Small Things Considered

Whose Planet Is It Anyway?

by Elio

This is the title my friend Fred Neidhardt recently used for a talk, and a good question it is. I suppose that most microbiologists and the readers of this blog would split the answer down the middle, the biomass of this planet and the chemical transactions therein being about half microbial, half everything else. However, it’s safe to say that most people, many scientists included, are unaware of the colossal importance of the microbial half, not only in biology and medicine but in geology, meteorology, and in our Earth’s habitability. This state of affairs should not be unexpected, given that we have only became aware of much of this during the last few decades. I lived roughly the first half of my life carrying only a vague notion of the global importance of the microbial world. But now we know, and the word needs to go out. A measure of microbial literacy is required for anyone to understand the workings of our living planet.

(Top) Upper atmospheric oxygen concentration, as a percent of current levels, plotted against geological time. (bottom) Phylogenetic history of life on Earth, scaled to match the oxygen timeline. Note that the origin of the eukaryotes and the subsequent diversification of animals both correspond to periods of increasing atmospheric oxygen. Source.

Through the years, many influential writers have endeavored to convey the global influence of microbes to scientists and non-scientists alike. We can now add to these efforts a new contribution that speaks to scientists of all spheres, but especially to other biologists. It was recently published as a Perspective in PNAS, a most appropriate venue. Entitled Animals in a bacterial world, a new imperative for the life sciences, it is authored by 26 scientists whose names are bracketed by those of Margaret McFall-Ngai and Jennifer Wernergreen. It deals specifically with the role of microbes in the lives of animals. While interactions with plants and the inanimate environment are not included, this seems a fitting focus given the anthropocentric interest of most readers. The other stories are for another day, to include the viruses, the most numerous of all players and which interact with all other living things.

Feynman Said “Just Look At The Thing!”

by Jan Spitzer

On October 28, 2010, Elio posted this Talmudic Question: “Richard Feynman, the famous physicist, said: It is very easy to answer many of these fundamental biological questions; you just look at the thing! To take him up on it, imagine a microscope that lets you observe single molecules in a living cell at one Angström resolution. What's the first thing you would do with it?” Thank you, Elio for allowing me to provide some thoughts on the matter from the perspective of a physical chemist/chemical engineer.

Such a microscope could indeed help address some of the fundamental issues in biology today. I must say upfront that I am surprised that microbiologists would want to look at (small) molecules (‘pure’ chemistry), or at the chemical details of ‘bigger things’, as suggested by the very notion of using a ‘Schaechter-Feynman supermicroscope’. This hypothetical instrument would have a resolution of 0.1nm with exposure times in the picosecond range (making it a bit akin to an infrared spectrophotometer) and would operate in Feynman’s quantum mechanical world. It would look at the chemistry of biology, dissecting cells into their molecular components that are then chemically characterized individually. But let me explain this more…

What Should We Look At?

Feynman suggested that ‘seeing better’ is ‘better.’ However, what we see often depends on what we are looking for. At such very high resolutions, we risk focusing on details so small that we lose context and perspective, like looking at the leaves of individual trees and losing sight of the surrounding forest. We will also miss the lakes, the meadows, and even the blazing sunset—the reddish light scattering forward from the nucleating particles of the nano-fog, the beauty of which, Feynman insists, a mere poet may miss (1). Similarly, a narrowly-focused molecular researcher overlooks the relationship of the detail to the living whole (2,3). I would suggest observing at a slightly larger scale, say dimensions of 10 to 100 nm and durations of a millisecond, to see the ‘metabolons’, ‘modules’, ‘hyperstructures’, and the many functional protein complexes (signalsomes, stressosomes, transcriptomes, dividisomes, etc.) to find out if and how they exist as discrete physical objects. We might then see these large, transient biomacromolecular clusters appear and disappear, and see them interact at the subcellular level. We could take full advantage of the atomic resolution of this supermicroscope to visualize ionic currents of ATP, GTP, phosphates, K and Mg ions, bicarbonate, glutamate etc., tracking them from their origins to where they sink and disappear. Even the vectorial ionic currents generated in the cell envelope with their movements through and around the large ‘omic’ biomacromolecular clusters could be visualized as the cell grows. What would we see when a bacterial cell begins to die? Will the ionic currents ‘die’? (4-6). So many events to explore with our supermicroscope!

Why Medical Microbiology Is Not Like Stamp Collecting

by Elio

Wonder, at the 2010 Edinburgh International Science Festival. Image credit: Edinburgh Festival Guide. Source.

I started teaching microbiology to medical students in 1958, at a time when biomedical science was in its full ascendancy. Grant money was there practically for the asking, jobs were plentiful, universities and their medical schools were frenetically building up their science base. Not entirely surprising, the general feeling of young Ph.D.’s such as myself in basic sciences departments was that we were doing the medical students a favor by stooping to teach them. Maybe I exaggerate, but not by much. We had a long ways to go.

The View From Hereby JohnCoffin

Searching For Achilles’ Heel

Why is it so hard to make an HIV vaccine? The answer lies in the unusual relationship of this particular virus with its host.

By and large, viruses of humans and other animals interact with their hosts in one of two ways. After an initial period of rapid (often symptomatic) infection, some viruses (e.g., influenza) are cleared completely by the immune system. Others (e.g., many herpes viruses) establish a lifelong latent infection, only to reappear much later when conditions allow. In either case, the immune system effectively clears the virus from the host. Once established, the adaptive humoral response can prevent future infection with antigenically similar viruses. This is what makes vaccines work.

Achilles Wounded in the Heel
by Paris. Sculpture by Charles
Alphonse Gumery, 1850. Gumery
shows Achilles as nonchalantly
inspecting his wound, even
though it will eventually kill him.
Source.

Relatively recently, we learned that some retroviruses, including HIV and its dozens of primate lentivirus relatives, have evolved to infect hosts other than their original ones. In the original hosts, the primary infection is usually fairly mild, but the virus is only partially cleared by the immune system. Later, virus replication and cell killing continue at the same pace for the life of the host, although at a lower level. Usually, this process has little or no effect on the host’s lifespan, allowing the opportunity for transmission to naïve animals. When the virus jumps to a new host (such as the recent transfer of HIV-1 from chimpanzees to humans and of SIVmac from monkeys called sooty mangabeys to rhesus macaques), the process of infection is essentially the same, but eventually something goes awry. Infection leads to the slow, progressive loss of the target CD4+ (helper) T cells, and thence the nearly inevitable immune collapse and death of the host.

Clearly, the benign relationship of primate retroviruses with their primary hosts is the product of a very long period of coevolution. In the process, the virus has evolved two features to avoid the immune response and therefore to make an effective vaccine highly elusive to produce. Both arms of the immune response, humoral (antibodies) and cellular are so affected.

The View From Hereby RichardLosick

Back to the Wild!

My dear friend Linc Sonenshein introduced me to Bacillus subtilis forty years ago when he was a graduate student with Salvador Luria. The remarkable capacity of B. subtilis to transform itself into a spore has been the focus of my research ever since. Before too long, Sonenshein and I focused on 168 and related strains, the E. coli K12 of the B. subtilis world. We did so for the reason that, thanks to the pioneering work of John Spizizen (with some magic from Charley Yanofsky and Norm Giles sprinkled in), strain 168 exhibited the remarkable capacity to take up DNA from its environment and recombine the DNA into its chromosome. This discovery of genetic competence opened the way to traditional and, eventually molecular, genetics in B. subtilis and made the bacterium a premier model organism. At the same time, and what I did not realize until many years later, we also paid a price for using a strain that had been passaged many times in the laboratory.

The View From Hereby JulianDavies

The "Parvome"

This is in response to Mark Martin’s prompt*; he is an interesting and eclectic character. Well, I was not inclined to write anything, but since this week has been spent on grant writing (for not very much money, this being the style in Canada) and today, being a sunny day, I decided to cut the grass but the handle kept on coming detached from the push mower which put me in a good mood for a rant (not a blog); I am also upset about the fact that Roger Federer lost again and I don't like to see bad things happen to my heroes. But to come back to Mark’s prompt, why do microbes make so many small molecules?

The View From Hereby CharlesYanofsky

We have invited a number of distinguished microbiologists to share some of their thoughts with us.

The Evolution of the Genetic Code

Although the genetic code is well established, a very exciting unsolved problem is discovering how codons were related to amino acids in the evolution of protein synthesis. How did a tRNA and a tRNA synthetase first evolve, and what was their ancestral source? How were the genes for the first tRNA and tRNA synthetase duplicated and how was their specificity varied? Can we offer any explanation for why there are two classes of tRNA synthetases? Can one predict which tRNAs evolved from one another? Similarly, can we predict which tRNA synthetases evolved from an existing tRNA synthetase?

A related series of exciting experiments would be to attempt to reproduce some evolutionary events and determine how many mutational changes it would take─and where─to evolve a tRNA synthetase with new specificity from an existing synthetase. Suppression studies many years ago showed that tRNAs may acquire new decoding specificity following single mutational changes, but synthetase suppressors were not recovered, as I recall. Also, we now know that synthetases recognize both the anticodon and acceptor end sequence of each tRNA─is this consistent with what is known about suppressing tRNAs?

Reference: Carter, C. W., Jr. 2008. Whence the genetic code?: Thawing the 'Frozen Accident'. Heredity 100: 339–340.

Yanofsky is Professor Emeritus of Biological Sciences at Stanford University and a 2003 recipient of the National Medal of Science.