Return to the Institute

7:30 AM Tbilisi time, Monday, November 15, 2004 (continued). Today I plan to get my act together at the institute to do some real probing into what the institute is all about. My hope is to start taking more notes and photographs, though the latter will be hampered by the need to recharge camera batteries, a task which continues to elude me as I await the return of my luggage. I also hope to pull together by the end of the week a two (or more) day excursion out of Tbilisi, perhaps to the Black Sea, which by taking up time will seriously restrict my ability to fully explore the institute. Below thus I’m going to attempt to pull together a summary of what I have learned so  far. It’s 8:15 AM as I write this. I wonder when the rest of us will be starting our our day.

The G. Eliava Institute of  Bacteriophage, Microbiology and Virology was founded either in the 1920s or the 1930s (a minor detail which I need to determine) by G. Eliava, either at the behest of or with the assistance of Felix d’Hérelle the French Canadian co-discoverer and sole namer of the bacteriophage phenomenon. D’Hérelle discovered that turbid broth (liquid) cultures of bacteria could lyse (that is, clear) if exposed to a seemingly infectious agent. He called these agents “bacteriophage” (phage for short) after their ability to “eat” (clear) bacterial cultures, transforming cultures from thick with to mostly lacking in bacteria. The early 20^th century, when phages were discovered, along with the late 19^th century was a time known as the Golden Age of Microbiology. During this time the causes of a large number of diseases were attributed to bacteria, such as cholera caused by the bacterium Vibrio cholerae. Medicine, however, mostly lacked the tools necessary for the treatment and cure of these diseases since antibiotics, that today we take for granted, were still decades off. Into this context came phages, entities which had an ability to destroy bacteria, including disease-causing bacteria. To d’Hérelle it was obvious that if phages could be harnessed against these bacteria then they could serve as a useful, perhaps crucial part of the physician’s arsenal against infectious disease.

In North America three trends appear to have impeded a widespread and immediate adoption of this so-called phage therapy. First was an ongoing argument as to the nature of phages, with one side (the anti-d’Hérelle faction) claiming that phages are merely bacteria-produced enzymes versus d’Hérelle’s assertion that phages, essentially, were viruses. It would be two decades before the electron microscope once and for all settled this controversy (d’Hérelle was right), but it seems that this controversy first led to the two other trends. First was a certain degree of phage-worker incompetence that stemmed from a failure to fully appreciate the nature of phages, i.e., essentially they are “living” things that vary greatly in terms of their abilities to attack and kill different bacterial populations. Second was d’Hérelle’s need to answer his critics (who with hindsight appear both shrill and incompetent) which led to distracting intellectual disagreements that seem mostly to have served to reduce d’Hérelle’s influence on the field. That loss of influence was unfortunate since d’Hérelle seems to have had a much firmer grip on what phages were all about than did his critics.

The above controversies seem to have forced d’Hérelle overseas to seek less contentious environments in which he pursued his hopes to employ phages as antibacterials. One place where he found an ally in these efforts was Tbilisi, Georgia, at that point a part of a not quite completely Stalinized Soviet Union. For reasons that still elude me, the application of phages to treat bacterial diseases took hold strongly in the USSR, and the institute in Tbilisi became what appears to be the center of those efforts. Meanwhile—back in North America—by the end of World War II chemical antibiotics, in particular penicillin, had reached the masses, a consequence of efforts to bring the drug in high quantities to injured soldiers. Though the USSR was an important component of the coalition that defeated the Axis powers, there were limitations placed on the sharing of war-making technologies. Most notably was a lack of sharing of nuclear technology, but perhaps also a limited transfer of antibiotic know how. Though the USSR compensated by inventing (or stealing) equivalent nuclear technologies, in terms of the treatment of bacterial disease the USSR followed an alternative route with increasing development of bacterial viruses as antibacterials rather than (or, presumably, in addition to) chemical  antibiotics. Consistent with other trends in the USSR where the state attempted to foster certain in-house technologies as a means of demonstrating a superiority of Russian technology, phage therapy was developed as an alternative path to the West’s increasing reliance, some would argue over reliance, on antibiotics as the sole means of fighting bacterial infections.

Skip forward to the 1990s. The Soviet Union is breaking up and in the resulting chaos civil war has broken out in Georgia. The economy of both nations is in shambles while at the same time access to Western technologies is increasing. The consequence is a decline in support for the Institute as well as a decline in the market for its phages. At the same time, ironically, the West is experiencing a crisis of a different sort, one that involves an increasing adaptation of bacteria to antibiotic resistance and a simultaneous reduced emphasis by the biomedical establishment on discovery and implementation of new chemical antimicrobials. The latter is a result of a declaration, of sorts, that man had won the war on infectious disease (yes, folks, there was a time, the late ‘70s I believe, when genital herpes was the most feared of infectious diseases). A third trend was an increasing marginalization of research on bacteriophage in the U.S.

While phages were becoming seemingly the antibacterial of choice in Russia (the 1950s and 1960s), in the U.S. (in particular) phages were being employed as model systems for the development of the field of molecular genetics, which today serves as the foundation of what is known as molecular biology, that collection of techniques that includes the all-important gene cloning. Phages represented easy to work with biological systems that were ideal for elucidating the basic molecular mechanisms of DNA replication, RNA transcription, and protein translation. However, the success of phage made the molecular study of more complex organisms increasingly more doable. As a consequence, at some point a phase-transition of sorts took place in biomedicine where phages became increasingly de-emphasized in terms of basic biomedical research particularly as funding opportunities dried up (this period occurred approximately while I was attending grad school). A counter trend—further complicating this already complicated picture—involved an increasing emphasis on phages as ecological entities, a result, in part, of the discovery that phages are so numerous in environments that they may constitute the most numerous organisms on Earth. The fit between basic research on phage ecology and basic research on phage therapy is a strong one, while at the same time the need for efficacious alternatives to chemical antibiotics is compelling. Thus, surprise, surprise, the spiritual center of bacteriophage research shifted somewhat to the East, to a struggling Eliava Institute; just in the nick of time so far as the institute was concerned.

I decided to visit Tbilisi and Eliava as a pilgrimage of sorts, one that was catalyzed by an invitation by my friend, Naomi Hoyle, who had come to Tbilisi from the U.S. to learn phage therapy from the masters. Fortunately, I already know many of the workers at the institute and many of those who I haven’t met at least know my web site, www.phage.org. Thus, with very little forewarning to the Georgians, I find myself poking around the G. Eliava Institute, exploring possible collaborations, and otherwise trying to get to know how phage therapy is practiced in Tbilisi. Getting further along in this effort is my goal for today. Who does what? How do they do it? What do they use? Where is it done? How are the materials made? What bacteria are treated? How do non-Georgians gain access to the treatment, and why would they want to? These are some of the many questions I hope to at least begin to answer during this trip.

“Natural selection is the process whereby replicators out-propagate each other. They do this by exerting phenotypic effects on the world, and it is often convenient to see these phenotypic effects as grouped together in discrete ‘vehicles’ such as individual organisms. This gives substance to the orthodox doctrine that each individual boy can be thought of as a unitary agent maximizing one quantity—‘fitness’.” p. 133, Dawkins, 1999.

Monday, November 15, 2004. Today I was taken to visit a company called Biochimpharm which is located in one of the wings of the Institute. They are a phage therapy company that supplies phages to Georgia. We talked about phage therapy and what they did, with some trouble always due to language barriers (gotta learn some Russian, though of course everybody insists that I should concentrate on learning Georgian instead). Eventually it was declared that they would be taking us to a 17^th century church (called Ananuri) located an hour or so from Tbilisi, in the same direction as our previous excursion out of town. I, of course, had no clue as to where we were being taken. Still, with good company and an interesting ride, I certainly wasn’t about to complain. At first I thought that we would end up at the same place as on Saturday, but those churches came and went as we really got away from it all. Eventually we came upon the dam and reservoir that is responsible for the Tbilisi water supply and then we kept on driving as the road because increasingly twisty into the mountains. Finally we crossed a bridge and came immediately upon the church. This church was without question the most interesting we had been to yet, in no small part because the fortifications surrounding it were still pretty much intact, and climbing on the walls was allowed. I recall when I was young that people were allowed to climb on less than 100% safe monuments or otherwise go exploring. I suppose in the great out of doors this is still possible. But in and about a 17^th century church? Ya right. At first Talia was afraid of the climbing, but soon she got the hang of it and insisted that she do it again and again and again. I had fun trying to figure out what the order of construction was. There seemed to be a church that was outside of the walls—a structure that formed part of the platform upon which the larger church sat. There also was an older church found within the walls that seemed to be the same age as the fortifying walls, plus there was a signal tower.

What I infer was that the newer, larger church had been built so as to keep the signal tower intact since the walls of the two structures come within a few feet of each other. The construction of the newer church is of a finer, honed sandstone, which contrasts with the cruder (and/or older) stone used for the rest of the complex. Unfortunately I spent the day with my camera batteries running on “air.” And no spares to speak of (since, though the luggage actually did show up today—amazing!—there was no time to recharge before leaving on this excursion; see http://www.rzuser.uni-heidelberg.de/~ci4/georgien/eklesiebi/ananuri.jpg for an image of the church).

Next we dined, yet again, on an amazingly wonderful Georgian meal, complete with a good house Georgian red wine but also what we all agreed was the worst white wine any of us had ever tasted. Oh well. At some point during the meal the white wine disappeared, clearly not because any of us had consumed all that much of it. But by then I was no longer much aware of what that might have been going on around me. The explanation for why is recounted as follows.

I’ve solved the chacha paradox. Give me enough distilled spirits on an otherwise empty stomach (and let’s not forget the wine with the meal) and, well, that leads to something quite less than sobriety. Three people were drinking vodka (not, fortunately, the driver, who managed to make it through the evening on only a half a glass of wine, so far as I could tell). We went through three bottles of vodka, and I suspect that the bottles were 500 ml each. That makes for 500 ml of vodka per person, which is enough that it took me until the next morning to pull off the math that three bottles divided evenly between three people makes for one bottle per person. I couldn’t believe it that the vodka just kept coming. I don’t know if it was being ordered or merely supplied. Good drink, though. Some Georgian brand, or at least so I infer from the Georgian writing (“one of only 14 alphabets found worldwide”). The food was great, too, as was the company. I held my drink moderately well, but my secret has nothing to do with my being a regular drinker and instead much to do with my 100 or so kilo mass. Again, many thanks to our driver, host, and translator (three different people), without whom none of this would have been possible. J

“…the idea of individual bodies maximizing one quantity relies on the assumption that replicators at different loci within a body can be expected to ‘cooperate’. In other words we must assume that the allele that survives best at any given locus tends to be the one that is best for the genome as a whole. This is indeed often the case… But it is easy to imagine cases where a gene might promote its own survival while harming the survival chances of most of the rest of the genome.” p. 133, Dawkins.

Tuesday, November 16, 2004. Not much all that novel happened today. I hung around the institute, working on collaborations, doing my e-mail (which takes forever given such slow internet access), and generally trying to take as many photographs as I possible could. The highlight of the day was walking the two or so miles back from the institute. I spent the walk taking as many photographs as I could get away with without being run over by a car. Clearly I need a telephoto lens for this camera if I want to take better shots of people. I just don’t have the nerve to consistently poke a camera in people’s faces and snap away.

“If a gene is favored by selection resulting from one beneficial effect, this will be because the advantages of its beneficial effect qualitatively outweigh the disadvantages of its other effects.” p. 137, Dawkins, 1999.

4:00 AM Tbilisi time, Wednesday, November 17, 2004. The city that never sleeps. That’s New York City/Manhattan, I think. But all cities can be busy day and night. With so many people so close together (Tbilisi is something like 1.5 million) somebody is bound to be awake at any given moment. The odd thing about Tbilisi is that it seems to be a city that not only never sleeps but, to a degree at least, never seems to stop building itself. A case in point is why I am up at 4:00 AM. Actually, I think I’ve been up since about 3:00 AM. This is not good given that I didn’t get to sleep until about 23:00 the previous evening, so I have most certainly not yet had enough sleep tonight. Though I feel quite ready to fall back to bed, and the couch behind me is looking awfully tempting, I won’t unless I can scrounge up some earplugs in the dark of our room. The reason I need earplugs is due to an incessant tap, tap, tapping that is going on somewhere out of doors. The tapping, with its rhythm and periodic pausing almost certainly is hammering.  Hammering has been going on in various guises since we arrived here. Prior to and then all through the first weekend, for instance, there was seemingly incessant hammering and sawing. This, according to Naomi, was a consequence of installation of hardwood floors in the flat above us.

That flat takes up the upper three floors of the building. Since this is a new building, I imagine that the floors were completed for moving in sequentially, starting with the bottom. The building constitutes essentially luxury suites (Tbilisi style). Naomi’s residence here is a consequence of an interesting string of events. These started with her fiancé’s father apparently owning a home/building that was located on the site that the new building is now found on. Apparently part or all the payment to the father occurred via a promise of a flat in the new building once it was completed. Unfortunately, the father died during the construction of the building (of causes that presumably were unrelated to the construction). As a consequence the son inherited from the father the flat, not yet constructed. At some point during that period Naomi entered the picture and together they worked with the builders to complete the place according to their desires. Pretty heady stuff from two people, neither of whom is over 25 years old—she American, he Georgian.

So, getting back to why I’m sitting here typing when I ought to be sleeping. I speculate that the tap, tap, tapping is somebody who is replacing cobbles on the road. The taps have a metal on stone quality to them. Off hand I don’t recall whether any of the streets in the immediate vicinity actually are cobbled, but it nevertheless seems to me to be a good working hypothesis. Replacing cobbles at night has the upside of being a time of reduced street usage. On the other hand, the worker is less visible. In Amsterdam we were amazed that this kind of street repair took place with light-power equipment (something with a digging bucket to carry sand and bricks) and a number of people but with minimal roping off of the work site. Here the same thing is accomplished—though typically on a much smaller scale, i.e., a few cobbles replaced rather than the entire surface—through the efforts of no more than about two people. One brings the cobbles (where from, I don’t know; perhaps from other streets?) while the other fits the cobbles into place. The cobble needs to be firmly in place and hence the tapping. The truly amazing thing is that, even at night, this person merely sits in the street, without reflective clothing and no protective barriers, replacing the cobbles. I saw this on a street that wasn’t terribly busy, but nevertheless the expectation is that cars will see this all but invisible body all but lying in the street and then slow down and otherwise avoid it. And, at least with the one car I witnessed, this is exactly what happens.

In Tbilisi the obstacles one encounters while driving are numerous, both quantitatively and qualitatively, and this apparently is just one more. There are pedestrians forcing their way across the road everywhere, seemingly regardless of road width or levels of traffic. Get not too far out of town and the problem becomes one of stray dogs, sheep, cattle, and even a loan pig at one point. My pointing out that the road is blocked up ahead, e.g., as by cattle, are not relevant since obviously the cattle will be noticed and what one does in Georgia is remain highly aware of one’s surroundings and adapt as necessary. Near the Institute there are a number of potholes that everybody sees and everybody avoids, even though they’re barely visible to me and I just as likely would have driven into them at high speed. But no matter how beat up a car, there apparently is a realization that smashing into potholes can cost one money and therefore is to be avoided, regardless of how likely that avoidance results, for example, in conflict with oncoming traffic (P.S., I tried a similar maneuver in Boston, driving on the left side of the street to pass three parked cars, then whipping back to the right side to avoid an oncoming vehicle—the oncoming driver seemed to be not at all pleased by these shenanigans).

Even on the sidewalks one must remain hyper vigilant since it is not uncommon for manhole covers to become missing. I speculate that these are stolen and then sold for their scrap value (or maybe just to replace elsewhere stolen covers). The results, though, are obvious hazards to pedestrians. Some covers have been replaced with steel-reinforced concrete, which have essentially zero worth to would-be thieves, though these don’t have nearly the durability of the metal ones, and so Talia and I have tried, as much as we can, to simply avoid stepping on anything that could crumble under foot. Still, I’m not nearly as vigilant as I ought to be. It’s hard enough to stay aware of all of the cars which could be coming from any which way (from over my shoulder behind me, turning right or left as I cross a side street, is my worst fear). Add to that my taking photographs, which I still don’t do enough of, plus fear of pickpockets, or even people who might snatch my camera and/or my daughter, and, well, tourists are just plain dangerous anywhere they lurk.

My plans today, should I ever get back to sleep and then wake up again, are to put together a lecture for presentation on Thursday at the Institute. I’ve tried to think of what I do that might be of interest here, and I’ve come up with this title: “Concepts of Phage Virulence.” This has been an interest of mine for some time that comes about from a combination of numerous definitions of the word virulence, numerous ways that the many concepts can be applied to phages, a sense in the phage therapy community that virulence among phages in one sense is good whereas virulence in another sense is bad, differences in what might constitute virulence depending on how one grows the phage (and who knows what dynamics of phage growth one might encounter in the complex environments consisting of bacterial infections of animals/humans), and finally part of the confusion of the ancient phage literature (early 20^th century) was a misunderstanding of the concept of phage virulence. This is all very enjoyable. Someday I hope to write up these ideas, though to do so I need more-facile access to the early phage literature, some 10,000 papers. Thus, one of my obsessions is to obtain (and translate/have translated) that literature, converting as much as possible of it into searchable PDF documents. Fortunately, I’m not entirely alone in this obsession, and it is a great excuse for becoming familiar with languages other than English, such as Russian (fun!).

“The true ‘purpose’ of DNA is to survive, no more, no less.” p. 156, Dawkins (quoting himself), 1990.

Wednesday evening, November 17, 2004. Went to the institute by taxi to do e-mail and pick up the CD left behind on Tuesday; walked back to flat instead of taking taxi, this time with Talia in tow; tunnels under road with drainage ditches missing gratings; spent the afternoon working on my talk which is scheduled for 13:00 on Thursday. Friday we hope to head into the mountains for a two-night trip; We return Sunday and fly early the next morning.

“…’function’ means adaptive benefit to the organisms.” p. 157, Dawkins, 1999.

“The r/K distiction itself, too, seems to arouse widespread doubts among ecologists, for reasons that have never been quite clear to me, and sometimes seem unclear to them too.  It is one of those concepts that is often used, but almost always accompanied by a ritualistic apology, the intellectual equivalent of touching wood.” p. 158, Dawkins, 1999.