The chip that generates the revolution

How the genes work in the first minutes of the formation of a cancer cell, which genes are active in the tissues of a young person and which in the tissues of an old person - these are just some of the discoveries made possible by DNA chips, a new and fascinating tool in the study of the genome

In a laboratory in California, similar to the thousands of computer labs in Silicon Valley, a group of technicians assemble chips using the same methods as the computer chip industry. But these chips are not made of silicon layers. They are made of DNA, the material that contains all the biological information of a person. And their goal - to read the huge amount of information written in the sequence of DNA units.

According to biologists, the company's DNA chips, called Epimatrix, are now attracting more interest than any other area of ​​genome research. The company's sales increased in the last quarter by 115% compared to the corresponding quarter last year.

Recently, Epimatrix and other companies began marketing chips that can detect mutations that can cause cancer, as well as chips that can measure the activity of thousands of genes at the same time. "This is a revolution in research," said Dr. Shirley Horn-Saban, Director of the DNA Chip Unit at the Weizmann Institute of Science. Until now, there was only one way to study the immense complexity of the genome: scientists had to spend years in the laboratory learning the activity of one gene and then relate it to the activity of another gene, hoping that one day they would be able to draw a picture of the activity of all genes. With the help of the DNA chips it is possible to check the activity of thousands of genes at the same time.

The chip is a glass square, smaller than a shekel coin, packed in a black plastic cartridge. The genes are printed on the glass. The researcher extracts the RNA (the negative of the DNA that transfers the recipe for protein production written in the DNA to the area in the cell where the proteins are produced, the ribosome) from the tissue he wants to test. The RNA is injected into the chip and its segments connect precisely to their original DNA segments, which are printed on the chip. The RNA fragments are dyed with fluorescent dyes, which emit light, and a device with a laser beam reads the chip. All the points on the chip where there is a match between the DNA and the RNA will emit light, while the points where there is no match will remain dark. The higher the activity level of the gene in the cell, the more light will be emitted from the point representing it.

DNA chip technology has captured the hearts of scientists. The chips make it possible to check gene activity in the first minutes of the formation of a cancer cell and follow it until it starts to metastasize. It is possible to check which genes are active in the tissues of a young person and which in the tissues of an old person, thus getting closer to discovering the genes responsible for aging and eventually even death. Only the imagination draws the line, said Horne-Saban.

One of the focuses of research in the chips is the p53 gene, a defect in which characterizes many cancer patients. When the gene is normal, it is responsible for controlling the rate of cell division. When it is damaged, it creates a chain of molecular processes that can lead to the development of cancer. Prof. David Gavol from the Weizmann Institute and Prof. Gidi Ravavi, director of the Department of Pediatric Oncology at the Sheba Medical Center, discovered that a gene named MIC1, a defect in which can cause prostate cancer, is actually activated by p53. The analysis of the chip showed that even when p53 is inactive, it turns a long line of genes into active ones and creates a situation that can also lead to cancer.

The uniqueness of the chip, according to Ravavi, "is that you can discover entire biochemical pathways that you didn't know existed before, or that you didn't know were involved in one process or another. It is possible to get real and much more reflective pictures than those obtained in the past, when we would look at one or two gardens and try to put together theories based on them. We are only at the beginning of the road, actually dozens more things are happening in the cell. But a large part of the problems that were considered incomprehensible - today it seems that in not many years they will be understood."

The huge amounts of information generated by chip analysis pose a new challenge: how to process so much information. The chip marketed by Epimatrix about two months ago already has 35 thousand genes. The chip scan measures the activity of each of them. But many of these genes are still unknown, we don't know where they are and what they are responsible for, and of course we don't know what the connections between them are either. "We are still far from the day when we do an experiment and understand everything," explained Ravavi. "We do an experiment for two weeks and analyze the results for a year."

In this ocean of information, the researchers start working on some genes they knew beforehand. And with the help of software developed by bioinformatics - a new science that combines computers and biology - they look for new and interesting targets for research and drug development.

In a study whose results are surprising, a team of researchers, led by Dr. Ash Elizada from Stanford University, discovered that a common type of lymphoma cancer, large B-cell lymphoma, is actually two completely different types of disease. The doctors knew even before that the chemotherapy and radiation treatments help 40% of the patients to recover, but they have no effect on the tumors of the other patients; These continue to spread until the patient succumbs to the disease. But the reason for this was not known. In the tests done today in the pathology laboratories in the hospitals, the tumors look the same. But when examining the gene expression in the patients' tissues, with the help of a chip, it became clear that there is a difference in the active genes in the tumor tissue, and therefore the drugs affect them differently.

"It is not certain that we will be able to cure all types of cancer," said Ravavi. However, "to date we have treated cancer with chemotherapy and radiation, these are very crude and undirected tools. Today, the feeling is that it is possible to plan a more intelligent treatment, adapt it to the patient and develop targets for drugs that will be specific, that will focus on the right molecule."

Ravei and Prof. Moti Shohat, director of the Genetics Institute at Beilinson Hospital, are about to start testing DNA samples of a family whose many sons suffer from hereditary kidney failure. They will do this by means of a "snippet chip": a SNP (acronym for Single Nucleotide Polymorphism) is a change of one DNA letter - for example, when instead of the DNA unit marked with the letter T there appears a unit marked with the letter G. For a large part of the "Pim has no effect, but others can affect a person's degree of risk of contracting the disease or their sensitivity to medication.

According to Shohat, studies they have done have shown approximately where the branch that causes the disease is located, and with the help of the chip they hope to find its exact location. "With the chip, this test can be done within a day; With conventional methods, it would have taken several months."

Although there is still no cure for kidney failure, identifying the defect could benefit its carriers, Shohat added. "Today a family member, a 20-year-old guy whose mother is sick, contacted me and asked if I could tell him if he was pregnant. He is considering donating a kidney to his mother, and if he were to get sick it is understood that this would be a big mistake. He also wants to get married; The family is religious, and if he is not married, it can help him in a match."

In the meantime, the Apimatrix company has already created, among other things, a chip with genes from the E. coli bacterium, which causes stomach poisoning, and a chip that can detect all mutations in the p53 gene, but the researchers do not depend only on it. With the help of a device recently purchased by the Hebrew University and the Weizmann Institute, they can design the chips themselves; To prepare a chip from the DNA of any organism - from humans to plants and viruses - and place groups of the genes they are researching on it.

Dr. Orly Reiner and Dr. Aviv Kahane from the Weizmann Institute are using this method to study smooth brain syndrome, a hereditary syndrome in which the brains of those affected have no folds and they suffer from severe mental retardation. Two weeks ago, Horn-Saban printed genes that Rainer produced from the brains of mice. She placed the gardens in trays with small holes in them, a different garden in each hole. A robotic arm with pins dips into dimples and moves and prints the genes on a glass surface. A laser scanning device reads which genes are expressed. Reiner will soon begin testing the differences in the gene activity of the brains of the healthy mice and that of the patients.

Rainer points out that the complexity of the brain is enormous and more genes are active in it than in any other human tissue. It is difficult to grasp the enormous complexity of the human genome. There are hundreds of types of cells in the body and they are very different from each other. In skin cells from which hairs grow, for example, gene activity is different from that in skin cells without hairs. The overall technology needed to understand this complex system is not yet there, says Ravavi, "We still don't have all the genes on one chip, and we are talking about 70-50 thousand genes. This is a lot, but these are not unlimited numbers, and we have the tools to measure them. From a technological point of view, we solved this problem."
{Appeared in Haaretz newspaper, 21/7/2000}

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