Prof. Sidney Brenner, who received the "Dan David" award yesterday at Tel Aviv University, is not impressed by the scientists' promises that "genes will solve all problems and diseases." But his achievements as one of the fathers of human genome research are unique, and the study of cell development he carried out in a worm has not yet been replicated in any other organism
Photo: Ariel Shalit: Prof. Brenner. "If the human genome is the 'book of humanity', then the pufferfish is a 'concise reading'"
When Prof. Sidney Brenner, one of the leading molecular biologists of the last half century and who developed several essential methods used in the human genome project, was asked this week about the decoded genome that was published with great ceremony, he said: "This genome is in a complete mess. People say now we have the foundation. Well, we're not even close to the base. I have worked a lot with the human genome, much of it is still not properly assembled.
The only chromosomes that we have actually finished deciphering are chromosomes 21 and 22, and they are the two smallest chromosomes."
Yesterday, Brenner was among the recipients of the "Dan David" award at Tel Aviv University, for "breakthroughs that hold great promise for the future" (he received 900 dollars with two other researchers, an amount similar to that received by Nobel Prize winners). But Brenner is actually a skeptic. "All the promises that the genes will solve all the problems and diseases", he says, "it is still not clear that any of this will happen. But scientists are like politicians, they have to make promises."
Brenner played a leading role in the "golden age" of molecular biology, in the fifties and sixties, when the mysteries of the genetic code and the production of proteins were revealed. The man, who was one of the fathers of modern molecular biology, is also one of the designers of the current "post-genomic era", the era after the announcement of the decoding of the genome, in which machines are used to quickly decode the entire genome of various creatures, from bacteria to humans.
His scientific quest is intertwined with innovative ideas, some successful, some less so. Another talent of Brenner is his ability to captivate and infect his listeners with his enthusiasm. At the age of 75, he has not yet retired from his scientific pursuits and is still engaged in research. Recently, he began working with a biotechnology company from California on new methods for detecting cancer based on small changes in the DNA structure.
At the same time, he is also trying to understand how we and the approximately 100 trillion cells that make up our body develop from a single cell, a fertilized egg. He also wants to extract from the genome clues about the distant past. During evolution, different creatures left their mark on the genome, which later evolved into other creatures. "There are many fossils buried in the genome, there are fossils of dinosaurs, of mice, of all kinds of animals", he says, "the clues are there, we just have to think of the best way to get them out".
Brenner was born in 1927 in a small town near Johannesburg, South Africa, far from the world's leading research centers. His parents immigrated there from Latvia and Lithuania. His brother, a geochemist, lives in Jerusalem.
He expresses himself in well-formulated sentences, which often end with a joke, and with a unique accent, a result of his youth in South Africa and his many years of work in England.
In the dry scientific world this is in itself an admirable quality. Nobel laureate Francis Crick, who together with James Watson discovered the double helix structure of DNA in the XNUMXs, once said of Brenner: "Sidney is unique, both in his characteristic sense of humor, which is evident in many of his insights, and in the importance of his discoveries . There is simply no one else like him."
The journey of deciphering the complete genome of an organism - all the genetic instructions found in each cell - began with a series of studies by Brenner on a small round worm, known as C. elegans. Today, the worm is studied in laboratories all over the world as a "model organism" - a creature simpler than man, whose investigation yields insights into the whole biology of life.
In December 1998, the genome of C. elegans was published, and thus the worm became the first multicellular organism whose entire genome was deciphered. C. elegans has turned out to be surprisingly relevant to humans, helping to decipher the human genome.
Interpreting the human genome is the task that researchers are now focusing on, and it will continue for many decades to come. The goal is to understand what each of the genes is, and what are the interactions between them. "People are terribly enthusiastic and like to compare the human genome project to landing on the moon," says Brenner. "It's exactly the same. Putting a man on the moon is the easy part, the question is how to bring him back."
Brenner first studied medicine at university, but biology was his true passion. However, South Africa at that time was a place cut off from global scientific activity. In 1952 he moved to Oxford. A year later, during a visit to Cambridge, he met Watson and Crick, who discovered the structure of DNA.
In his book "The Eighth Day of Creation", the biologist Horace Judson writes that "Crick liked his (Brenner's) sharpness and in 1956 brought him back to England, to a job in the Cambridge laboratory of the British Medical Research Council", from which Brenner retired about two years ago. Together with Crick, Judson continues, he proved that all three units of DNA dictate a type of amino acid - the building block of proteins.
In 1960, together with others, he proved the existence of "messenger RNA", the transcript that carries the genetic message from DNA to the cell's protein production site. Biological development and understanding the brain were the two burning questions that Brenner studied during his years of work as a researcher at Cambridge. In 1964, he decided to investigate them by investigating the sea-langus worm. Scientists then worked, for decades, on another model organism, the fruit fly. "But the fly is too complex," says Brenner, "for my purposes I needed something much simpler; An organism with such a simple nervous system, that I can calculate its behavior by knowing the connections between the nerve cells."
This idea was actually among Brenner's least successful ideas. After 14 years, he and his colleagues did construct a diagram of the worm's brain, but the 5,000 connections turned out to be too complex a system for making further analyzes and predictions.
However, the work on the worm bore other fruits. Together with two of his students, Prof. John Selston, who won the "Dan David" award with him, and Dr. Robert Horvitz, they drew a map depicting the lineages of each of the 959 worm cells - the path of their formation from the fertilized egg to their transformation to a mature cell. This pioneering achievement has not yet been achieved with any other organism. Selston began to decode the worm's genome, and this experimental project gave scientists confidence that they could reproduce with a larger organism, even one like man.
"At a certain point I got tired of being called 'the father of the worm' everywhere," says Brenner, "and I turned to general problems in genome research." One of the questions that preoccupies him now is what kind of device the cell is. "There are two types of machines," he says.
"One, like computers, can calculate an answer to a problem; The other is a set of tables, with all the answers written in them. What type does the cell belong to? Cells are spreadsheet machines, not software. So who does the calculation work for the answers in the tables? Evolution calculates them. She finds the answer and stores it in our genes. I imagine the genome as a library where books with important data created through the process of evolution were stored; It is an inelegant process, but it works."
Brenner's ideas are not always immediately received with enthusiasm. This, for example, happened to his initiative to decipher the genome of the puffer fish. This fish has almost no "junk DNA", which makes up about 98% of our genome. Junk DNA is DNA that is found between the genes, without a clear purpose, and makes it difficult for researchers to locate the genes responsible for the functions they seek to study. Brenner believes that deciphering the fish's genome will make it possible to find all its genes more quickly, and use them as a comparative basis for the human genome. "If the human genome was said to be the 'book of humanity,' then the fish genome is a 'concise reader,'" says Brenner. But according to him, "For years it was almost a private project of mine. It never gained the status of an 'official genome'." The leaders of the American genome project joined only recently, with a modest budget, and the bulk of the decoding work, some of which has already been published, is funded by the Singaporean government.
The human genome project, says Brenner, began as an international public initiative. "Over time, the initiative turned into a project, and as with any project, a factory was needed. So we built factories for genome decoding" - halls full of machines that worked day and night on decoding the DNA sequences. "And then they were dragged into a competition against the American company 'Celera' (which at the same time was engaged in decoding the genome, XNUMX). At the beginning there were many participants in the project, Japanese, Europeans, Americans. But the pace had to be accelerated, and so they stopped giving funding to the small groups. In the end, only three American and one British laboratories remained in the project." However, the genome project is still presented as an international project.
In 2000, in a ceremony at the White House with the participation of President Bill Clinton, Dr. Francis Kolnis, head of the Genome Project in the USA, and Dr. Craig Venter, president of Celera at the time, the two competing groups announced a tie, and the "completion of deciphering a draft genome the person". At the press conference, which was broadcast all over the world, President Clinton said: "Today we know the language that God used to create man." "I heard him say that," says Brenner, "and I thought to myself: What a stupid sentence. What do we need the genome for? Already today we have the Bible, the language that man used to create God."
