Viruses: More Friends Than Foes (Revised Edition). Karin Moelling
between 250,000 and 30,000 years ago, after which the Neanderthals became extinct. Then there is a gap. A great surprise was the detection of an HIV-like virus in rabbits, RELIK, dating from 12 million years ago.
Other HIV-like viruses can be dated back 4.2 million years, in lemurs (relatives of monkeys) on the island of Madagascar. Nobody had anticipated that HIV-like viruses had been around for so long and can even be inherited.
A new field of science, paleovirology, has been a hot research topic at Princeton and in London throughout the last ten years. Sequences from Ebola virus 50 million years old have been discovered in the genomes of bats, pigs and monkeys, while Bornavirus sequences have been found in humans but not in horses. Only the horses get sick with Bornavirus, while humans do not. Thus, endogenous sequences and their products protect an organism against the corresponding viral diseases. These RNA viruses should not normally be integrated into DNA at all, but they are — by “illegitimate” mechanisms using some cellular-molecular tricks such as a foreign reverse transcriptase. Even our human placenta we owe to relatives of HIV, the human endogenous retrovirus, HERV-W, from about 30 million years ago. Human endogenous retroviruses, which can be found in our human genome, are estimated to date back 35 to 100 million years. Some of them are intact viruses, which can form particles, yet normally are no longer infectious. Endogenous viruses are probably much older than we can judge, because they cannot be recognized as viruses any more. A dinosaur, now in the Natural History Museum in Berlin, suffered 150 million years ago from a virus infection caused by a paramyxovirus similar to measles virus, osteodystrophia deformans, which led to bone deformations, a disease still in existence and known as Paget’s syndrome.
Back to about 200 million years ago we can witness viral footprints, but there our journey into the past ends. Virus information disappears in the genetic “background noise” due to mutations. Endogenous retroviral fossils can be detected as proof of viruses. The newly rediscovered fish Coelacanth, which was assumed to have become extinct, has been around for the last 300 million years; it is genetically surprisingly stable and it also harbors retroviral fossils.
There are tricks however, that lead to even older clues to early viruses. The giant viruses can be found in today’s amoebae, but also in macrophages, two lineages which diverged from each other 800 million years ago and developed independently, and which are therefore both thought to have been infected already before they diverged. Further evidence going farther back than 800 million years is almost unobtainable. Yet that leaves an enormous gap back to the origin of life, about 3.8 billion years ago. Viruses probably belong to the oldest biological fossils known. A real surprise are the viroids, which are virus-like structures and present till today — not only as such, but also as ribozymes or relatives of circular RNA in all our present-day human cells. They date back to the epoch when there was no genetic code — maybe 3.5 billion years ago. In a scientific publication I once tried to reconstruct the evolution of life on the basis of today’s viruses. The article’s title was “What contemporary viruses tell us about evolution” — and the editor added “A Personal View”, to be on the safe side! (Archives of Virology, 2013)
When the human genome was sequenced for the first time and published 15 years ago, the Frankfurter Allgemeine Zeitung (FAZ), printed a whole page filled with only 4 letters: A, T, G and C, the alphabet of life, without any interruption, no words, no sentences, no paragraphs. The page was awarded a prize. It indicates exactly what we know about our genes, just the letters! Almost all the rest is still waiting to be understood. The “text analysis” is ongoing. What do the letters mean? There are about 3.2 billion of them in the human genome, corresponding to 20,000 genes; however, the genes are encoded in only 2% of the whole. What is the “rest” for, the majority of the letters? Is it also genetic information, or is it the often-quoted “junk DNA”, or what? I will already let the cat out of the bag as to what the rest is: mostly information for regulating the expression of the genes themselves. To understand the details will keep scientists busy for perhaps the next 50 years. The project is known as “ENCODE”: Encyclopedia of DNA Elements.
Here are a few numbers worth remembering: Viruses such as HIV have about 10 genes, phages have 70, bacteria 3000, humans 20,000 to 22,000 and bananas have 32,000 — what, more than humans? Yes, surprisingly! Yet, bananas are not smarter than we are. This was even once called a paradox: the sizes of the genomes or the number of genes do NOT correlate with the complexity of a species. Humans do not have the greatest number of genes, but they have the longest genes and most importantly, these genes can be much better recombined (by splicing; see the next section) to increase their overall complexity, overtaking in this respect all the other known species. Finally: one gene of a virus is made up of about 1000 nucleotides.
Before we go on, every reader has to learn two words, or at least their abbreviations: RNA and DNA. One can just memorize them, together with some extra information. RNA and DNA are large molecules, the carriers of genetic information organized in regions as genes. The primary genetic information is normally encoded in DNA; only viruses can also use RNA, or even mixtures of RNA and DNA, as primary genetic information. DNA is called the molecule of life. It is known to everybody as the double helix, resembling as it does a circular staircase with two handrails (strands) connected by horizontal bars like stairs (stacked bases). This structure was discovered by James D. Watson and Francis Crick in 1953, then young, adventurous and ambitious scientists in Cambridge, UK, “never in a modest mood” — at least that is the first sentence that Watson used to describe Crick in his famous book The Double Helix. They wanted to win the Nobel prize and they did. Important information also came from Rosalind Franklin, who produced the structural data by X-ray diffraction pattern analysis, which she tried to hide. Did she really tell them that their model was wrong, that it had to be turned around, inside out? Watson himself describes the discovery in his book, a bestseller. A new theatre play deals with Franklin’s picture, Photograph 51, a detective story by the American playwright Anna Ziegler on how Franklin’s X-ray picture contributed to the discovery without her ever knowing about her important contribution. She died of cancer as a consequence of her experiments with X-rays, sadly so, as she was still young. Less often mentioned is Franklin’s head of department, whom she did not accept as such, and who shared the Nobel prize: Maurice Wilkins. He received the starting material, lots of pure DNA, from a Swiss colleague who handed it out generously. Wilkins used it as an essential source for crystallization. Later, he came under the political spotlight for possible involvement in communism, and is less widely recognized.
DNA is double-stranded, whereas RNA is single-stranded, more flexible, rope-like; it undergoes variations more easily and is very important for new sequence discoveries by viruses. Crick formulated the “central dogma of molecular biology”: from “DNA to RNA to protein” describing the flow of genetic information inside the cell. Some people say that Crick was not dogmatic in his thinking but anyway his name has become attached to the dogma. DNA dominated the thinking of molecular biologists for half a century, but now RNA is catching up in importance. RNA came earlier in evolution, before DNA, so the reverse of the dogma is also true: RNA can turn into DNA. This is what we have learnt from the viruses. So, dear reader: more molecular biology is — almost — not needed. Many details can be skipped and some more details are listed in the Glossary.
A sailor and splicing
While I went on a sailing trip across the Baltic Sea on the three-masted schooner Lily Marleen, a sailor surprised me one morning with a present: a “spliced” rope. He had connected two ropes by “splicing” them together as a demonstration-piece for the students in my virology lectures. Splicing requires some skill, he said, and it kept him entertained during the boring night watches. A book entitled Splices and Knots teaches the art of these as used in sailing. A book with the same title could also be important in molecular biology. A splice is in a sense the opposite of a knot. Only when a rope is spliced can a sailor pass the connected pieces, quickly and without any hindrance, through the pulleys to pull up the sail; a knot would provide an obstacle to this. The same principle holds true in the molecular world. Double-stranded DNA is transcribed into single-stranded RNA, a flexible copy of the stiff DNA. The RNA — like a rope — can then be shortened