BENG 100: Frontiers of Biomedical Engineering

Lecture 9

 - Biomolecular Engineering: Engineering of Immunity


Professor Saltzman talks about the importance of vaccines, and particularly the role of bioengineering in vaccine development. He first addresses the question of “what is a vaccine” and the role of the immune system. He then describes the biological basis, symptoms, and history of smallpox as a devastating disease worldwide, and how–starting with the work of Edward Jenner–an effective vaccine was systematically developed from cow lesions. Next, methods to deliver vaccine to a wide population are introduced. Finally, Professor Saltzman touches on the possible reemergence of smallpox as weapon for bioterrorism.

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Frontiers of Biomedical Engineering

BENG 100 - Lecture 9 - Biomolecular Engineering: Engineering of Immunity

Chapter 1. Introduction [00:00:00]

Professor Mark Saltzman: Okay, this week we’re going to continue in our discussion about the immune system. But talk about sort of engineering the immune system, how to produce immunity in individuals. And we’re going to do that by talking about some examples, some historical examples, in the sort of technology and vaccine development.

And what I hope to do over the course of this lecture and the lecture on Thursday, is complete what’s described on this outline slide here. First, using a couple of examples that have turned out to be very important, one is the example of smallpox, and the second is the example of polio. Talk about how vaccines were developed in these particular situations, and how the development of the biology is coupled with delivering this through populations, and how these sort of intricately woven together. It’s not enough to understand the biology of how to create a vaccine, if you can’t make enough of the vaccine or deliver it to people in ways that it’s useful. And so we’ll talk about how that happened in the–using the examples of smallpox and polio. And that will bring us to a general discussion of sort of the tools that are available now for vaccine development, which we’ll talk about on Thursday.

I don’t have to say too much about why vaccines are important. You know about this, and this is a slide that I showed you. The graph is something I showed you on the first day of class, that over the last hundred years in particular, but what’s shown on this slide is over the last 300 years. Life expectancy for humans has increased dramatically. And one of the reasons that’s most responsible for that is that humans aren’t dying at as young an age from infectious diseases as they did three or four hundred years ago. And there are many reasons for this, our success in eliminating infectious diseases as causes in the developed world. And you know what those reasons are. One is that doctors started washing their hands in between when they saw patients. That had a remarkable effect on reducing transmission of infectious diseases, in doctor’s offices and hospitals. Another is that we learned a lot of things about engineering of public systems, like water supplies. Separating our water supply from sewage and learning how to do wastewater treatment was a really important part of reducing infectious diseases.

But vaccines, and particularly in the last hundred years, vaccines have been one of the most important elements in our progress. And so what this slide just reminds you of how much progress we’ve made. Also, shows you something about the challenge of it, because we are susceptible to attack from lots of different kinds of microorganisms. So, not just a spectrum of viruses, but there’s viruses and bacteria and parasites and other microorganisms that can cause disease. And so this slide just illustrates that in a simple way, the range of different kinds of organisms that your immune system is trying to–whoops! [laughs]

Wait a minute, I’ve lost control of–I’m not–Oh, there it is. It’s not showing up on the screen for some reason. That, this shows the range of morphologies of microorganisms that your immune system has to potentially encounter, from complex organisms like the syphilis pathogen here, a virus, this is a false-colored image of a virus, very tiny, not shown to scale here; and bacteria like salmonella and staphylococcus. So these organisms like this are abundant in the world around us and our immune system prevents us from getting sick most of the time.

Chapter 2. Vaccine [00:04:42]

So what is a vaccine? A vaccine is a prepared, it’s a preparation, that’s prepared in some way. We’re going to talk about how they’re prepared, but it’s a preparation that is intended to stimulate your immune system. So, what that really means, you know, from last week’s lecture, is that the vaccine stimulates these particular cells in your immune system to give you immunity. We’re usually talking about adaptive immunity here. So, either stimulates the production of–and differentiation of B-cells, to produce a specific antibody that can neutralize the virus, or stimulates the production of cytotoxic T-cells that can kill infected cells within your body. But in any event, the vaccine is intended to stimulate the immune system to produce an effector response–either antibodies or specific cells–that can combat spread of the microorganism through your body.

Usually it’s done by taking all or part of the infectious agent, and showing them to your immune system in some way. And so we talked very briefly last time about this business of antigen presentation, how your immune system–one of the things that it does especially well, is recognize what’s part of you and what’s not part of you. It can separate between what’s part of yourself and what’s foreign, and it does that by presenting, by recognizing antigens that are presented in the context of the major histocompatibility complex, MHC.

So a vaccine is designed in order to engage that biology, in order to provide antigens that will stimulate specifically your immune system. Usually it involves pieces of the infectious agent itself, to cause that engagement. So, that’s what a vaccine is, and vaccination is the process of taking that vaccine that you’ve developed and giving it to people, either individual people or groups of people, or as we’ll talk about today, people all over the world. And so that’s a very different thing, right? Designing something that works in a particular individual, and designing something that can be used in people all over the world, involve different sorts of accomplishments.

Well, we’ve all had some experience with vaccines. You can’t go to school in this country, and in many countries, until you’ve had your prescribed set of vaccinations. And so they’re already very safe, very effective vaccines available for many infectious diseases. There’s a partial list that’s shown here, starting the top of the list with smallpox, and that’s what we’re going to spend most of the time talking about today. There are vaccines for rabies, for typhoid, diphtheria. Most recently, or more recently, there was a vaccine for varicella, which you know is chickenpox that was developed in the last ten years.

Now, so there’s probably a number of people in this room, so when I first started teaching this class 20 years ago, everybody in the room had had chickenpox. Right, now are there people here that have not had chickenpox, right? Because you had the vaccine, presumably, and so you didn’t get the disease. And so this is a substantial change in the interaction of a microorganism with a population, right? A lot of didn’t get sick from it now, and we got sick from it before. You also know that there’s some vaccines that are not yet available, for diseases that we would very much like to prevent. HIV infection and AIDS is the one that comes first to mind, and is responsible for this slide, I think this is data from a few years ago, 700,000 deaths per year. That number is undoubtedly higher than now. AIDS is a tremendous problem, deaths from HIV infection and AIDS a tremendous problem in Africa and other parts of the world.

But there are other diseases that are numerically even more important. The whole category of diarrheal diseases, caused by viruses called enteroviruses, where they, it infects your gut. Your gut’s unable to function in the normal way, and so you get severe diarrhea. You can become dehydrated and die just as a result of the loss of water there, because of your body’s natural response to the infection. And that causes five to ten million deaths per year. And children are particularly susceptible to these. Children get diseases from a class of viruses called rotaviruses, for which we have no vaccine, and- and so no way to protect them. Malaria causes a million deaths per year, and schistosomiasis, which is a parasitic disease, is unfortunately a common cause of death in the world.

And so these are situations where we would very much like to produce a vaccine, but we can’t yet, and the question is ‘Why? ‘. Why is it difficult in some cases to produce a vaccine when we’ve been successful in so many others? And so one of the points I want to make here, on this slide, is that this is a very disease-specific thing. Learning how to turn on your immune system to protect you from a specific pathogen turns out to be very particular to that pathogen. That shouldn’t be too surprising given what we talked about last week, that your immune system, the adaptive immune system in particular, responds to individual antigens differently.

Just to think about what’s most important in the U.S., of the top five reported infections in the U.S., and this is again from a few years ago, but I’m fairly sure that the numbers haven’t changed, three of the top five infectious diseases, or the infectious diseases most commonly reported in the U.S., are sexually transmitted diseases: Chlamydia, gonorrhea and HIV infection. None of these do we have vaccines for, and it’s turned out that sexually transmitted diseases for a variety of reasons, we’ll come back to later, are particularly difficult to develop vaccines for. We’ll talk about why that’s been the case as we go through.

And this just is another list, I mainly wanted you to have it in your notes of diseases that are important around the world, for which there are very active programs to develop either vaccines or more effective vaccines. You know that there is a vaccine for hepatitis B, for example, which is on this list. And you’ve all been vaccinated, I would guess, for hepatitis B. It’s the one where you have to get three shots over a period of six months, and so you have to remember to go back, you get a first ba–you get a first shot, you have to remember to go back after a month and get a second shot, you have to go back after six months and get a third shot. Then they test you to make sure that you have adequate protection, and some people need an additional shot after that. And so that’s an effective vaccines. But it’s only an effective vaccine in the context where you have people who can go to the doctor’s office, or to an urgent care, some kind of medical facility, three times, reliably, at a specified period of time. And that’s not possible in all parts of the world, not everybody has that opportunity to interact with medical professionals that often.

And so there’s a lot of interest, not just in developing vaccines for diseases that we don’t have vaccines for, but for delivering vaccines that are more effective. For example, what if you could make a hepatitis vaccine that was good in one shot instead of three shots? Or vaccines that could be transported more easily–the hepatitis vaccine that we get is not stable unless it’s refrigerated. It’s in solution, it’s refrigerated, and it’s very difficult to transport refrigerated vaccines to all the remote parts of the world where you would like to transport them. And so that very practical consideration turns out to be important in how we use vaccines in real populations. So if you could make a hepatitis B vaccine that didn’t require a shot or that didn’t require refrigeration, that would be a tremendous advance in spreading that vaccine through the world. So, that’s another example of the difference between a vaccine that works, and a vaccination that works, right? A vaccine might work if the person is there and you can interact with them. A vaccination, for it to work around the world, has to be inexpensive, transportable, possible to use without advanced medical personnel, and those kinds of things.

Chapter 3. Smallpox and History of Early Vaccine Development [00:13:57]

Okay, so let’s talk about the example of smallpox, which is one of the world’s great successes in the battle against infectious diseases. Just to say a little bit about smallpox, because unlike chickenpox, which if you haven’t had, you’ve probably seen a case of it. None of us have seen a case of smallpox, it hasn’t existed in the world for many decades now. But smallpox was, at one time, one of the most frightening diseases on the planet. It’s a devastating, frequently fatal infectious disease. If smallpox occurred in your community, about 30 percent of the people that acquire the disease would die from it; the other 70 percent could be disabled or permanently disfigured as a result of the disease. It’s an infectious disease; it is spread by–through the air.

So, it first infects you because you breathe in some of the infectious agent. Smallpox is a virus called variola, it’s a virus that contains DNA. The name of the virus is variola. It’s part of a family of viruses, and we’ll talk about at least one other member of that family of viruses as we go through here. But it can be acquired in the air, from patients that are from- from other individuals that are infected. You breathe it in, it infects the cells of your respiratory tract, and the virus begins to reproduce, and then it spreads throughout your body. And so during the first period after you come in contact with the disease, you have an incubation period where you get sort of the kind of symptoms that we associate with lots of kinds of viral infections that we contract through our respiratory system; you might have a fever; a malaise, which is just that feeling that you don’t want to get out of bed and go to class. You might have that commonly, but even more severe than normal; aches; and a rash. And this is what’s characteristic of smallpox, is that as the virus spreads through your body, it particularly, it particularly affects cells of your skin. So, you get a rash, or a redness of the skin.

And then you would recover for a while, that initial phase of the illness would disappear, your fever might go down, you might appear to be normal. Then you start to get lesions on your skin that are very characteristic of smallpox. They start as what are called vesicular lesions, or like blisters, where they’re filled with a fluid. They evolve to become very dense, hard, pustular lesions, which are filled with what turns out to be tissue debris. It’s really just the result of the virus dividing within cells of your skin, and producing a lot of dead cells. And so that debris fills up a little spot that would feel, according to reports, because again we don’t see it now, feels like a little pellet underneath your skin. And this fluid eventually starts to leak out and those lesions would heal, but they leave scars in most cases. These are very deep lesions that go not just on the surface of your skin like a blister would, but down into the dermis or deeper layers of the skins, as well. In fact, certain areas of the skin would be impacted most, most dramatically, the face and the chest, the arms, but more distal point of the arms, like the palms of your hands.

And so you can imagine that even in its–with all of this activity on your skin, even at its most–least serious level, it’s a terrible disease. I’ll show you a picture in just a moment. But in some cases, that progressions of the disease would start to affect other organs, in addition to your skin, and your body would become overwhelmed with the infection and eventually die. And as I mentioned before, death would occur in 20-30 percent of the cases that got the most severe form of smallpox. And so, if this was a disease that entered your community, you could have expected several centuries ago. At the end of this sweep of the disease through your community, one in four, or one in five, of your neighbors would die from the disease. And that says, that’s a dramatic effect on communities.

Well, smallpox affected world history, it’s–just as HIV infection is affecting world history now. Smallpox affected world history hundreds of years ago, and it was a disease that was common in Europe, but not common in the Americas until the Americas were colonized. And so there are famous reports of how the Aztecs, that whole civilization, was devastated by smallpox. That disease was brought to them by the Spanish when they came to these continents in the 16th Century. And the Spanish, a much smaller group of people was able to overtake the Aztec civilization, very well established, because that group of people was devastated by the disease. And they were weakened as a result, and so the Spaniards, even in fewer numbers, were able to conquer.

So these are just some pictures to show you what the smallpox lesions look like on the face of a child, and then distributed over the whole body of an adult, to give you some better idea of what kind of a disease this was. So, the process of developing a vaccine occurred over a long period of time. In fact, there’s evidence that even thousands of years ago, Indian and Chinese healers were using a form of something that we would recognize as vaccination. And they did this by taking–they recognized that somehow, if you had a mild exposure to the disease, your body could then develop protection against more severe forms of the disease. And so, the older way, the more ancient way of exposing you to disease, was in the case of smallpox, to take pieces of tissue from somebody that was infected, and usually it was one of the scabs that formed as a result of these skin lesions, and to grind up that scab somehow and expose it to somebody who you wanted to protect from the disease.

And the way that India healers did this was by putting pieces of this in your nose, or injecting it under your skin. And there was a feeling that this could protect you against the disease. And it turns out that there is. We now know what the scientific basis of that is, it involves activation of our immune system. And it was a practice that was not broadly used until somebody really studied systematically. And that person who really studied it systematically, and is given credit for developing the first vaccine, is a Scottish physician named Edward Jenner. And he started with a similar but different observation, and that was that cows get a disease that’s very similar to smallpox. We know now that it’s caused by a related virus, called vaccinia, remember the virus that causes smallpox is called variola. But variola, which causes smallpox in humans, and vaccinia, which causes a disease called cowpox in cattle, turned out to be, we now know, viruses that are molecularly very similar.

What was known at that time was that there was a disease in people, and there was a different disease in cows, and they looked the same some way. And Jenner made the observation that others had made, that people that were around cows a lot tended not to get smallpox. And in particular, dairy maids, whose responsibility was to milk cows, and so they had a very intimate relationship with cattle, often didn’t get disease. And sometimes they developed a mild form of the disease. They would get lesions on their hands, for example, the part of their body that was really in close contact with the cows. And he hypothesized that they were getting the disease in cows, which the disease from cows that caused a milder disease than smallpox, and that protected them from getting the more severe forms of smallpox later.

Well, I mentioned that this was just sort of a more modern observation of one that had been made in the past. This process, I said, this ancient process of taking scabs from patients and introducing them to people you wanted to protect, was called variolation. And Jenner was making another observation that might be useful that way. There were other individuals that were making this observation at that time. In addition to Jenner, there was a farmer named Benjamin Jesty, who recognized that farmers, being in contact with cows, didn’t get disease as often as non-farmers did. So, he intentionally inoculated his wife and two children with fluid that he got from one of his sick cows. Right. So, he took fluid from a cowpox lesion on a cow, and he injected it into his children and his wife, reasoning that this would protect them from disease, even though they didn’t have as much contact with cows as farmers did. And he was right; they got immunity and were protected from smallpox when it affected their community.

Jenner did this in a much more systematic way. He used not just his family, but he used whole populations of people. And he produced a fluid from cowpox lesions, so these were these lesions, these skin lesions on cows. He took this pustular fluid that was produced at this very specific phase of the disease, and he developed a way for giving that to people. So, ‘vaccination’, the word vaccination, comes from this event. Vacca is the, I’m sure there’s a Latin scholar in here that will correct my pronunciation, but vacca is the Latin word for cow. Vaccination from cows, and that’s where the first vaccine came from. And Jenner, because he was a trained physician, because he knew something about the scientific method, did something that these more ancient healers had not done in the past, was that he wrote down what he did. And he kept track of how many people he gave the vaccines to, and then he kept track of what would happen to those people when a smallpox infection occurred in their community. And as a result of writing it down and keeping track, he produced a very clear record, and scientific evidence, that using this procedure could protect a population of people from the disease. So, that was the start of the modern practice of vaccination.

There were problems with Jenner’s approach, and you can imagine what some of those problems are. One is that you got to get the vaccine from cows, so you got to have an infected cow in order to produce the vaccine. So, it’s awkward to have to wait for a cow to get infected before you can vaccinate a population. What if you’re talking about a group of people that don’t have any cows in their vicinity, let alone a sick cow? How do you get the vaccine to them? Well, that problem was partly solved by saying, ‘Well, if I’m giving the inoculation to one person, and they develop a lesion locally…’ and that’s what would happen. When you would take the fluid from the cow, and you would inject it underneath the skin of a person you wanted to protect, then at that site where you injected it, you would get a lesion that looked like a smallpox or cowpox lesion. And it would go through these same phases that I described before. And it would, you’d get a clear blister-like region, it would turn pustular. Eventually you develop a scab, as it healed, and then it would–and then the scab would fall off, and you’d be left with a scar.

But what if instead of taking the fluid from a cow, I inoculated–he inoculated me, let’s say, and waited until I had the lesion at the right stage, then took some of my fluid and gave it to Brian and Nate and Mirtalla and spread it through the community around me. Now we don’t need the cow anymore because you could pass it from one person to another, and pass the immunity from one person to another. And that works. The problem with it is that you also can spread other diseases in that way. You’re not only spreading the infection. If I happen to have some other infectious disease, then not only would you passing the protection to smallpox, but you’d be passing that disease among the population as well. And it turned out that another, not quite as deadly, but still very serious disease called syphilis was also common in this part of the world at that time. And so you could pass diseases like syphilis from one individual to another. And that’s not great, right? That’s not perfect.

The other problem is that as it was passed from me to another individual, to another individual, then the vaccine could change in some ways that were hard to predict because what accumulates in the lesion in my arm is different in some way than what accumulates in the lesion on a cow. And as you move through the human population, the kind of response that you get could change because the virus itself mutates or because you’re also passing on some factors that provide some protection that changes the course of disease in the recipient. So, as the vaccine was passed from arm to arm, it became less potent, and the length of protection that it would give you varied. So, if you were someone that was getting it after it had been passed through many people, you wouldn’t have as strong or as lengthy a protection as the first individual did. And we’re going to just keep that in mind. We’re going to talk about the reasons for that as we go along, particularly at the beginning of class next time.

Chapter 4. History of Modern Smallpox Vaccinations [00:29:06]

But what was really needed in order to do this was a defined preparation, right? We–what you would like to give is everybody in the community exactly the same preparation, so that you could predict what everybody’s response to the vaccine would be. It wasn’t until the 20th century, so almost 200 years later, that we learned how to do this. And it was based on a couple of things. One was, a better understanding of what you were doing when you vaccinated. And I’ve already given you some clues about this, in that this process of vaccination that Jenner had developed was intentionally injecting into healthy patients, a microorganism. In this case the virus vaccinia, which causes a serious disease in cows but only a mild disease in people, and injecting that–because it was similar to variola, or the smallpox causing virus in some way, so that your immune system would develop a response to vaccinia. But because of the similarity of the viruses, the immune response that people developed would also protect them against natural infections with variola.

And so we call that now, that process of infecting with a life virus, that produces an immune response that cross-reacts with another, that’s called a naturally occurring, attenuated vaccine: naturally occurring because we took a virus that occurred in nature; attenuated because it causes an immune response in people but a mild form of disease, not the full form of disease. And so this is an example of a naturally occurring, attenuated vaccine. So, how could you produce–the question is, how could you produce large quantities of this- of this microorganism, this virus vaccinia under controlled conditions?

Now, you know, because we talked about cell culture already, that a great–that we talked about last week, manufacturing of cells. We talked about two weeks ago, that if you had a population of cells, you could grow those population of cells and you could make, if they adapted the culture properly, you could make an infinite number of cells from one starting solution. Well, if you knew a cell that could serve as a host for a virus, you could use this process of cell culture to make large quantities of virus, right? You just grow up cells until you’ve got a lot of cells. You infect them with the virus, and you let the cells, in culture, produce the virus. Well, it turns out that we could not identify, at least at that point, a cell culture that would serve as a host for vaccinia. So cell culture production wasn’t an option.

The only way that we knew how to grow it reliably was to grow it in its natural host: cows. And so in the 1940s, a group of people led by Collier started to develop a large scale production method for making a reliable source of vaccinia virus. And they did that by intentionally infecting calves, by harvesting their skin when they were at a certain point of the disease, and by isolating the virus from the skin of the calves. And of course, you could imagine that this took some time to develop. You’d want to make sure that you separated the virus from all the other parts of cow skin so that your ultimate preparation was enriched in the virus and didn’t contain quantities of other things that would be hazardous. And so that’s what was done in the 1940s.

And then they found that they could freeze-dry this preparation of virus, and freeze-drying to lower the temperature, freeze it, then extract out all the water, so you’re left with a powder, basically a powdered form of the virus, that could be shipped all over the world, and then reconstituted by adding water to it. Right, so it’s like–it’s like Kool-Aid, but more potent. But used the same way, right? The powder you could ship anywhere, and reconstitute it onsite, and then it gets injected. And they also developed a very reliable way for introducing the virus, so that when they had a defined preparation of virus, then you want to make sure that everybody gets it in their skin in the right way. So, they developed this bifurcated tool, which would be appl–you’d put the stuff on the surface of the tool and then you’d scratch the skin in a certain way so that you could produce sort of a reproducible introduction of the vaccine into the skin.

Availability of this freeze-dried vaccine made it, then, possible to think about vaccinating people all over the world. And so it didn’t take long, once this vaccine were–was available, for people to want to get organized and think about ways of delivering this vaccine to all the regions of the world where people were potentially infected. It was the World Health Organization, or WHO, which led this effort. And the goal was to eradicate the virus, to get rid of it so that there were no natural sources of the virus on the planet. And that was possible in smallpox because of a few characteristics of the disease: one is that it’s a–it’s purely a human disease, humans are the only organisms that are affected by it. That’s important, right? Because if it was a disease that was carried by both humans and squirrels, for example, then in order to get rid of it on the planet, you’d have to vaccinate not only all the people but all the squirrels, right? Otherwise you could have a squirrel host–I’m using squirrels, because I think that’s funnier than other animals to think of–but it could be any potential host, right? And it would be really difficult to vaccinate a wildlife. So there are no non-human reservoirs.

There were no asymptomatic carriers. So if you got infected with smallpox, you got the disease. There weren’t people that got infected, like you can get infected with hepatitis B or tuberculosis, and not even know you’re infected. You might not know have any symptoms, you might just have a latent source of the microorganism somewhere in your body. And that didn’t happen with smallpox. That’s important, too, because you need to be able to tell if the virus is present in the human population. And so because of those two things you could think about eradicating the virus. They did this very systematically, by giving quantities of the vaccine to countries all over the world. That’s part of it, right? Give enough of the vaccine so you have a dose for everybody in the world, or a large fraction of the people. We’ll think about it in section, how you don’t need to vaccinate everybody, but you just need to vaccinate a critical number in order to stop the disease from progressing through a community. And we’ll think about that in section on Thursday.

But so you needed enough doses, but this is real, and this is a lot of people, right? So you need hundreds of millions of doses, at least, and you need a way to distribute that around the world, and you need a way to keep track of who got sick and who didn’t after they got vaccinated. So you needed some way of reporting. And the WHO had all those, had that whole infrastructure in place. So they kept track of country-by-country, when cases of smallpox occurred, and as it was eliminated from regions of the country, they then certified those regions to be smallpox free.

And so it went, through the years from the 1950s through the 1970s. The last reported case of smallpox in the–naturally occurring smallpox, was in 1977, a man in Somalia was infected. There were no reported cases after that, and so by the late ’70s, the world was certified sort of free of smallpox worldwide. The U.S. was certified free in the early ’70s, years before that. I was born before 1970, I got a smallpox vaccination. None of you got smallpox vaccinations, because once a country was certified to be smallpox free, there was no reason to–there was no reason to vaccinate people any longer. So, none of you in this room, I’m 100% confident, never ever got a smallpox vaccine.

Well, that’s a great story, and it’s an example of a great success in medicine. But it’s also an example of a great success in biomedical engineering. And the engineering part of that is sort of the part that I talked about in one slide, when I talked about how do you convert this scientific advance into something that can be delivered all over the world. And the technology that was used in this case was growing the vaccine in a natural source, harvesting it, figuring out how to produce a preparation that could be distributed but was still biologically active; that is, still could protect against the disease.

We now know, and I’m going to talk about next time, lots of ways to do this, alternatives to this method of bioengineering. And you could guess what those techniques are. You could use cell culture, so you don’t have to grow the virus naturally in animals. But you can grow it in cultured cells, and the advantages of that are that you can do this under very reproducible conditions. Much easier to keep a flask of cells under very sterile, very reproducible conditions than it is to keep a small animal, right? Even–or a large animal like a cow. And much easier to purify and know what you have at the end, than if you’re trying to harvest it from a whole complex organism.

We have techniques of recombinant DNA, and those can be used to produce either modified viruses, we’ll talk about that. So maybe I could take an infe–maybe I could instead of getting lucky, like we did in smallpox and finding a naturally occurring organism that causes an attenuated form of the disease, maybe we could genetically engineer a virus, to make it less pathogenic, right, but still immunogenic, right? And those words mean different things: immunogenic means that it stimulates your immune system for a response; pathogenic means that it causes a disease. So maybe you could figure out how to use what we know about molecular biology, to engineer a new virus that’s still immunogenic, but not pathogenic any longer. And that’s a new approach to producing vaccines.

Or maybe you don’t need the whole virus. Maybe you don’t need the whole virus, but you could just use a piece of the virus, right? Just use a piece, an antigenic piece of the virus. And then I don’t have to produce the whole virus in order to make a vaccine. I just have to produce many, many copies of a piece of the virus, a protein, say. And how would you produce a protein in large quantities? Well, again you could use recombinant DNA technology. Get a gene, put it in a plasmid, get that plasmid expressed in a host, could even be a bacterial host, right? Like we talked about with insulin; make large quantities of this recombinant viral protein, and use that as a vaccine. And we’re going to talk about how that–how those steps can happen next time.

Chapter 5. Threat of Bioterrorism and Conclusion [00:41:28]

I want to end with this picture. So this is the cover of the New England Journal of Medicine, one of the most famous and influential medical journals in the world. And this is from April of 2002. And I talked about eradicating smallpox in 1977, right when officially the last case was reported, and it was certified to be eradicated shortly after that. But on this cover, you can see that there are several stories about smallpox. One is called the ‘Clinical Responses to Undiluted and Diluted Smallpox Vaccine’; one is called ‘Current Concepts, Diagnosis and Management of Smallpox. ’ Why would one of the most prominent and influential medical journals in the world be publishing a review article about how to manage cases of smallpox when there had not been any cases of smallpox for 25 years? Yeah.

Student: Bioterrorism?

Professor Mark Saltzman: So, the concern at this time, and still remains a concern, is that infectious agents, particularly very deadly infectious agents like smallpox, could be weaponized in some way, or converted into a weapon. And if smallpox was somehow introduced into a city like New York City, what would happen? Well, there’s a whole population of people who are younger than me that never got smallpox vaccines, right? You don’t have it, you don’t have any immunity to smallpox, you don’t have any reason to immunity to smallpox. And so you would be susceptible to infection by this organism. In addition, even people–I got vaccinated 40 years ago, right? Is my vaccine still protective? Probably not. And so even people that got vaccinated, most of us either have questionable or no protection against the virus at this point.

And who, where would–If it was, if it was converted into a weapon, where would the vaccines to protect the rest of the country come from? There’s no company that’s making smallpox vaccine anymore because there’s no reason to make smallpox vaccine, because nobody would buy it, right? Because there’s no naturally occurring smallpox. And so there was great concern that we were vulnerable in this way, because the disease is still a disease that could affect people. There are still some active smallpox virus specimens kept in the world, and there are two sources of small–two places where smallpox is stored now. One is in the U.S. at the Centers for Disease Control, where there is a sample of variola, which is kept, you know, frozen on ice in a heavily guarded facility. There’s another sample which is in Russia, part of the former Soviet Union, where there are samples that were stored. And these samples are used for scientific purposes. They are kept track of very closely, but because there’s still smallpox that exists on the planet, there is some concern that that could be obtained and used to develop a weapon. So, that’s the reason for it.

Shortly after this, and why did that come up 2002? Because of what happened in 2001, is why that became a concern. The government, after this time, did issue contracts to manufacturing companies to produce new quantities of the virus. They also found some stockpiles of the virus from the 1950s that they still had on an Army base in Maryland, I think. They tested those to see if they were still active, and they were. So, there’s been an active effort to reestablish the process of smallpox vaccination in case that’s needed. There are even some military personnel now who get immunized against smallpox in the event that when they’re going into areas, they might be exposed when they’re in combat areas.

And so, I give you this example to say even though tremendous progress was made. This is one example that, without fail, people would say is a marvel of medicine and bioengineering, but that it’s still something to keep track of. There are still opportunities to use what we know about this to develop even better methods. I think the smallpox vaccine we made now would probably be better, more effective, and safer than the vaccines we made in the ’50s. So, I’m going to continue talking about vaccines on Thursday. In particular, we’re going to focus in the beginning, on polio virus, which is another great success story, but where a very different approach to vaccine development was used. That will be instructive in thinking about what vaccines in the future might look like. Questions? Great, see you on Thursday.

[end of transcript]

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