A Most Personal Note

by Elio

Wonderful, wonderful Copenhagen
Friendly old girl of a town
                   Wonderful Copenhagen, lyrics by Frank Loesser

At the June General Meeting of the ASM in Boston, there was a session called From Bacterial Physiology to Cellular Genetics: Reflections on the 50th Anniversary of Schaechter, Maaløe, and Kjeldgaard. The participants were Fred Neidhardt, Stephen Cooper, Amy Vollmer, and myself.

Fifty years ago, it so happens, I was wrapping up my postdoc in the lab of Ole Maaløe (pronounced something like Moh-lö — "umlaut" on the o) in Copenhagen. It was also at that time that our two papers on growth physiology of Salmonella enterica var. Typhimurium appeared. (For PubMed citations to these papers, click here and here.) So, what is all this current fuss about? Our work and that of others led to the realization that when organisms grow in various media, their size and gross content of cell constituents (proteins, DNA, RNA, lipids, etc.) is directly proportional to their growth rate. The faster they grow, the more of these constituents they have. This holds true as long as the cultures are growing exponentially and thus are at a steady state. Two media differing in composition but supporting the same growth rate give the same measurements. We concluded that a bacterium can exist in any one of a number of physiological states depending on its rate of growth. As an illustration, cells of the same species observed under slow versus fast growing conditions can vary in volume by a factor of 10 or more!

This work helped clear up what had been a rather confusing state of affairs regarding bacterial growth. The classical, more-or-less S-shaped growth curve could now be interpreted as an exponential phase bracketed by two transitions, first from slow to fast growth and then from fast to slow growth (a shift up and a shift down). Details and further interpretations will soon be available in a review by Cooper recently accepted for publication in BioEssays.

What came of this?

At 0 time, a culture of Salmonella was "shifted-up"
from glucose-minimal medium to nutrient broth. The
graph shows the log of the measurements vs. time.
Note the abrupt change to a new rate of increase
for both total RNA and optical density of the culture
(a measure of cell mass), followed shortly by total
DNA. This is also reflected in the increase in the
number of nucleoids per cell (insert). Meanwhile,
the cell count continued at the old rate for ~70
minutes, which allowed the cells to increase to the
size characteristic of the new medium.

In time, many more people showed up at Maaløe's doorstep and contributed to the "Copenhagen School of Bacterial Growth Physiology." One of the interesting conclusions derived from this work was that when bacteria are growing in a steady state, their rates of chain elongation of proteins, RNA, and DNA are roughly the same even when growing at different rates. This implied that the relevant biosynthetic machinery works at top efficiency regardless of the growth rate of the culture. It follows that in order for a bacterium to grow faster and make proteins faster, it must make more ribosomes, which is something we later showed experimentally. If you want to find out more about this way of looking at cell physiology, read a singularly eloquent essay by Fred Neidhardt.

Now, why have these papers survived all this time? After all, the norm is that older papers are superseded by more recent ones and soon forgotten (much to the surviving authors’ chagrin). So, why not these? My best answer is that, the success of the Copenhagen School notwithstanding, for a long time there was not much interest in what a whole cell does. Greater attention was paid to molecular mechanisms of gene expression, a reductionist view that only tangentially touches on cell growth. In Boston, I told the story that I had visited Francis Crick (of Watson-Crick fame) at the time and told him of our results. He said, "Congratulations, you started a new field. But it’s over!” In his view, the topic went from inception to oblivion in one quick step.

But why is this story being revived now, showing perhaps that Crick had been wrong? (Let me interject that several people who have "rediscovered" our work have been surprised that I'm still alive.) This work has become part of the infrastructure of Systems Biology (aka Growth Physiology), a point I wrote about elsewhere. To study the cell as a system, it pretty much has to be growing. And our old work helped provide the basic parameters of cell growth. In the words of Terry Hwa, a physicist who has turned to such questions:

The microbial growth laws on the growth rate dependence of macromolecular compositions discovered by Schaechter et al. 50 years ago are among the most robust quantitative characteristics of microbiology. At the dawn of the era of systems biology, there is a renewed interest in these growth laws as concrete bridges linking molecular biology to physiology.

An aside. In my talk in Boston, I tossed out the offhand statement that my work in Copenhagen must have been influenced by the nature of the surroundings. Then, as now, that city had a magical fairy tale ambiance, as if designed with Hans Christian Andersen in mind. Witness the photo included of the whimsical church spire that I could see from the lab window. Now I have no proof of this, and welcome comments about this conjecture, but my enchantment for that city must have affected my thoughts, as it did my feelings. At any rate, our lifestyle was Danish. We commuted and traveled to the countryside by bicycle, delighted in Danish pastry (the real stuff), open-faced sandwiches, and beer, and then returned to the US with a houseful of lovely modern furniture plus an appreciation for the social conscience of the Scandinavians.

Back to the Boston meeting. Surprising to me was that the large room where the session was held was over half full. Apparently these people had an interest in historical aspects of microbiology. Either that or they had nothing better to do.

Thanks for staying with me.

Postscript

Many thanks for the kind comments sent in response to this post. Those who know me personally may agree that I tend to look forward rather than to dwell much in the past. So, it was an unexpected surprise to me that the event at the ASM General Meeting in Boston (the basis for this post), turned out to be so well received. I was dubious that anyone would be interested in the old stuff and quite amazed at the large audience (many of whom seem to have stayed for the whole session). For reasons I already explained, not many people have such a chance to share old work with scientists of today, at least without seemingly being a cause of immense boredom. I am truly grateful for this.

Hard at work, around 1957

Copenhagen’s Tivoli Gardens at night

Our Savior’s Church, across
from the lab

Ole Maaløe and Niels Ole Kjeldgaard in front of the lab building

Comments

[Bob Murray]

It must have been fun to discuss the glorious time spent in Ole Maaloe's lab and relive the excitements. There is no doubt, you are right and I know it. The Copenhagen environment was an important part of the stimulus and the productivity. To be able to look out the lab window at the tower of Vor Frelser's Kirk while cogitating takes some beating for pleasures. I climbed up that spiral several times alone and with visitors. The first time I got to the turn to the very last step and there was a small boy hugging his knees grinning like a gnome. My mind fills with images. You are certainly justified in placing the environment and the creative atmosphere of such marvelous colleagues. I enjoyed Ole also, for his many qualities.

[Cesar Sanchez]

(This follows Elio's answer to my previous comment: see http://tinyurl.com/6x4oq6 )

Elio, you're probably right: the limiting factor for not consulting older literature may be just the unwillingness to spend time on the "old stuff." However, there are some moments when it should be a must: when devising or starting a new project, or when writing a comprehensive review, or when you need some fresh ideas (paradoxically!).

Anyway you have my vote for a 25 hour day!

[michael goldberg]

elio,

while not officially representing ASM I can report how pleased those I talked were about you presenting in Boston at the General Meeting. This was the first time the General Meeting was held there and it was a wonderful opportunity for some of the more than 7700 scientists attending to listen to a personal perspecitve on an important experiment

[John D. Trawick]

Wow! It is great that they celebrated your postdoctoral work, Elio. Believe it or not, I think about that figure of the Salmonella growth shift often because it really is critical to what we do in so-called systems biology. By the way, when I took Bacterial Physiology in the '70s (as taught by Palmer Rogers at U of MN), we discussed your papers.
Congrats, and nice photos.

[stan zahler]

My God, Elio! Are you THAT old Schaechter?

-- stan zahler

[Cesar Sanchez]

"(...) older papers are superseded by more recent ones and soon forgotten"

That's sooo bad. Hopefully, most editorials will soon convert all their old paper content into digital format, so that the full text of older articles becomes searchable (and, ideally, freely available). How much work might have been unnecessarily duplicated because of not been aware of previous literature? Or, how many new ideas might have been spurred if one had the chance to read some apparently unrelated, old paper? If all "the shoulders of giants" (and of dwarfs) were fully searchable and available on the internet...

Thanks for sharing some personal memories, Elio. Keep them coming!

Cesar,

I want to say something in a slightly optimistic tone. Today's searches in Google or PubMed are easy and effective. True, not all the older material is available, but a surprising amount is, including books. There should be more, of course, but the limiting factor may be the willingness to spend time on the "old stuff." I was not that eager to do it when I was young, hence would not be surprised if this is even more true nowadays. What we need is a 25 hour day!

Elio

[Autumn Cochrane]

Wow! So you were one of the first to get into Systems Biology! I personally find it astounding that people are trying to study cells as an integrated system - studying one single process can be so complex!! I am in awe.

[Mark O. Martin]

Dear Elio: I'm sorry that I missed your talk at ASM, but appreciate the update (and photographs). I think that the history of microbiology sheds not simply light on the past, but helps guide microbiology toward a quite remarkable future. The things we take for granted today! Someday, I would like to teach a course on the history of microbiology, but I don't know enough critical theory and deconstructionism to get it past the curriculum committee, I suspect. Anyway, thanks for sharing your remembrances and insights.