Читать книгу Viruses: More Friends Than Foes (Revised Edition) - Karin Moelling - Страница 31

What is a virus? First of all, the word “virus” in Latin means sap, slime, or poison.

A colleague — Eckard Wimmer from Stony Brook in the USA — studies one of the smallest human virus particles, the one that causes polio, which contains 3,326,552 carbon atoms, 492,288 hydrogen atoms, 1,131,196 oxygen atoms, 98,245 nitrogen atoms, 7501 phosphorus atoms and 2340 sulphur atoms. Because it is possible to set out this molecular-style description, he designates the virus as a chemical, at least as long as it resides outside of the cell. Inside the cell it is not really only a chemical any longer, since it replicates itself and multiplies. Such a separation into two life forms is quite unique. Are then humans also only chemicals? That cannot be the answer.

It was just 120 years ago that viruses were first transmitted experimentally, causing diseases. The filtrate of sick tobacco leaves was transferred to healthy ones, which in turn became infected. The discoverer was the Russian botanist Dmitri Ivanovsky in 1892. However, he always believed that he was looking at something related to bacteria. It was therefore the Dutch microbiologist Martinus Beijerinck who is credited with the discovery of viruses, even though he himself acknowledged Ivanovsky’s work. Beijerinck coined the word “virus” to distinguish them from the larger bacteria, which cannot pass through the filters, the so-called Cham-berland filters, where only the small viruses run through. In animals, Friedrich Loeffler and Paul Frosch discovered almost at the same time — in 1898 — a transmissible small agent causing foot-and-mouth disease in cattle. The virus infects cows and is extremely contagious, and for that reason the first research institute for studying this virus was founded on a peninsula in the Baltic Sea. However, the wind was enough to spread the virus even from there. This research institute, named after the two aforementioned pioneers the LFI, is the biggest of its kind in Europe. Its reopening a few years ago attracted so many curious people that finally nobody could get there because of the traffic jam. The sterilization chambers (autoclaves) there are big enough to disinfect cadavers of whole cows.

Until recently it was taken for granted that all viruses are small, are nanoparticles, can only be detected in the electron microscope, cannot be kept back by filters, and contain either RNA or DNA often within symmetrical protein structures such as icosahedra; they do not replicate by themselves, they are parasites, they need cells within which to replicate, they cannot perform protein synthesis and they need energy from the cell. They are mostly specialized to living in certain hosts, and are sometimes covered by a coat that can be derived from the host cell and which often also carries receptors for binding to specific host cells. They are pathogens, cause diseases, are dangerous, steal their genes from the host, betray and abuse their host cells for the benefit of their own progeny, use disguises and hide in Trojan horses. In short: Viruses are enemies.

In recent years we have found out that almost all of this is wrong. Viruses are not only small; they can be bigger than many bacteria. Viruses themselves can be hosts of viruses, can be much bigger than nanoparticles — or even much smaller; in fact, they are not always particles! They can have sizes varying by a factor of 10,000 — a very broad range — they have very different morphologies, about a dozen different types of genomes, and a variety of totally different replication strategies. The number of genes that a virus can have reaches from zero (!) to 2500 — for comparison, humans have 20,000, only ten times more. “Zero genes” are present in viroids — though these are not generally accepted to be viruses. There are viruses that consist only of nucleic acids, without proteins, or (the other way round) only proteins without nucleic acids. The latter are the prions, which are often not considered as viruses either, but I would like to include them as well. There are viruses that have only foreign genes and none of their own, such as the very exotic plant viruses, poly-DNA-viruses (or polydnaviruses PDVs), a fact that may tell us something about evolution. Then there are the endogenous viruses, which never leave their host cell, and the rudimentary viruses that jump around in our genomes. These two types of virus do not have coats and are therefore locked-in viruses, unable to move between cells.

Viruses are mobile (genetic) elements — is that perhaps a useful definition? Viruses need energy, yes, but not necessarily from a host cell. Chemical energy will do, and that can come from around the black smokers, where life may have started and where no sunshine ever reaches. Viruses need niches, compartments, clay as catalysts — Darwin’s warm little pond — so that the concentration of components can be high. Such a first kind of containment could have been lipid bags, and one can ask whether this was an early virus or an early cell. There was initially no sharp boundary between viruses and cells — rather, they together make up a continuum. Especially the newly discovered giant viruses break taboos, because they are almost bacteria; they even have a hallmark normally only assumed to exist in bacteria: components for protein synthesis. This is often used as a definition of life, the ability to synthesize proteins. Thus these “almost-bacteria” represent a transition between viruses and bacteria, between lifeless and living. The discovery of giant viruses has revolutionized our view of viruses and has shifted viruses more towards “life” than had previously been assumed. A minimalistic definition of viruses includes their inability to perform protein synthesis, which is regarded as a hallmark of life. But the giant viruses can “almost” synthesize proteins — after all!

Viruses are found wherever life is. Viruses can take up and deliver genes, can mutate, recombine, insert, delete, or mix genes. Their replication is error-prone and therefore innovative for the virus and the host. Tumor viruses can pick up genes from the cell and mutate them during replication, which can increase their oncogenicity. But the opposite is also true: they can deliver genes to the cell, supplying new features, sometimes beneficial and sometimes detrimental. They can bring oncogenes into a cell and cause cancer, or they can introduce genes to cure cancer. More genes go into cells than come out. Viruses do not cause “wars” or lead to “crossing swords” or “arms races”; these negative descriptions are inadequate. They play ping-pong with their host. Horizontal gene transfer, between microorganisms and all other living hosts have led to complicated genomes. This is how our genome became such a colorful mixture of genes from very different other organisms and other genes. Every organism has a complex number of genes taken over from many other organisms, most frequently in fact from viruses. The viruses have by far the largest repertoire of genes, the largest sequence space available on earth — most of it is not even used. Viruses have a higher variety of genes than cells have, supporting the assertion that viruses were first on the scene, earlier than cells (more about that later).

How far back do we know about viruses? Let’s go backwards. 35 years ago HIV started to invade the human population, so far causing more than 37 million deaths. 100 years ago the influenza pandemic during World War I killed perhaps up to 100 million people. Measles killed the Mayas after being imported from Europe by the conquistadores. During the Middle Ages plague bacteria killed one-third of all Europeans, about 25 million people. Some 600 years earlier, in 542, the “Plague of Justinian” devastated Rome and spread as a pandemic around the Mediterranean Sea to Constantinople, at its height killing 6000 people there each day. Thucydides described an unknown disease in Athens during the Peloponnesian War in about 400 B.C. which could have been caused by Ebola, pox, measles or other viruses, or pesti bacteria. An Egyptian Pharaoh must have suffered from polio virus 3500 years ago as can be judged from a crippled leg shown on a gravestone. Retrovirus-like elements existed in Neanderthal Man, who lived 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.