are delighted to have with us, John SantaLucia, who is a member of our church. You know John has a PhD in chemistry, a Professor at Wayne State University. And as you can see on the screen, the co-founder of DNA Software, Incorporated. He is going to be presenting today. And Dr. Keith Bellovich, also a member of our congregation, who is Chief Medical Officer of Ascension St. John Hospital is going to be talking next week.

Rev. Susan Mozena:

John’s topic today is “the science of the virus”, and Keith’s topic next week is going to be all about [“the virus in our community”]. So having said all of that, welcome and thank you so much, John, for doing this for us. I didn’t have to track John down about this. He offered and I’m very grateful for that. So with no further ado, Professor John SantaLucia, dear friend of ours and member of Memorial Church. Thank you again, John.

John SantaLucia:

Thank you, everyone, for attending. I’ve gotten so many requests from family and friends. They know that I do science related to infectious disease about this topic that I thought it would be appropriate to give a community outreach talk that would be accessible to all users. And so even children, I think, will be able to get something out of this talk today. So I’m trying to hit it at the people where they’re at. I’ll tell you a little bit about me.

John SantaLucia:

As Rev. Susan Mozena introduced me, yes, I’m a professor at Wayne State and I’ve also co-founded a company called DNA Software. And my expertise is in development of diagnostics for infectious diseases, including COVID. I also have expertise in thermodynamics of DNA, ribosomal [structural] biology, bioinformatics and clinical diagnostics. But I am not a medical doctor. So just truth in advertising. I know a lot about the science of this virus, but I don’t know everything.

John SantaLucia:

I’m aware of the fact that some of you may know more than me about some of these topics. If you see something I said that was wrong, please just let me know and I’ll be happy to correct that. And if you have medical doctor type questions, then you can save that for next week’s presentation with Keith Bellovich. So here are the basic topics that we’re going to cover today. My goal here is to provide you, most of all, with the most accurate information that I can possibly give you.

John SantaLucia:

With that being said, since I’m not an expert in all of these areas, I do my best in them. And if I can’t answer your question, we’ll try to find someone who can. So we’re going to cover some basic terminology to start off with, and then we’ll get into the biology of the SARS coronavirus type two. We’ll talk about where the virus came from and what progress we’ve made scientifically, both from a public health diagnostics and other approaches. We’ll mention vaccines, et cetera, and draw some information about the different types of testing that’s out there. I know there’s a lot of confusion about these questions. Do masks work? What therapies have been developed? What is herd immunity?

John SantaLucia:

Before I start, the science of coronavirus is super-duper interesting. This disease is, of course, a terrible disease and we’re all suffering from it at various levels. Some of us have actually lost loved ones, some of us know someone who’s not fully recovered from this disease. Of course, it’s had terrible economic devastation and a huge loss of jobs. And I’ll just say this, this disease does not know any political or socioeconomic boundaries. In a sense, we’re all a target of it.

John SantaLucia:

It’s amazing to me that so many of you are coming to hear a talk about COVID when we’re sick of it all. And we all have this question about when it’s going to end. Unfortunately, I think it’s going to get worse before it gets better. And yet, I hope that the things I present to you today will give you some hope, that better times are coming.

So, first of all, let’s talk about some basic terminology. What about the name of the virus? The name of the virus itself, the actual formal name is SARS-CoV-2. And that is an acronym for Severe Acute Respiratory Syndrome, Coronavirus type two. And the disease is named COVID-19. All right. So there’s a difference between the disease and the virus that causes the disease. All right. So the name of the disease is coronavirus disease 2019, which is abbreviated to COVID-19.

John SantaLucia:

You’ll hear some of these terms, like epidemic, pandemic, endemic. They sound very similar, but they have different technical meanings. Epidemic is the rapid spread of a disease to a large number of people within a short period of time, but it is a limited geographical area. A pandemic is when an epidemic of an infectious disease has now spread across multiple continents or worldwide even, affecting a lot of people. All right. So the SARS-CoV-2, COVID-19 disease was declared a pandemic in March of this year. Endemic is a place that we don’t want to get to. An endemic disease is a disease that is regularly found in a group of people.

John SantaLucia:

COVID has spread over so much of Planet Earth at this point that we are approaching the point where it is likely to be endemic. Even once we have found drugs and some vaccines, this virus is likely to be with us for quite some time. All right. Community spread is a term that you’ll hear a lot. This is the spread of an illness. So basically, it’s a spread when we don’t know where it came from anymore. So you don’t know how you got it. In the early days of the SARS-CoV-2 pandemic, in the early days, there were so few people that had the disease that if you got the disease, it was relatively easy to figure out where you got it from. When it gets to a point where there’s so much virus out in the community and people start getting the virus without knowing where they got it, that’s called community spread. All right. That’s just some basics upfront.

John SantaLucia:

So, why is it called the coronavirus? Where did that name come from? If you look here, the picture, this black and white picture is showing you what’s called an electron micrograph, a picture of the actual virus itself. And these electron micrographs show these … the circular part is the core of the virus. And the outside of the virus are these studs that look like points on a crown. And they look a lot like a solar corona. Corona means crown, and they’re called coronaviruses because these early pictures look a lot like a solar corona.

John SantaLucia:

Now, those spikes that are sticking out of the crown are actually very important for the biology of this virus. So shown on the bottom left here, I have a picture of a cartoon, a picture of what this virus is, how it’s constructed. And these spikes on the outside are called the spike glycoprotein, or the S protein. This S protein is a major protein for the immunological response and how this virus gets into the cells, but there’s also some other aspects. I’ll be showing this picture again, to show you more about how this virus is put together and its various components.

John SantaLucia:

So the outside of the virus are this spike protein, which is the first thing that our immune system sees. Inside of the virus, you have a lipid bilayer membrane. And then packaged inside of that is the genome of the virus, which in this case is an RNA and is coated by a protein called a nuclear protein, or the N protein. That’s this helix in the middle here is the RNA genome of the virus. So now, before I give some more information, I need to give you a little background into the science of biology. And I’ll just introduce this as simply as possible. Well, here it is.

John SantaLucia:

There’s a central principle in biology called the central dogma, the central teaching of molecular biology. And this teaching has to do with the flow of information in the cell. All right. So in the cell, information is passed from the genome, which in the human cells is made of DNA. That is then passed to RNA, called the messenger RNA. And then the messenger RNA is translated into a protein. And this picture down here shows that in a pictorial form. So the DNA is your genome, which is a double helical structure. That double helical structure contains all of the genetic blueprint that make up a human being, for example.

John SantaLucia:

And DNA, of course, can be replicated or a small section of DNA can be transcribed into a shorter piece called a messenger RNA. That messenger RNA can then be translated from a DNA code into a protein amino acid code. All right. They’re translational. These proteins are the enzymes that catalyze the chemical reactions that are in your cell. What’s unique about the SARS-CoV-2 virus is it doesn’t work the way most living organisms work. Since it’s a virus, it’s not living. This virus directly replicates its RNA without going through a DNA intermediate. So it’s the RNA part of the virus that gets into the human cell and is replicated, and then makes viral proteins in the human cell.

John SantaLucia:

We’ll see, later on that to detect the virus with diagnostics, we want to be able to detect the viral RNA genome. To do that, we will reverse transcribe the RNA. We’ll go backwards. Instead of doing the normal way, going from DNA to RNA, we will use an enzyme called reverse transcriptase to make a temporary copy of the DNA portion of that RNA. And then we’ll replicate that DNA in a process called the polymerase chain reaction, that we can detect. So I’ll show you more pictures of that. Here’s a little bit more about the virus itself. I know this is technically detailed here, but I really want to give you the true science behind this virus.

John SantaLucia:

So the virus, this is a relatively large virus. It has a genome just under 30,000 bases long. Most viruses are smaller than that. A few are bigger, like the poxviruses, for example. But this is a large RNA-based virus. It has multiple genes in the virus. It has 12, what are called open reading frames, or ORFs. These open reading frames, each code for one or more protein. In the case of the SARS-CoV-2, the 12 open reading frames code for about 30 proteins. And these 30 proteins self-assemble into the virus structure I showed you earlier. This is showing you a little bit about how the virus gets into the cell and how it replicates.

John SantaLucia:

This virus is transmitted through respiratory droplets. So if you inhale a droplet that has a virus in it, and it goes into your lungs, then in the alveolar cells of your lungs, there are these receptors that are called the ACE2 receptor. The ACE2 receptor binds to this spike protein. Remember, we talked about solar corona, with those spikes. The spike protein of the virus is its means to enter the cell. So the receptor on the cell binds to the spike protein. And then the virus, it does a process called endocytosis. That brings the virus into the cell. All right. It’s called the receptor-mediated endocytosis.

John SantaLucia:

Once that virus is inside of the cell, the virus is unpackaged. It falls apart and the viral RNA genome is exposed. Once that viral RNA genome is exposed, it can be translated. I mentioned the process of translation. So the human ribosome reads the viral RNA and makes the viral proteins, the 30 different viral proteins that I talked about. Then later on, the viral proteins, and there is a viral RNA polymerase that makes copies of the viral genome. So we have viral RNA and viral proteins. They self-assemble into a new virus. The new virus then leaves the cell and can then infect other cells once that happens. Or be excreted it in your breath to infect other people. All right. That’s the basics of the replication of this virus.

John SantaLucia:

Now, one of the interesting things about this virus is perhaps, you wondered, why it is that people talked about hand-washing and why it’s really important to wash your hands. Well, this virus is what’s called an enveloped virus. It has a lipid bilayer membrane as a part of the structure of the virus. So let’s go to that slide. Remember, this slide here, showing a blow up of the structure. So it has this part. There’s a part that’s in red; it’s called the lipid bilayer. That lipid bilayer is soluble in soap. So when you wash your hands, you are actually disrupting the structure of this virus, which makes the virus degrade relatively quickly.

John SantaLucia:

Sometimes, the simplest things are the most effective things. So you don’t need … so an antimicrobial or an antibacterial soap, well, bacteria are different than viruses. Those [antibiotics] don’t really affect a virus. In this case, the best thing to do is just using soap and water. And the reason is because it’s an enveloped virus.

John SantaLucia:

Okay. So here is a common question that I get about this virus, which is, where did the SARS coronavirus type two, where did that virus come from?

There’s a lot of conspiracy theories out there. All right. One suggestion is then that the SARS-CoV-2 was invented by the Chinese government as a biological weapon, and they did it at the Wuhan Institute of Virology. This is a totally false story. This is not true, and we can prove that it’s not true. During this talk, I want to make sure that I give you the most accurate factual information possible. So I’m not just going to make statements, I do want to back them up with the evidence.

John SantaLucia:

In this case here, the genome sequence of this virus was determined shortly after the discovery of the disease. And the genome sequence immediately shows that this virus was not invented by humans. It does not contain any of the elements that a human would have put into a synthetic virus if they were to try to make one. It doesn’t contain things like restriction enzyme sites, which are used to do cloning and make artificial gene inserts. It doesn’t contain virulence factors that would make it more deadly. If you’re trying to make a weapon, you’d want it to be more deadly. If someone made this, then they would want to have a way for them to be immune or have a drug to make it so they didn’t get it. It doesn’t have anything like that. It doesn’t have the kind of selectable markers or coat-on bias that you would expect in a human-made virus.

John SantaLucia:

And furthermore, there’s been surprises about this virus. As we learned things about the structures of this virus, the actual 3D structure, for example, of the S gene, the spike protein has shown that it has an unexpected and unique interaction with the ACE2 receptor that’s different, for example, than the interaction found in the SARS virus. All right. So SARS is not SARS-CoV-2, but the SARS virus from the year 2003. That virus also has an S gene and an ACE2 receptor interaction, but it’s different. And a human wouldn’t have known to do that.

John SantaLucia:

Lastly, we currently don’t have, as humans, at least I hope we don’t have the technology to create a truly new virus like this. So this is just a false story. Globally, we are learning how to minimize this disease, and we’ve made mistakes along the way, including the scientific community. And some of the misinformation that is out there has been not ill-intended, just we’re learning as we go. Other things have been more insidious. I’m speaking here a little bit. This may be the only political thing I’ll say during the entire talk, or could be construed as political.

John SantaLucia:

It’s true that China has made some mistakes. All right. They should have regulated their food markets better. I’ll show you a little bit about that. They should have had some more transparency, maybe in some of the things that they’ve done. But it’s also true that China did notify the world within just a few weeks of the outbreak. If we had an outbreak in America, I think it would take us some time to just figure out what was going on. Is this new, or what is this? But they did notify the world quickly about this disease. They sequenced the genome at lightning speed, remarkable speed, and released that to the world scientific community, which was crucial in developing our response to this virus.

John SantaLucia:

They’ve also invested for years, China has, in monitoring the animal reservoirs for this virus, which I’ll show you more about in a moment. And they provided technical help. So in my scientific opinion, I think it is really wrong to blame the Chinese for the presence of this virus on our planet. So if it’s not from a lab and then humans didn’t make it, where did this virus come from? Well, there are some [diseases that arise from transmission from animals] that are called the zoonotic disease. There’s your nickel term, your nickel word that you can learn for today. Zoonotic, it’s a word [that would be a great Scrabble word]. A zoonotic disease is a disease that comes from animals, and jumps from one animal to another. All right.

John SantaLucia:

In the case of SARS-CoV-2, being honest here, we do not know 100% for sure, the animal origin of this virus. But we have like a 99.9% understanding of this, and I think we’ll understand more as time goes on. But the current best hypothesis or best data that we have has to do with what we’ve seen for viruses for years. All right. When you hear about the influenza virus, for example, you hear it called the avian flu, the bird flu, or the swine flu. Why are they called that? Well, it’s because their viruses were initially in animals, birds or pigs, for example. And then there was some sort of recombination event that occurred, or a mutation that occurred that allowed the virus to jump from one animal to humans. And then now, it’s a human virus.

John SantaLucia:

So these viruses, related to the viruses that cause disease in humans, these viruses have been circulating in animal populations for thousands of years. And humans interact with animals, either as pets or with farming, or the food that we eat. Particularly, eating exotic animals and things like bushmeat, things like that, those can lead to a transfer of the virus from animals to humans. So the viruses can be adapted to the human host. And once this adaptation we’re talking about here is mutations that occur in the viruses to make them able to replicate in humans. This is literally, evolution occurring in action.

John SantaLucia:

In the case of the SARS-CoV-2 virus, that are present in bats. And one in particular, one isolate for one particular bat is 95% identical to the human SARS-CoV-2. In general, the SARS-CoV-2 virus is actually about 79% identical to the SARS virus from 2000. Now, a plausible pathway is that this virus went from the bat to a exotic animal called a pangolin, which looks like an Armadillo. And I say that because there have been five isolates from pangolins that are 99% identical to humans. So you can see what happens here.

John SantaLucia:

There was initially, reports that people were getting a disease who had eaten fish. And this led additional reports to be that there was this food market in Wuhan, China, which is the origin of the outbreak. Wuhan is a city in China, and they have this fish market and meat market in general. And at that meat market, there are some, let’s say, unregulated activities that occur where exotic animals are sold, either butchered for meat or sold as pets. And so that created a situation where this virus, probably someone ate a pangolin or ate some bat meat. And this led to a transfer from an animal source.

John SantaLucia:

So it may have gone directly from bats to humans or from bat to pangolin, to humans. We don’t know that for sure. But once these viruses were in humans and adapted to humans, then they started spreading and causing the global pandemic. By the way, you’ll see at the bottom of each of my slides, I give references for where I got the material and where you can learn more about them. And we will be providing these slides, as well as a recording will be publicly posted so that if you have questions or want to look up more information, you can find that.

John SantaLucia:

One question you might have is, this transfer of diseases from animals to humans really happens all the time. But why was the Centers for Disease Control so alarmed about COVID-19? Once the initial reports of this came out in late December and early January of 2020, there were folks who specialized in virology who were ringing the bell very loudly, “We needed to pay attention to this virus. This is a very dangerous virus.” They were saying things like that for a reason. Here’s the reason why; humans are completely vulnerable to this disease. It is a new disease.

John SantaLucia:

Humans have no immunity to this disease. We have no drugs, no vaccines. This virus is highly contagious. About the only virus that’s more contagious than this was the measles virus. Maybe just a few. Anyway, it has a reproduction number, R naught of three. I’ll say more about that in a minute, what that is. If we don’t take action, then this virus could get very bad, very quickly. It was also thought that this virus would have a high death rate, and that is born out. The death rate for this virus seems to be around 1% or so, of people who acquire the virus die. So when you see things like the number of infections in the United States, 200,000 people on one day getting infected, the real number of infected people is higher than that, first of all.

John SantaLucia:

Second of all, the death rate is a 1%. Well, if you see 200,000 people who have the disease, then 1% of them are going to die. That’s 2,000 people. We all definitely should be taking note of this. So essentially, the reason why this disease was so alarming and it continues to be alarming is that humans are basically, from a biological standpoint, we are defenseless against this disease. Our only defenses are things like hygiene, things that were done for centuries. Things like wearing masks, social distancing, sheltering-in-place, contact tracing, quarantine, hand washing. These are very basic public health measures. They’re the most effective thing we have, however, until vaccines come on board, which I’ll be saying more about that.

John SantaLucia:

Now, fortunately, in a sense, we have been warned as a planet about these problems with pandemics. This is not the first pandemic. There have been pandemics occurring for thousands of years. Just in modern times, going back a 100 years, the Spanish flu killed about a 100 million people worldwide, out of about 1.5 billion total. You think about that. It’s 7% of the world died in that, and that was even worse than the COVID. In the United States, that one, 675,000 people died of the 2018 Spanish flu in the United States. We may approach that number in the United States with COVID-19.

John SantaLucia:

Some of the other epidemics here, the AIDS epidemic, measles pandemic, the Ebola outbreak, Zika virus, SARS in 2003, and now SARS-CoV-2 in 2019. There’s also been bacterial pandemics in the past. You may have heard of the Black Death, cholera, typhus, tuberculosis, leprosy pandemic. So there are a wide variety of threats that are things that we should be concerned about. Now, fortunately, we did have a little bit of a pre trial run with SARS, which is not the same as SARS-CoV-2, but is related. As I said, it’s 79% sequence identity.

John SantaLucia:

I’m [talking about] studies of the SARS coronavirus and also studies of another one which is not on my list. Oh, here it is, 2012 to present is the Middle East Respiratory Syndrome (MERS), also a coronavirus, but not related. This one is very distantly, only 50% sequence similarity to SARS-CoV-2. So MERS, we can learn a lot about how we treat patients. Deaths are caused by similar mechanisms, replication mechanisms. So we were able to learn a lot about the science of coronaviruses from these previous outbreaks, which allowed us to go faster. So I wanted to give a slide that gave a little bit of information about what science has achieved so far. And I just have to say, wow.

John SantaLucia:

I’ve had a small part in just a little bit of information about diagnostics, but the global community, the scientific community has really stepped up to try to control this virus. So, as I said, previous knowledge about the 2003 SARS virus was very helpful in educating our approach to this newer virus, the SARS-CoV-2. So the epidemic originally started, the COVID-19 epidemic started in December 12th is the first documented case in Wuhan, China. And in a remarkably fast timeframe, the first genome sequence was published in January of 2020. So within one month, the SARS virus was isolated from a patient and sequenced. And that sequencing information was absolutely critical to developing our approach to combating this virus.

John SantaLucia:

So within two months, the very first diagnostic kits were manufactured. The very first diagnostic kits were manufactured in early February, in South Korea, and now many, many more have been developed in a very quick timeframe from companies like Hologic, Abbott, Thermo Fisher, Cepheid, Lab Corp. So those companies have all made important contributions. And I had mentioned that this is a global scientific community working on this. The first SARS-CoV-2 genome was determined in January, but now, just eight months later, we have more than 100,000 genomes. This would be unthinkable; just a few years ago, it would have been unthinkable that a 100,000 isolates from different patients would be sequenced, have their whole genome sequenced and deposited into a public database, which that has allowed us to track mutations in this virus.

John SantaLucia:

And this virus has mutated by the way. There are several hundred mutations that have been documented now, but most of them are just random mutations so they don’t seem to be consequential. So we’re monitoring this virus worldwide to understand its evolution and to modify a response appropriately. Within just two months, that critical spike protein that I mentioned at the very beginning of the lecture, the crystal structure of that protein was determined, which is absolutely remarkable that these used to be efforts that would take years and years of effort. So here, within a very short period of time, we’ll see that these are very important for our approach to developing therapies and developing vaccines.

John SantaLucia:

In March of 2020, a previously existing drug called Remdesivir, this drug was developed by Gilead Sciences to treat Ebola. Ebola is a very different virus than the SARS coronavirus, but it is an RNA virus and has some similarities. So there was some thought that perhaps an existing drug like Remdesivir would help. And it was actually shown in March, very early on that this drug had some efficacy, and that has been born out with later studies. Convalescent plasma therapy is an approach, and we’ll show a little bit more about how that works. President Trump received that convalescent plasma therapy [actually he received monoclonal antibody treatment not convalescent plasma] as part of his treatment when he got the disease. So these are like miracle, 21st century approaches to science here that have really, really come about.

John SantaLucia:

Now, normally, the development of a vaccine takes decades or a decade, a long time to develop a vaccine. But in the case of the SARS-CoV-2 virus, we have our first vaccines made and clinical trials completed, or at least phase one, phase two, phase three have been completed on large scale, and manufacturing occurring in just eight months. This is just absolutely … from a scientist, I’m personally in awe that we were able to accomplish this. Some of this is due to the US government’s effort, called Warp Speed, in which the US government funded companies like Moderna to develop these vaccines on a timescale, unlike what we’ve seen before. So kudos to our government for having the vision and our President in this case, for having the vision to go after this approach that led to the development of vaccines very quickly.

John SantaLucia:

And I will say, all of these scientific achievements are only possible because of previous investments made in science. All right. So we would not have been able to get very fast therapeutics and very fast vaccines, very fast development of drugs were it not for the basic funding to the National Institutes of Health, the National Science Foundation and our various government agencies, the Department of Defense, which is an agency I’ve worked with, for example, to develop diagnostics for the coronavirus. And there’s also been a public government and private sector partnership. So there have been amazing contributions from biotechnology and pharmaceutical companies, some of which are above, but there are many more.