I’m at the Niels Bohr Institute in Copenhagen for the week drinking coffee and talking about bacteriophage all day with a couple of the scientists here. The institute is a small collection of two or three old non-descript but charming beige stone buildings that together look like an old manner, in the North part of the city. Actually, Bohr’s family lived in one of buildings before the rest of the institute was built around it. In the back is a big park, which was apparently the green where Copenhagen executions took place in the old, old days, and later where Werner Heisenberg walked around cursing himself when his calculations didn’t work out. Now, the University of Copenhagen is built around it, for which the Niels Bohr Institute functions as the Physics Department. Two blocks in front of the building is a series of long man-made shallow “lakes,” that were actually built as moats that protected the inland side of Copenhagen from invading cavalry in the really old, old days. They’re only about two feet deep but apparently in the middle there’s a deeper crevice so the horses couldn’t get across. Today swans, ducks, cranes and seagulls swim around the lakes, and the swans eat the weeds growing on the bottom by dunking their heads and sticking their tail feathers straight up and out of the lake in perfect adorable form. In the spring, on most days it’s gray and it lightly rains on and off, but on other days its cooler and blazingly bright out. The Danes are impermeable to the cold, they bike and jog in the rain and cold and at night in the winter.

Niels Bohr is a giant in physics history, most famous for describing the quantum nature of the atom. The atom itself is a brilliant, tripped-out idea, still not intuitive to me: that the matter comes in discrete quantities. Life and experience are too squishy for this to be intuitive. The idea of discreteness is at the heart of quantum mechanics, and also at the heart of genetics, but more on those in a minute.

Carlsberg is the national beer of Denmark. Every country has a cheap light beer made by some huge conglomerate company that they export. They all taste the exact same, Carlsberg, Heineken, Budweiser, Corona, etc. However, Carlsberg occupies a unique place in beer history because Jacob Christian Jacobsen, the founder of the company, was the first guy to apply modern scientific thinking to brewing. He was a great admirer of Louis Pasteur and thus established a laboratory at his brewery outside of Copenhagen and hired professors to study the biology of the yeasts used in the brewing process. Before this, while it was known that yeast was required for fermentation, and that the specific slurry of yeast determined the flavor of the beer, there was little effort to prevent contamination of the slurries that were propagated, which caused unpredictability in the brewing process. But one of the guys working in the Carlsberg lab, Emil Hansen, isolated several strains of Saccharomyces pastorianus (named in honor of Pasteur; it turns out that this species is a hybrid of S. cerevisiae and S. uvarum – Whereas S. cerevsiae, which produces ales, feeds at the top of the “wort,” or pre-fermented beer, at room temperature, S. pastorianus, which produces lagers, settles to the bottom of the wort and requires cool temperatures, and a much longer time to brew. Lager apparently means “to store” in German) and found one that makes delicious beer from a pure, uncontaminated culture. From then on Carlsberg made sure to make their beer with pure cultures, which made the brewing process much more predictable and revolutionized industrial-scale brewing. As a result, the pure-culture brewing method, founded on ludicrously simple microbiology principles, became the worldwide standard, and Carlsberg made a bazillion dollars.

In addition to having a deep appreciation for science, J.C. Jacobsen didn’t like his son, and so instead of bequeathing his fortune, he endowed the Carlsberg Foundation, to this day run by the Royal Danish Academy of Sciences, which not only ran the Carlsberg Laboratory, but also funded Danish science. Science as an institution is opportunistic about these twists of fate. For another example, the Howard Hughes Medical Institute funds a moderate amount of science in the U.S., only because its namesake was psychotic and refused to pay his taxes, and so the feds made him a deal that he could either pay them or give them to a philanthropic cause, hence the HHMI. So anyway, when Niels Bohr began campaigning for funding for an institute for theoretical physics, the Carlsberg Foundation was a natural place to go, and they ended up endowing what became the Niels Bohr Institute.

For much of his later life, Bohr was an organizer, and the Institute functioned as a headquarters for physicists from around Europe. The auditorium is preserved in the original style with 10 or so white pew-like benches facing a chalkboard, designed by Bohr, that has like 5 nested layers that you can roll up, down or to the side as you’re doing your calculations. Near the back entrance there are a pair of historic photos, taken in the auditorium, showing a handful of visitors to the institute, including Max Planck, Lise Meitner, Wolfgang Pauli, Werner Heisenberg, and a young Max Delbrück circa the late 1920’s.

And so back to discreteness: the quantum mechanics folks were studying the meaning of discreteness at the level of fundamental particles. There was, you might say, a parallel effort in biology whereby scientists were trying to understand discreteness of inherited traits. Of course the proposition that either matter or biological information came in discrete chunks was not new. The idea of the atom went back to the Greeks, and the observation of discreteness in biological inheritance was made by Mendel. But the understanding of the reason for discreteness for either field wasn’t made until the 20th century. With respect to the atom, there were several key experiments and insights, but perhaps the most relevant cases for this story are i) Ernest Rutherford’s experiment where he bombarded thin gold sheets with alpha particles (i.e., helium nuclei), showing that while not all of them ran into something, some did, suggesting that the gold matter was not a continuous solid at microscale, but was heterogeneous in space due to atomic nuclei; and ii) Bohr’s idea that electrons occupy discrete orbits around the nuclei with specific energies (Bohr had gone to work with Rutherford, on a fellowship from the Carlsberg Foundation before his institute was endowed). With respect to biology, the outstanding questions was: what is a gene? By definition, at that time, a gene was simply the discrete unit of inheritable biological information, but no one knew anything about its physical nature.

Aight, how do these ideas of discreteness in physics and biology connect? A key figure is Max Delbrück. Delbrück went to work with Bohr on quantum mechanics in Copenhagen. It is said that Bohr had a deep interest in biology in addition to physics, in particular the question of whether biology was reducible, in principle, to the laws of quantum mechanics, and so I suppose he had an influence on Delbrück in this respect. Otherwise, I’m not sure how Delbrück defected so cleanly to biology. He might have realized the magnitude of the outstanding problems in biology, but then it takes a lot of moxy to assume that you’re going to be able to walk in and solve one of the biggest problems in biology, the nature of the gene. From Copenhagen, Delbrück went to work with Thomas Hunt Morgan at Caltech. But Delbrück quickly realized that fruit flies are far to complex for a physicist. Physicists are trained to reduce problems to the simplest possible versions. What are the simplest biological entities: viruses. To be specific, bacteriophage, or viruses that infect bacteria. Initially Delbrück tried to work on Tobacco Mosaic Virus (which infects tobacco and other plants), but even that was too complex. Bacteriophage are the simplest viruses, which is certainly linked to the fact that they infect the simplest life forms, bacteria.

At the time, people didn’t know what bacteriophage were, just that there was something out there that could kill bacteria. Actually, the first indirect evidence of bacteriophage is worth mentioning (slight digression). You may have heard about the sacred properties of the Ganges River. It is said that it has therapeutic, healing, properties, and so people in West Bengal and Bangladesh drink its water and bathe in it. The Ganges delta is also the source of all cholera in the world; cholera is a terrible bacterial disease caused by the bacterium Vibrio cholerae. A British microbiologist named E. H. Hankin went to Agra, on the Ganges, to study V. cholerae at the end of the 19th century and he had the instinct to put a drop of Ganges river water in one of his bacterial cultures. Whattaya know but a few hours later the bacteria were all dead. It is now known that the Ganges is swarming with both V. cholerae and lytic Vibriophage, the bacteriophage that kills V. cholerae. That is, this was probably the first observation of the effects of bacteriophage. The real reason to mention this story though, is that Mark Twain happened to be present to witness this experiment. No joke. He seems like the kind of guy who would pop out at opportune historical moments around the world, wearing a white linen suit and smoking a pipe. While he was disgusted by the fact that the locals were drinking water from the river into which they were also emptying sewage, he wrote in his travel journal:

“A word further concerning the nasty but all purifying Ganges water. When we went to Agra, by and by, we happened there just in time to be in at the birth of a marvel and memorable scientific discovery… that in certain ways the foul and derided Ganges water is the most puissant purifier in the world!”

He even went on to write a lost, unfinished novel called “3,000 Years Among the Microbes,” in which the main character was a “cholera germ” called Puck.

Anyway, it wasn’t until the early 1940’s that we could see bacteriophage under an electron microscope. Before that it was thought that they might be “naked genes,” not that we knew what genes were either. The point is that for Delbrück and company, this was the ideal system with which to try to understand the nature of the gene. Delbrück and the other physicists who were interested in the problem did what any old physicist would do: bombard the phage with particles. They figured they could play the same game that Rutherford played in order to figure out “how big the gene was.” It was very adorable of them. What’s cool is that while they didn’t figure out how big a gene was, what they did succeed in doing with this experiment is mutating the bacteriophage. This undoubtedly got Delbrück thinking about the nature of mutations. Again, these were all fairly abstract concepts – the structure of DNA wasn’t solved until 10 or 15 years later. Delbrück and a radiologist-turned-microbiologist, Salvador Luria, decided to use a bacteriophage-bacteria system to try to understand the nature of genetic mutation, and answer a central question in evolutionary biology: was Darwin or Lamarck right with respect to how organisms evolve?

Darwin’s theory was that variation in traits occur randomly, and that the ones that are advantageous result in a higher rate of reproduction in a given environment, and therefore outcompete less advantageous variations in that trait. Lamarck’s theory was that organisms sense their environment and actively evolve certain traits that will be advantageous in that environment. Even though Darwin is king today, this debate actually hadn’t been solved by the 1940’s. Delbrück and Luria won the Nobel Prize for performing a ridiculously simple experiment in which they mixed bacteria and bacteriophage, and measured the probability that a given bacterial culture would give rise to a strain of bacteria that was resistant to the phage. Then, without going into too many details (although the original paper is worth reading), they used reasonably straightforward statistics to show that the number of phage-resistant bacteria in several replicate cultures could only be explained if the mutations were pre-existing, supporting Darwin.

That and the rest is history. I really didn’t know most of it before I showed up here, but it’s good to be here talking about bacteriophage at the source. I wish I liked light beer so I could drink a Carlsberg tallboy for Bohr, Delbruck, and Jacobsen. Actually, even better, I can pour one out for them.