British researchers have revealed the first clues to the high failure rate of cloning and gene therapy - the concentration of genes at the core of the nucleus.

The discovery, announced at the annual meeting of the British Association for the Advancement of Science in Glasgow, shows that DNA has an internal structure that scientists were previously unaware existed. It also provides clues to how active genes and ‘junk DNA’ might work together.

“Our genes are not uniformly distributed,” said Dr Wendy Bickmore, head of the research team based at the Medical Research Council Human Genome Unit in Edinburgh.

“They are clustered together, and they are clustered on the chromosomes that are sequestrated in the central portion of the nucleus. We have a very active compartment in the centre of the cell nucleus, and a much more silent, passive compartment around the edges.”

The team’s findings suggest that geneticists working on technologies such as cloning and gene therapy need to much more keenly target the genes at the core of the nucleus.

Dolly the sheep may have been a success, but she was preceded by 277 stillborn, miscarried or dead sheep - a failure rate that has remained relatively steady since she was born in 1997.

Gene therapy - inserting ‘good’ genes to replace defective ones - has also been dogged by a high failure rate.

“It may not be sufficient to stuff genes into the nucleus and hope for the best,” said Dr Bickmore. “We may need to think about targeting them to specific environments within the nucleus. We need to think of the genome not just as a linear DNA sequence but as a three-dimensional structure.”

The results may also have applications in the understanding of diseases. There are a growing number of human diseases that may be caused not just by genes, but where they appear on the genome.

“We call these ‘position effects’, which means we really don’t yet understand them,” Dr Bickmore said.

She gave the example of anirida, a hereditary condition in which individuals are born without an iris. Geneticists know it is caused by mutations within the PAX6 gene, and while there is nothing wrong with the gene itself, as soon as it is broken and rejoined or inverted - as soon as its spatial condition changes in the nucleus - the condition arises.

“For the first time, [this] enables us allows us to think about how human genetic diseases can result not just by mutating gene sequences, but also by placing genes in the incorrect environment,” she said.

It might also suggest why so much of the human genome is ‘junk DNA’. DNA is made up of four bases that code for hereditary characteristics, known as genes. Humans have some three billion bases, but one of the surprises of the Human Genome Project is that humans were found to have between 30,000 and 50,000 genes. Scientists had expected closer to 100,000.

Some scientists have suggested that introns, or the remaining non-coding DNA, are not junk at all. In yeast and fruit flies, scientists have observed genes being shut down by being shuffled from the centre of the nucleus to the periphery.

Dr Bickmore said that genes might use the core of the nucleus as the ‘active’ region, consigning to the outer edges those genes that are rarely used.

“You might ‘turn off’ a gene by taking from the centre to the edge,” she said.

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Scientists have pinpointed the Methuselah gene - a stretch of DNA that confers healthy old age on men and women - raising the prospect that researchers may one day be able to create drugs that extend human life.’There is no reason why we cannot do this,’ said Kari Stefansson, chief executive of DeCode Genetics, an Icelandic biotechnology company. ‘We know the location of this gene. Soon we will study its exact DNA sequence and work out how it works in the body. You can then think of making drugs that could replicate its action.’

The discovery was made by DeCode researchers who used Iceland’s unique birth and death records, which stretch back to Viking times, to trace individuals, many of them still living, who had lived exceptionally long lives - to ages over 90 or more.

‘We wondered if these people were related,’ said Stefansson. ‘Fortunately that is easy to find out in Iceland. We are obsessed with genealogical records. So we compared a group of about 1,200 long-lived people with a similar group who had lived to an average age - and found that, yes, the former were far more closely related to each other than the control group.

‘Of course, their longevity could have been produced by them sharing a common environment, but that seemed unlikely given that Icelanders all have similar lifestyles.’

So DeCode researchers began to study Icelanders’ blood for genetic markers that might help pinpoint factors that predisposed some of them to live to their nineties and beyond. This proved relatively simple: the company already had a bank of blood samples from 60,000 islanders, which it had used to identify genes that predispose people to schizophrenia, asthma, strokes and osteoporosis.

‘Our tight heritage and records are ideal for this sort of work,’ says Stefansson. ‘We have the same genes as everyone else on the planet, but because we have a small, tight population of only 270,000, it is much easier to pinpoint those of us that carry genes that have interesting functions.’

A genetic disposition to long life could work in two ways, the researchers calculated. It was possible the Methuselah group simply came from families that did not inherit genes that predisposed them to illnesses. Alternatively, group members were inheriting a single gene that protected them against the rigours of middle and old age.

‘We simply did not know, until we studied our mark ers, and to our surprise found that old age behaved as if it was being conferred by a simple, single gene,’ said Stefansson. ‘Somehow this gene is making a protein in the body that is helping people live to ripe old ages.’

But the gene will not make you immortal, Stefansson stressed. If you also inherit other bad genes that make people ill in young adulthood, you won’t reach an age when the Methuselah gene will add years to your life.

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Dr. Phillip A. Sharp and Dr. Richard J. Roberts were awarded the Nobel Prize in Physiology or Medicine by the Karolinska Institute in Stockholm for their independent discovery in 1977 of “split genes.”

That discovery proved that genes can be composed of several separate segments. It shattered scientific dogma that had held that genes were continuous segments within DNA, the chemical basis of heredity. In making their discovery, the scientists worked in the laboratory with adenoviruses, which can cause colds and conjunctivitis, or pink eye.

Dr. Roberts did his award-winning work at the Cold Spring Harbor Laboratory on Long Island. Dr. Sharp also worked there before moving to M.I.T. in Cambridge, Mass.

“Everybody thought that all the interesting stuff had been discovered,” Dr. Roberts recalled yesterday. “In fact, there were several very prominent scientists who went on the public record saying that the age of molecular biology was dead and there were no more interesting discoveries to make.”

The discovery of split genes has been of fundamental importance for today’s basic research in biology, as well as for more medically oriented research concerning the development of cancer and other diseases.

The discovery has changed our view on how genes in higher organisms develop during evolution as split genes were frequent in higher forms of life, including humans.

The discovery also led to the prediction of a new genetic process known as splicing which led to the recognition of what are known as introns and exons, two different sequences in genes.

The discovery has given scientists a better understanding of how some hereditary diseases and cancers develop while other researchers have used the discovery to better elucidate a genetic form of anemia and one type of leukemia in which splicing errors occur.

The discovery of split genes “does not give us cures, but the possibility to know how we are going to do therapy with genes in the future,” Gosta Gahrton, a professor of medicine at the Karolinska Institute, told reporters in Stockholm.

Scientific understanding of genetics has constantly been changing, ever since Gregor Mendel grew sweet peas in a monastery garden and discovered factors responsible for dominant and recessive patterns of inheritance. Wilhelm Johannsen , a Danish biologist, called the factors genes.

For much of this century genes were defined as discrete elements arranged in linear order in chromosomes. The concept was based on studies of simple organisms, particularly bacteria and viruses that infect bacteria. Scientists assumed the concept also applied to higher forms of life.

But the concept was radically revised in 1977 as a result of the studies that Dr. Roberts and Dr. Sharp carried out on the genes of the adenovirus, which causes respiratory infections.

Although the genome of the adenovirus has many properties resembling human cells, its simple structure made it useful for studying the function of genes in higher organisms.

Dr. Roberts and Dr. Sharp sought to determine where different genes were situated in the adenovirus, and in biochemical experiments they found that one end of a messenger RNA in the virus did not behave as expected. By using the electron microscope, they then found that genes could be discontinuous, each present in several, well-separated DNA segments. Other researchers then found that such splitting was the most common gene structure in higher organisms.

“Everybody thought that genes were laid out in exactly the same way, and so it came as a tremendous surprise” that they were different in higher organisms, such as humans, Dr. Roberts said.

Dr. Walter Gilbert of Harvard University, a co-founder of Biogen, named the segments exons and introns. Exons are the vital biochemical sequences that contain the information to create a protein. Interrupting the exons are introns: long, rambling biochemical stutters that do not contribute to the construction of a protein. For that reason, they are often called “junk” DNA.

The average gene is composed of about 15 to 20 exons, broken up by lengthy introns. During the multistep synthesis of a protein, intron sequences are deftly clipped out and the exons are then stitched together into a continuous string of instructions that tell the cell how to propagate a complete protein. Possible Role in Evolution

Scientists suspect that the introns lying between the protein-making instructions, while serving no purpose in the current life of a cell, have been vital to the evolution of organisms. They suspect that the introns have allowed the exons to be easily shuffled around over time to generate an almost infinite variety of molecules.

Some of the estimated 5,000 hereditary diseases were a result of errors in the splicing process. The most studied of such diseases is beta-thalassemia, a form of anemia that is common in some Mediterranean countries. The disease occurs because of a faulty protein, beta-globin, which forms part of the hemoglobin, the main constituent of red blood cells. Small defects have been found in the genetic material of some patients, leading to errors in the splicing process and thus in the synthesis of poorly functioning beta-globin.

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