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They've Got Bread Mold, So Why Can't They Make Penicillin?

Written by Robert Gottlieb

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.

Disease

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 effects 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.

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.

Equipment

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 17^th 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 ...