They’ve Got Bread Mold, So Why Can’t They Make Penicillin?
The above is one of the more common questions asked by readers following the 1632 series, especially those who are interested in the subject of disease and medicine. Unfortunately, there is no simple answer to the question. There are thousands and thousands of different kinds of mold. True, a few of them produce various effective medicines, like penicillin. But many are useless, even leaving aside those which produce hallucinogens like LSD, or which are outright poisons. The process of isolating a specific mold that produces an antibiotic is expensive, time consuming, and severely constrained by the availability of resources.
The purpose of this article is to give readers who lack technical education in the subject a general overview of the problem. Let’s begin by reviewing the major diseases which the characters in the 1632 series have to deal with.
There were a number of frequently fatal diseases sweeping across Europe during the Thirty Years War. The two most devastating were bubonic plague and typhus. In addition, there was smallpox, syphilis, influenza, tuberculosis, and any number of infections caused by wounds, badly stored food, and general unsanitary conditions.
The most devastating disease during the second half of the war was bubonic plague, which is often simply called “the plague.” There are three forms of the disease:
- Bubonic itself, the most common form, is not usually transmitted from one person to another, and is frequently fatal;
- Septicemic, which is usually quickly fatal, often before plague symptoms even show, and is easily spread if it reaches the lungs;
- Pneumonic, in which the infection starts in the lungs and spreads to anyone breathing nearby. This version is almost always fatal, the sort of thing that gives Dr. James Nichols nightmares in the series.
Plague is caused by the Yersinia pestis bacterium. It is usually spread by fleas, especially those found on rats. Plague can be treated by many antibiotics, including sulfa drugs, but it is not affected by penicillin. Modern vaccines are good for only about six months. (It is interesting to note a recent discovery that a genetic mutation in some people that makes them resistant to plague also makes them resistant to AIDS.)
Prior to 1630, the most devastating disease during the Thirty Years War was probably typhus, also called “gaol fever,” “camp fever,” and “the Hungarian disease.” Typhus was spread from person to person by body lice, common especially with armies. The disease probably caused far more deaths during the Thirty Years War than the armies caused directly in the course of fighting battles. It devastated many German cities.
Typhus is caused by a rickettsiae, a small kind of bacteria, with the specific name Rickettsia prowazekii. It is fatal about one-third of the time, and more so in the sick and elderly. It is rapidly and effectively treated by the antibiotics tetracycline or chloramphenicol, but not penicillin or sulfa drugs. It can be prevented by getting rid of body lice, i.e., by sterilizing clothes, using insecticides, and bathing.
Smallpox was also endemic during this time period. It is caused by the Variola virus, and is spread only by breath at close contact. It did not tend to spread as rapidly as the plague or typhus. Still, it was frequently fatal, with no known treatment until Edward Jenner discovered that vaccinating with cowpox, a very mild infection caused by the Vaccinia virus, prevented the spread of the disease. It is not treatable by antibiotics. Many of the people in Grantville who are over the age of forty will have some resistance to smallpox due to childhood vaccination. They probably won’t have enough resistance to prevent the disease, but are likely to have enough to reduce its severity.
Syphilis was apparently a much more lethal disease several centuries ago than it is today. Spread mainly by sexual contact, it killed half its victims after several years, many of them going insane before they died. Syphilis is treatable at an early stage with penicillin and other antibiotics, but not sulfa drugs. The first effective drug was called salvarsan, a fairly toxic mercury-based compound.
Tuberculosis, commonly referred to today as TB, is an infection that usually starts in the lungs. It is bacterial in nature, and the airborne version mainly infects those who are sick or elderly. A different version is spread from unpasteurized milk, and affects mostly children. Also called consumption, it weakens its victims over time before often killing them. It is difficult to treat, but can be treated with streptomycin, as well as some TB-specific drugs, such as isonazid.
Fortunately, the childhood version of the disease can be prevented by pasteurizing milk, a process which will be rather quickly available in the 1632 context given the modern knowledge of the characters. But an even simpler method which can be applied immediately is just to boil milk before using it. This is one of those diseases which can be prevented by the application of simple prophylactic measures known to modern medical science.
Staphylococcal bacteria often caused infections in wounds, as well as food poisoning. They are usually treatable with antibiotics. Streptococcal bacteria cause strep throat, as well as scarlet fever, in which the infection reaches the blood stream and often infects the heart. It is also treatable by antibiotics.
Today, there are a large number of antibiotics available to treat various kinds of infections. The reason so many different antibiotics are needed is that the bacteria that cause the diseases mutate, or change, to better survive in their environment. So while in the 1950s there were originally only half a dozen different kinds—such as penicillin, tetracycline, and streptomycin—now there are many dozens, some of which are no longer used because they don’t work as well against today’s mutated versions.
Almost all the antibiotics used today are initially grown from pure cultures of some mold or other microorganism, and then slightly modified chemically to be more effective against newly resistant bacteria. However, the first antibiotics were synthesized, chemically produced from simpler compounds. These include sulfa drugs and chloramphenicol.
It takes many steps to develop a usable antibiotic. This is called the “drug discovery process,” and is long, expensive, and labor-intensive.
As a start, consider the equipment needed for isolating a drug. This is probably the biggest problem in finding an antibiotic in the setting of the 1632 series. Large quantities of supplies and equipment are needed—and there are no laboratory supply stores in Germany in the 1630s.
First, the characters in the series need something in which to grow cultures. Lots and lots of cultures: thousands of them. They need something with a relatively flat bottom, because it will be filled with a material that the samples grow on. The material, called a growth medium, is poured in as a liquid and then gels to a solid, and so a container that is not flat requires more growth medium. Also, it is harder to handle things that don’t have a flat bottom. It is important that the sample grow without being affected by other mold or bacteria, so it needs to be covered. The container shouldn’t kill or grow the cultures, so metal and wood are not suitable. To process many samples, it is best if all the containers are the same size and shape. The containers need to be reusable, so the medical industry doesn’t have to make more and more of them. Finally, it is best if they don’t break easily, so that lab workers handling them are not exposed to dangerous germs.
We currently use something called a “petri dish” to do that. It is a pair of round glass dishes, one slightly larger than the other, with flat bottoms and straight sides. It requires only a little growth medium, has a top to prevent dust and spores from landing on it, and can be baked in steam and reused. It is made of pressed glass, a technology that wasn’t well known in the 17th century. This involves making metal molds, taking a measured glob of molten glass, putting it into the mold, and then pushing a top to the mold to shape it before the glass has a chance to cool. Molten glass is very hot, and very dangerous. This will take a lot of work to develop, and a lot of time.
They also need large flasks and small flasks, as well as test tubes, for growing the possible antibiotics and for growing the germs to be attacked by them. It is convenient that the plug on the top come in standard sizes. The plug will probably be a wax-impregnated cork, because that is far more available than rubber in 17th century Europe. Flat bottoms are better, because the flasks need to stand up. Narrow tops are also probably better. The same safety factors apply as with petri dishes. For medium size flasks, wine bottles will probably do well. Gallon jugs are probably suitable for large flasks. There should be no problem obtaining empty wine bottles from the Germans (as well as the people of Grantville).
Growing the molds and bacteria presents another problem: food. Surprisingly, molds and bacteria can be very picky about what they eat. For mold, potato glucose should work. For bacteria, it really depends on the bacteria. Some will probably like an extract based on blood. Others will like glucose or other things. Figuring out the right foods will require some trial-and-error.
A gelling agent is needed to provide a solid surface for some of the steps in the process. This is the most difficult ingredient to obtain. While gelatin can be used, it still has to be wet when the mold or bacteria is put on the dish, and larger quantities of samples are needed. The best gelling agent is agar, which is made from red seaweed. Since seaweed will rot, it will need to be boiled and dried where it is found, on the coast, and transported to the lab from there. That means that someone with the needed knowledge will have to make a trip to the coast—in a continent torn by war—locate the seaweed, and figure out a way to make it into agar. Then they will need to hire and teach some people how to make it, and arrange for transport and payment.
Discovering an Antibiotic
Once the equipment and supplies are there, the work itself can be started. First, a large number of samples of molds and other microorganisms need to be collected. This is a lot of work, as each sample is collected from a different source, often from dirt. Penicillin was originally collected from mold from an overripe cantaloupe, by the way, not from bread or an orange.
As each sample is collected, it is placed in a test tube and transported back to the lab. The sample is swabbed onto the petri dish and placed in an incubator at body temperature. It is grown until cultures appear on the plate, which usually takes two or three days. From there, individual molds are selected and swabbed into test tubes containing diluted food for the mold. This gives pure samples which are grown for several days. Some of a given sample is taken and spun very rapidly in a centrifuge, causing the denser cells to go to the bottom of the tube, leaving what chemicals are produced by the mold in the top of the tube with water. The liquid at the top is removed very carefully with a long glass straw. This can be concentrated further in the same way that sugar is produced, by heating the mixture in a vacuum chamber. A low-tech vacuum pump can be made from the same kind of piston used on a steam locomotive, but in reverse; instead of having steam push the piston to drive the wheels, an engine pushes the piston, sucking air out through the cylinder. Another dish is swabbed with the bacteria, and then a large drop of the extract is placed in a spot in the center of the dish, and this is grown. If a circle containing no bacteria appears in the center of the culture, then this makes a possible drug. (The identification, isolation and pure culture of disease-causing bacteria to test with is yet another challenge, by the way. But that’s beyond the scope of this article.)
That’s the easy part—just lots and lots of repetition. But it is not without risk! If the people doing the work get sloppy, they could get one of the diseases they are testing against, and kill themselves and their co-workers as well. A cut from a broken test tube or petri dish, a spill of germs, and there could be trouble.
Once a mold is chosen, it needs to be grown in greater quantity, in larger bottles. A lot more extract is made and purified. It will probably be made into a powder so that it is at a consistent dosage. This is carefully measured out, and a small amount is fed to a lab mouse. If it dies, this probably isn’t a good drug. Larger amounts are fed to mice, until they figure out how much is safe for the mouse to take. Then, they infect mice with bacteria. Some are given doses of the drug by injection, with a few other mice given no drug for comparison. If the dosed mice live when the undosed mice don’t, then you have a drug that will cure mice of the disease.
A promising start. But it’s risky, because if the sick mice bite or scratch anyone, they run a very real risk of getting the disease. This process is repeated with larger animals, such as pigs or dogs. Again, if it cures the disease, it increases the likelihood that people can benefit from it.
Next is the really scary part: trying it out on people. It would be nice if the drug could be initially tested to see if it was penicillin or tetracycline, but that is beyond the Grantville high school chem lab’s capability. To start with, you need healthy people, and they must be volunteers. This is important, for both practical and moral reasons. People must know what you are doing, and what risks they are running. You start by giving a few volunteers single small doses of the drug, and see if it makes them sick. If not, then the process is continued with larger and more doses until you reach the level that it worked (per weight) in animals. At this stage, it is easily possible that they could become quite sick or even die. If it does not make the volunteers sick, then it has passed the first step in testing the drug.
Next, you need to find a sick volunteer. This is risky to the volunteer if there is an alternative treatment that works. It could waste valuable time if the drug doesn’t work, making them more sick. In some cases, using both an alternative treatment (like sulfa drugs) together with a possible antibiotic is a good idea, because sulfa drugs work more slowly. The idea is to see if the drug works to slow or stop the disease. If so, then it has passed the second step in testing the drug.
Finally, the drug is tested against any alternative treatments to see if it does as well or better than any alternatives. If it does, then you have an antibiotic.
But don’t celebrate yet!
Making flasks of the antibiotic for testing has been done. But translating that into mass production is a far more difficult problem. First, they will need larger equipment that can be sterilized, so it doesn’t get contaminated. Stainless steel vats are probably required. Large quantities of food for what is grown required. Because it only grows where there is air present, on the surface, lots of sterilized air will need to be bubbled thru the vat, and the contents of the vat agitated, like a giant bread mixer. The fluid will need to be drawn off, either continuously or in a batch process, and the drug isolated from the fluid and purified.
There is then one last step. Many antibiotics produced in this manner have problems being administered to people. Penicillin produced this way needs to be injected, because it breaks down in stomach acid. In this form, the body removes about 95% of it through urine. Modifying it chemically into a slightly different drug can permit it to survive in the stomach, be retained in the bloodstream, and generally be more effective. This will require figuring out what they have actually made, so that it can be modified into a known form by following some steps similar to drug synthesis.
Synthesized drugs are those that are made by taking other, more easily made chemicals, and processing them to produce the desired drug. In one way, this is better than hunting for an antibiotic, in that there is a specific process to produce the drug. If the source chemicals are pure, and the processes are not done in a faulty manner, then by doing step one, then step two, then step three, and so on, the drug can be consistently produced. But there are lots of steps, and each one needs to be done correctly, with the right ingredients, at the right temperature, and in the correct order.
The source chemicals are limited to what can be obtained or made by Grantville in the early 1630s. As all these drugs require variants of a chemical called benzene, that is one starting point. The easiest way to produce benzene in quantity is from coal tar. This is made by baking coal to a very high temperature. A number of flammable gases are produced, and these gases are captured, cooled, and carefully separated. Benzene is one of the products. Roughly ten pounds of benzene can be extracted from every ton of coal. This is then processed through a series of steps, along with other chemicals made by Grantville, until the desired drugs are produced.
Some of these chemicals are difficult to make, and can be quite dangerous if misused. Exposure to benzene, for example, can cause liver cancer. Again, another critical factor is purity. If another chemical is present with the one that is required, it could contaminate the process. This makes the results of all the previous steps worthless, and requires starting over again.
One example of a chemical that is difficult and dangerous to make is a special acid, produced by cooking sulfuric acid and chlorine gas under moderate pressure. Both ingredients are highly corrosive and poisonous. (Chlorine was used as a poison gas during World War I.) That means that stainless steel is almost a necessity to safely produce the acid.
Many other chemicals are similarly dangerous in a variety of ways, some exploding when mixed with water, a few burning when simply combined with air. Almost all are poisonous in one way or another.
The very first antibiotic was called Sulfanilamide, a member of a family of drugs called sulfa drugs. You may have seen it in a World War II movie, where a medic sprinkles a white powder over a wound. The ability of sulfa drugs to stop infections and allow people to heal was miraculous for its time. It was discovered by accident, when people found that a red fabric dye stopped infections. This took a while to figure out, because the dye itself didn’t stop disease in the lab, but rather broke down in the body to make the antibiotic.
Sulfanilamide is fairly toxic, and there is not a lot of difference between a dose that has little effect and one that makes a person sick. It’s not an ideal drug, but still one which in many ways deserves the term “miraculous.”
Once scientists figured out what the drug was, and how to produce it, they tried a variety of chemical variations to see what might work better or be less toxic. They found a couple of dozen varieties, with differing ability to stop different diseases with more or less toxic effects.
Today, sulfanilamide is not used anymore as a medicine, but it is often made as an exercise in sophomore organic chemistry lab. It is the easiest antibiotic to synthesize. Sulfa drugs are less effective than penicillin and other drugs commonly used today. That’s because they do not actually kill bacteria, but rather stop them from growing, requiring the immune system to do the killing. They are also limited in what they work against: they have no effect on typhus, syphilis, or smallpox, and only some effect on plague. But they are fairly effective on wounds and skin infections.
Chloramphenicol was originally grown from microorganisms, as were penicillin, tetracycline, streptomycin, and the other half dozen or so antibiotics available in the 1940s and 1950s. Once the structure of the drug was determined, a method of making it from chemicals proved cheaper than growing it. This gave it a large competitive edge over the others in terms of price. In the context of the 1632 series and the resources available to the characters, it is the only powerful antibiotic that can be synthesized. Its chemical formula is even listed in Encyclopedia Britannica, as well as the Physician’s Desk Reference, or PDR.
In some ways chloramphenicol is ideal, in that it can treat a wide variety of infections. Unfortunately, it has a couple of disadvantages as well, which is why most people today have never heard of it:
First, it is often not properly processed by newborns, leading to something called “Gray Baby Syndrome.” Fortunately, this syndrome usually reverses itself when the newborn is taken off the drug. But, obviously, it limits chloramphenicol’s effectiveness for very young children.
Secondly, and more damning, is the fact that in about 1 in 25,000 people, it causes aplastic anemia. This is a disorder in which some blood cells are no longer produced, resulting, about two weeks later, in the patient suffering a very unpleasant death.
As documented in the book Adverse Reactions, a number of cases of this were allegedly reported shortly after its introduction, and yet the manufacturer continued an aggressive marketing campaign. It was over a decade before Congressional committee hearings and lawsuits revealed the very real dangers to the public and stopped the deaths of many patients. Because of the danger, chloramphenicol is no longer used today in the United States or other wealthy industrialized nations. But it is still a drug of choice in Africa, where its cost effectiveness overrides the occasional fatal side effects.
In the context of the 1632 series, however, chloramphenicol is an ideal drug. The drug can effectively treat typhus and syphilis, which sulfa drugs cannot. It is far more effective at treating plague and most other bacterial infections than sulfa drugs. And when the death rate from the drug—1 in 25,000, or.004%—is compared to a 33% fatality rate for typhus, and a higher one for plague and syphilis, it is easy to see the advantages. If someone has one of these diseases, chloramphenicol is the only treatment available, and is arguably the most valuable man-made product in the 1632 context. Obviously—as was already touched on in the novel 1633—there will be many issues needing to be dealt with regarding fairness and the cost of the drug. But that’s true of the availability of up-time medicine in general.
While it will not be easy to produce chloramphenicol with the resources at hand, it can be done—with a lot of Grantville’s money and skilled people. Early production would probably be limited to bucket quantities, however, enough to treat perhaps a hundred people per month. Only with the advent of stainless steel and chemical plants will production on a larger scale become likely. And for some time, the people capable of manufacturing the drug will be limited to a small number of the up-timers with a pharmaceutical or chemical background.
I’m afraid there isn’t an easy answer to the development of penicillin or other grown antibiotics. It will take time, effort, expense, and some risk. Ultimately, in a decade or so, the characters in the 1632 series will succeed. In the interim, chloramphenicol and sulfa drugs will have to fill the void, and save as many lives as possible.
Chemical Engineering in 1632:
It’s not just a job, it’s an adventure.
My thanks go to Rick Boatright, Drew Clark, Laura Runkle, and other members of the 1632 chem group for their contributions to this article, as well as to my wife, Marla, for editing it.
History of Chloramphicol: Adverse Reactions, by Thomas Maeder, Harper Collins: 1994.
Synthesis of Sulfanilamide: Experimental Organic Chemistry, a miniscale and microscale approach, second edition, by John C. Gilbert and Stephen F. Martin, International Thomson Publishing: 1998; pp. 545-559.