Small Things Considered

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.