In Grantville Gazette, Volume 10, vaccinations in the 1632 universe were discussed as something Grantville would introduce to early modern Europe and beyond. Vaccinations are an extremely useful and beneficial healthcare innovation both from the societal and personal perspective. Widespread use of vaccinations can prevent many different diseases which were the major killers in the early modern era and kept life expectancy down. However, they have one major inadequacy: they do not work once you are infected (the exception being rabies which can be vaccinated against after infection but before the onset of clinical symptoms).

In our current modern era, we have found various means by which we counter disease even after infection. Bacterial diseases can be cured by use of antibiotics. Many viral diseases can be contained by various antiviral medications and most parasites have become so rare in the developed nations that people no longer know what they are like. Many of the diseases caused by parasites have effective remedies. With artemesium derived drugs against malaria and organo-arsenic drugs against trypanosomes (which cause sleeping sickness in Africa or Chagas disease in South America), parasites have mostly become a matter of inconvenience in the Western world, such as head lice in school age children, rather than life threatening. All in all, aside from cases of the sniffles, infectious disease has become relatively uncommon in the developed world. Even though many doctors are justifiably concerned about the emergence of multi-drug resistant bacteria, infections of all kinds are not the major killers they used to be because they are so effectively controlled by modern sanitation, inspection of the food supply and effective drugs.

In our history, we have more extensively used something else to fight disease which just about everyone still recognizes by the word or action, but many of us do not know the origin of the concept. These are anti-toxins, anti-venoms and antidotes. Here, I would like to discuss and propose that together with making vaccines, introducing improved sanitation and making people familiar with the germ theory, the use of anti-toxins and antidotes would also be a vital tool in the battle against disease.

What precisely are antidotes?

An antidote or anti-toxin can be defined as any substance which can counteract a toxin. A toxin is a substance which causes bodily harm usually through poisoning. To differentiate a toxin from a simple poison, it is said that even though toxins come in a very wide variety of different molecules, they are often proteins and produced by living (micro) organisms. Likewise, antidotes are often antibodies which bind and neutralize toxins. The easy way to envision the action of an antidote is to think of different locks and keys. For the body to work correctly, different locks and keys (proteins called enzymes which do anything and everything from help you create usable energy in your cells to making new building blocks for your proteins or DNA) have to work perfectly together. If a toxin interferes with a specific key being able to fit in a lock, that process is disrupted. If this process is something essential, the toxin can be deadly. An antidote can work in different ways but usually it binds to the toxin and prevents it from interfering with the lock and key in question. Toxins we have commonly heard of are Tetanus, Botulinum and Diphtheria. Although Botulinum toxin is the most deadly toxin known to man, it is currently more associated with the temporary removal of wrinkles than with death.

Why should Grantville bother making these antidotes?

These days everyone in the Western world and even most of the developing world gets immunized against tetanus and diphtheria. What we are actually immunized with are the tetanus and diphtheria toxoids, the inactivated forms of the toxins that are produced by the tetanus and diphtheria bacteria. In addition, when we go into the hospital for a tetanus shot when we have scratched ourselves on a dirty nail and we haven’t had a shot for a decade or longer, the tetanus shot may come with some tetanus immunoglobulin, a concentrated antidote, in addition to the tetanus toxoid. Without these vaccinations, diphtheria and tetanus would manifest themselves widely as the very deadly diseases they are.

The development of the first antidotes against these toxins during the 1880’s was one of the first steps in modern medicine, together with smallpox vaccinations, that made a major impact on the childhood mortality rate. I believe this technique will be favored by the up-time medical staff because they could make such a large difference and most of all because they can be used and still be successful after someone is already infected.

What are antibodies and how are they produced?

Antibodies are the end product of one of the two major branches of vertebrate immune systems. These two are called the cellular and the humoral branches. I will not be discussing the cellular branch, aside to say that it provides for a massive amount of professional literature and still keeps a lot of research scientists quite busy. The humoral branch is so-called because the end product can be found in the humor “blood” and these are antibodies. They are proteins which evolve so that they can bind very many different kinds of molecules. The manner in which they are developed in the body is reminiscent of the theory of evolution. A type of cell called a “naïve B-cell” is stimulated to differentiate, i.e. to start to develop down the pathway to become an antibody-producing cell called a plasma cell. During this process, the cell is presented with an antigen, a sample of what the antibody is going to be binding to, the B-cell divides and of the offspring only those making an antibody with some capacity to bind to the antigen survive. Those cells that fail to make binding antibodies commit suicide. This process is repeated at least three times with increasingly higher hurdles for the binding. In the end, it results in a specialized cell producing lots of an antibody with strong binding to the antigen. This whole evolution can take as long as three weeks. The process in itself, of course, is much more intricate involving many different changes in the cells and requires interaction with other cells and their protein products which can stimulate or break off this process, called differentiation, from a naïve B-cell to a plasma cell.

Once a plasma cell has been produced, it will now continue to pump out antibodies. These cells are terminally differentiated, which is to say they no longer divide and they no longer develop any further. They do, however, have a tendency to settle down in the bone marrow where some of them continue to pump out antibodies for sixty to a hundred or so years. Not all plasma cells are that long-lived, some survive for merely a few weeks, others months or years. That is why vaccinations for tetanus are repeated every 10 years but you only need two shots of measles vaccine. If you actually have a disease, you tend to have a very long lived memory of that particular form of the disease in the form of long surviving plasma cells churning out antibodies all day every day. This immunological memory is much enhanced by some of the progenitors of the plasma cells in the B-cell differentiation process called memory B-cells. In the process of producing the plasma cells, the intermediates have a step where the cells can already bind fairly well to an antigen, however these cells retain the capacity to divide and enhance their capacity to bind to the antigen. These memory B-cells also stick around, favored hangouts for them can be found in the spleen and tonsils as well as the appendix and other locations around the intestines. If you come across a particular pathogen again, after you are vaccinated or have had the disease, these memory B-cells can rapidly multiply and develop to become many more plasma cells that can produce an overwhelming quantity of antibodies to corral the disease in a much shorter period of time, a mere matter of days a compared to the few weeks it takes to develop immunological memory the first time. Since most diseases require more time than that to gain a foothold and to spread, the system works extremely well to contain diseases the individual already has encountered before or been vaccinated against.

How can antibodies be induced against a specific disease?

Vertebrates have evolved in an environment which is rich in bacteria and viruses as well as opportunistic parasites. Since these are so much smaller and simpler, these organisms have an advantage in that they replicate much faster. Vertebrates therefore cannot just accept getting infected without having mechanisms to cope with preventing these microorganisms from using our bodies as a food source. Many bacteria and viruses have co-evolved and instead of being harmful to us they can be beneficial. For example, much of our DNA consists of sequences which were introduced by viruses over many millions of years. We have yet to discover whether many of these sequences have any particular function, but for some of these we have identified specific beneficial and/or detrimental effects. Similarly, bacteria, which do not hop a ride on our DNA, have also evolved to become co-dependent. We have bacteria living on our skin, in our gut and all our body cavities. Most of these resident bacteria try to make certain that bacteria that can cause us harm do not obtain a foothold. Some of these bacteria produce nutrients from food we cannot digest, some produce vitamins, some actively suppress harmful bacteria and some function as friendly sparring partners for our immune systems to learn from.

Bacteria have several features which the vertebrate immune system is particularly alert to. When bacteria enter the body, they often find it a very hostile environment, and they tend to break up frequently. This then spills their cellular contents which among other things contains the bacterial DNA. This DNA is something that a percentage of antibodies are naturally made against, and humans commonly make these kinds of antibodies with a high affinity to DNA. This is one of the reasons why we can have an inflammation reaction when we get a bruise. The cellular damage to ourselves, even when not exposed to outside microorganisms does cause the spillage of our own cells cellular contents among which is DNA. This DNA is then recognized by our antibodies which then help to recruit the rest of the immune system to come in and clean up the mess. This can cause the area to be inflamed, even though it is not infected. That is why it is beneficial to ice the bruise and perhaps take aspirin to reduce the inflammation so that the immune system doesn’t go haywire and try to clean up more than just the damaged cells. Another common feature recognized by antibodies are the cell walls of bacteria, which frequently have a large amount of specific carbohydrates, different kinds of sugar-like molecules. These are relatively specific per bacterial species, but as molecules in general, they provoke a very strong immune response. Again, the human immune system naturally makes antibodies which bind these carbohydrates. Both the DNA and the carbohydrates can be injected in isolation and cause a very strong inflammation response. This is important since it attracts the immune system to a location with a big sign of “here is an invader.” Substances which proverbially carry these signposts are called adjuvants and are used with most kinds of vaccines to enhance the response against a particular antigen.

Thus, the two ways in which we can build up immunity against a disease are either having the disease and surviving or being vaccinated. For many diseases we don’t have an option, we just don’t know much about them or there is too much diversity in the disease. The common cold is a good example of a disease with large diversity. As there are so many different kinds of viruses that cause the common cold, having had one doesn’t protect you against the next. Similarly, malaria can be very different from one round of infection to the next. Although for this disease, if people are infected enough and survive they do build up a substantial degree of immunity, however, trying to get to that point is deadly for over 1 million children a year in the developing world.

Historical uses and production of immunoglobulins.

Going back to the early modern age where Grantville landed and the medical establishment of the time, we come across a particular mindset. Disease was perceived to be caused by an imbalance of humors, the bodily fluids. It could be caused by bad odors, but the disease in itself was thought to be an imbalance. The manner in which they attempted to re-establish these imbalances was by drawing out the various humors in many different ways, blood letting being a particular favorite. Strangely enough, some patients actually did get better after treatment. While most of this can be attributed to natural resilience in the human animal, sometimes drawing blood or making someone vomit can be the medically correct course of action. All this blood letting left a solid impression on western medical science and is not entirely without merit. Much about the health status of an individual can be discovered from examining their blood, at least we are able to do so in this modern day and age. Since the blood serves as the supplier of materials to the body, so it serves as the sewer by which waste from the various organs is brought back to be disposed of, usually by either the liver or the kidneys. By the time Pasteur and co-workers discovered that one can vaccinate animals and people by injection of dead or weakened micro-organisms, the fight was on to see which micro-organism caused which disease. A leader in this effort was a German by the name of Koch. In his laboratory, many people worked in the identification of these organisms. Diphtheria, tetanus, cholera and tuberculosis (TB) bacteria were a few that they identified. As a next step, Koch and collaborators infected animals with these organisms to create animals which had immunity to these diseases. This would be followed by periodic draining of some of their blood. This blood would contain antibodies against the disease in question. This worked very well for making antitoxins against several diseases, especially against the tetanus and diphtheria toxins. However, it also failed miserably in some instances, such as TB. Koch declared that he was able to make an antidote against TB, but was unsuccessful, resulting in the general and medical population doubting his theories and harming the development of future useful antidotes being available. The other large drawback from these antidotes was that it required injecting humans with blood derived products from animals. Some antidotes were made from human donors but those where not always available and almost never in sufficient quantities.

The disadvantage of using plasma or antisera from animals in humans is that although we are related to these animals, and the immune systems in animals such as horses, sheep and goats work in a very similar manner, the antibodies the animals produce are not exactly the same as ours. Immune systems can be quick to identify something as non-self, and when it does so, it starts to make antibodies against it. And so it is with these animal-derived antidotes. The use of these antidotes generally worked very well in a first and perhaps a second application, but after that, the person in question would develop immunity against the cure, which could lead to life threatening side reactions. Antisera derived from other humans lack the capacity to induce such a response, so are much preferred. However, finding the right donors is difficult, and since this is a blood-derived product, the danger was and is always in the possibility that the donor can be infected with another disease that could be carried over. There are times when the danger of infecting someone from a transfusion or an immunoglobulin injection is minimal compared to the danger of dying of the disease. Grantville is very much present in a time where the choice to use an antisera would save many more people than the remote danger of losing them to an unknown infection.

Diphtheria is an excellent example. Adults who have had the disease are safe and generally won’t get ill again if exposed to it, whilst children are very vulnerable. In the early modern era, it was a major childhood disease, often hitting communities every five years or less and killing about 30-40% of children it infected. Since this is a very distinctive disease, with very memorable symptoms, people would often know if they have had or currently have the disease. Should there be an outbreak in the community, there would be a rapid source of donors for immune serum. In a household where a young child may get sick, there would likely be their parents and perhaps older siblings who have previously survived the disease. By taking serum from these re-exposed individuals, there are likely to be very high levels of anti-diphtheria antibodies present in their blood. True, they may not have gotten ill themselves or perhaps had very mild symptoms, but they will have still been strongly exposed to the bacterium and their immune systems will have geared up their memory B-cells and made many new plasma cells all pumping out loads of antibodies against diphtheria. Now it becomes a question of how to get these good antibodies from these immune people to those who really need it, namely those who are trying to fight the disease the first time.

How can Grantville go ahead and use antidotes?

At first glance, starting to use antidotes is a no-brainer for Grantville. It works, people get cured and the concept is pretty simple. Where it gets difficult is the usual place, the devil is in the details. If we look at the things which are required to make antidotes from scratch, just having the right available donors is one thing and in the middle of an epidemic the best, but the tools to transfer the antibodies to those who really need it is quite another problem.

One example of the difficulties is, in order to get at the antidote, you need to get access the blood. Now, in the early modern era, one would say this is not much of a difficulty, just cut someone and let them drip. The early modern doctors were very good at exsanguinating patients, to the point of having bled them white while still keeping them alive (albeit just barely). So that problem is easily solved. But doing this in a manner where the blood was captured in as sterile a way as possible was not something they knew how to do. To do so with a high degree of success, one has to use a needle, tubing and a sterile collection container, be it a tube, bag or flask. The only people with training to do that in Grantville, would be the doctors, nurses and their retired compatriots, the vet and perhaps some of the EMTs. This is only a handful of people. Luckily, training someone to draw blood is not very difficult. Given a couple of days and a reasonable knowledge of the veins in the arms, just about anyone who doesn’t faint at the sight of blood and has a steady hand can learn to draw blood.

The next hurdle is finding a needle. For anyone who has had blood drawn in the hospital recently, it is not a big deal. You go in, most times a nice person puts in the needle with a minimum of pain and effort and a tube or two are drawn and before you know it you are pressing a piece of gauze on the site. Having a closer look, you may notice that the needle (usually a so-called butterfly needle these days) disappears into a red container with big warning labels on it. These red containers collect the sharp items which are contaminated with human body fluids. These get collected and incinerated regularly. That also means that the beautifully shaped butterfly needle was a single use item. Grantville doesn’t have that luxury. Prior to single use needles, there were needles which were used time and time again, beautifully precise instruments made of flexible steel and “needle” sharp. In order to keep that needle sharp, it would need to be sharpened after every two or three stabs. That means a nice butterfly needle, even if it gets reused, would wear away after about 100 uses. The type of steel used in a hypodermic needle is special. It is very soft and very malleable, so it doesn’t keep an edge long. It is also susceptible to rusting. As it happens, blood is a very good catalyst for making steel rust. Having even a very tiny bit of rust flake off while injecting someone can cause a nasty reaction. If that bit of rust were to travel in the blood to the heart, lungs or brain and get stuck in a capillary, it could even cause a fatal heart attack, embolism or stroke.

Grantville is stuck with a limited number of needles until they can make the correct kind of steel specifically required. This also limits how many people get to learn to draw blood properly. Are there any alternatives to steel needles? There are some plants which produce hollow needles which are surprisingly sharp. Some bird bones are small enough and hollow to function and can be sharpened. One of these could be found of possible use, but the danger of leaving a small fragment of broken needle made of plant fibers or bird bone in a vein makes me hesitate to suggest this line of development. Other alternatives may be the use of more malleable metals. Bronze comes to mind, although here the danger may be copper toxicity. This alloy tarnishes readily and would only be useful for a very limited time.

In aggregate, it means Grantville will need to make use of the needles it has. It would mean reusing the needles they have. The combination of the GP’s, the retirement home and the vet’s practice would yield a supply of needles that would need to last until they can make new ones. Most of these needles would be for injections and not bloodletting though. The difference is mostly in the size of the needle. To draw blood, you would like a fairly wide needle so that blood can flow easily through it. If you make the needle too thin, the blood ends up being sheared while it is drawn. This leads to broken red blood cells and makes the serum unusable. To reuse one of the suitably wide needles, it would have to be cleaned, sterilized and then “baked” dry. In the case of most butterfly needles, the tubing is attached and cannot be readily detached. That means that the tubing would have to survive this process as well or has to be discarded and new tubing has to be attached before each draw. That leads to needing reusable or easily replaceable tubing. Tubing these days is mostly plastic which replaced the rubber derived tubing used in the earlier parts of the twentieth century. Making plastic tubing would require a long process of which a petrochemist will have a field day explaining; starting with crude oil, there are quite a few steps to get to nice sterile tubing. That means Grantville again has to work with what it has available and find ways to reuse as much as it can.

All right, say we have used the precious needle and sterile tubing and collected blood into a sterile container. This blood will start to clot almost immediately unless an anti-coagulant is used. Making an anti-coagulant which doesn’t also make the blood unusable is an entire story by itself. Luckily, for making antisera, we don’t care, the blood can clot. This clotting will tie down all the cells in the clot. Now we can isolate the serum. The way it is done in a modern lab is by centrifugation. The blood is separated in tubes and these are spun around with enough centrifugal force to have the red blood cells settle on the bottom and leave the serum on top. This serum can then be drawn off by a sterile pipette and can be immediately used or stored refrigerated for a couple of months. The centrifugation itself is not very difficult, and even simple hand-cranked devices will work and can be readily made and designed in Grantville.

The last step is to place this serum in a syringe or more likely an IV bag/bottle and let it drip into the patient. The amount that one would have to provide a patient is not trivial. Since a person’s serum contains all the different antibodies that person produces, the antibodies against the one disease you are trying to protect the patient against may not be all that abundant. That means anywhere between 100 ml to a liter of serum may be needed. On average about 250 ml should suffice. That is about the amount of serum you can get from a person giving a unit of blood. If you average that out, you have to have a donor for every one or two patients. That is a lot of needle work, a lot of tubing and work to help relatively few patients.

The way we solved this in the modern era is to concentrate the antiserum into an “antidote.” As it turns out, the antibodies present in the serum can be isolated. This can be done by letting the antibodies precipitate out of the serum by adding in acetone and centrifuging the precipitating antibodies down. This leaves a pellet that can be dissolved in a much smaller volume of saline than the original serum. Now this adds a few items on the list for things to have. It requires relatively pure acetone which is quite a simple organic chemical but would still need to be made without the presence of other potentially dangerous organic substances. By concentrating and storing the antibodies from people in saline and refrigerating or even freezing these concentrated antidotes, you can potentially keep them around for years. Antibodies are fairly hardy proteins which normally last on average about 3 weeks in the human blood stream. When frozen they can last for decades, and refrigerated they can last for at least a year.

Thus, if I were on the medical committee in Grantville shortly after the Ring of Fire, with the first refugees coming in to take shelter in Grantville would be quite a few people who will have survived various diseases. It makes sense to interview these people and if it can be determined that certain people had been in recent contact with particular diseases because they still have a sick relative with them for example, to have some blood drawn and start to make a small but highly useful stockpile of antidotes against various down-time diseases. Similarly, the doctor's records will show who were the last people to be vaccinated. The individuals would be very useful as donors for immune serum against various diseases for which they now no longer have readily available vaccines, such as tetanus, measles, mumps, rubella and so forth. These small stockpiles will be useful for small outbreaks of disease, but a serious epidemic would quickly exhaust it.

What diseases will they focus on?

The first diseases to focus on are those which historically have a good track record for being treated with antibodies. That would most definitely be diphtheria and tetanus. Making the vaccine against these diseases is definitely not trivial, since both organisms are anaerobic, meaning they live and replicate under circumstances where there is no oxygen around. Only then do they make the toxins which are so dangerous to human health. It is precisely because these toxins are so potent, that making the toxoids for the vaccine is very difficult and would require a lot of safety procedures to prevent people from getting killed just making it. That means recent vaccinées would be selected and asked for donations. The other diseases people have been vaccinated against would follow. Vaccines being something which has become mostly something given to the very young, it is difficult to wish to drain a substantial amount of blood from a two year old. Aside from the parents concern, the child simply doesn’t have that much blood to give. Especially since a little doesn’t go a long way, I feel it is likely for most childhood vaccinations very little antiserum would be stockpiled.

The strongest focus would be in the communities surrounding Grantville. Many cities and towns of the era maintained “plague” houses outside the city walls. This would be where, especially the poor and destitute were sent to convalesce or more often to die when they became ill. In times of epidemics these facilities would be full of people with a particular disease. Coming in as up-time medics, I can imagine creating good will by curing people suffering from diseases which we know how to cure and then exacting a price in blood. Since bloodletting was such a common phenomenon in the era, this would not even be seen as strange, although, asking relatives of the patient for blood rather than the patient him/herself may require some degree of diplomatic persuasion.

Diseases I think, which would invoke a strong response by the Grantville medical community, would be typhoid, typhus, cholera, the plague in both bubonic and pneumatic varieties, smallpox, measles and diphtheria. In lieu of vaccines, antiserum will have to be a first line of defense. The early modern era, being what it is, rife with disease, I wouldn’t think it would have been long before this method of defense would be tested, especially in a Germany with large armies moving about and refugees all over the map.

What kind of results would the use of antidotes have on health, epidemics in specific?

How much of an impact can these antidotes make? Considering this method would be hard pressed to help more than a few dozen people at first. What it would require is a lot of planning and as much stockpiling as possible of relevant antidotes as different diseases manifest themselves. Here it will not make sense to take a defensive position. Disease will not pass by a community such as Grantville, which has such a large highly susceptible population with so little immunity against the majority of serious down-time diseases. That means public hygiene becomes the concern of everyone. Diseases need to be reported rapidly and quarantines established. Local down-time communities have to be monitored for the appearance of different diseases, even ones which the locals may not take much notice of. Overall, the medical community becomes as much an army in defense of Grantville as those carrying guns. That requires the logistics and support to create the infrastructure, as well as the foot soldiers to take the fight to the enemies. In that overall scheme, antidotes would play a vital role in being able to contain disease quickly and cure those people coming down with disease. This system would become overwhelmed during a massive epidemic, but in situations of lesser medical disaster, the use of the antidotes can change the disease impact on a community severely. Where diphtheria could end up killing as much as 30% of people, mostly children not previously exposed, the use of the antidotes in a timely manner could reduce that to close to zero.

Conclusions

Providing the early modern era with the means to take on serious killers by means of antidotes could be among the greatest gifts of Grantville to the early modern world. Even though it will be difficult to implement the infrastructure to produce antidotes, the major impact it has in making the difference between life and death, will make it a technology which they will not leave on the backburner. They have the knowledge of an effective means to fight death and the many paths that can lead to it and they will use this ability to drive the grim reaper back. Childhood mortality in Grantville itself should remain low. By spreading the germ theory and rapid response of medical units to the sites of emerging epidemics, antidotes will be highly effective. All in all, it makes me wonder what they are going to do in regards to birth control.;o).