Jumping gene research
Dr. Gideon Rechavi, who founded Sheba Cancer Research Centre, was in Vancouver in January for an international conference at which he presented new findings on “jumping genes.” (photo from Sheba Cancer Research Centre)
Dr. Gideon Rechavi, who founded Sheba Cancer Research Centre, in Ramat Gan, Israel, was in Vancouver in January for an international conference on DNA and RNA methylation.*
“I described a new work we just published, regarding ‘jumping genes,’” he told the Independent about his presentation at the conference. “Forty-five percent of our genome, part of what people used to call ‘junk DNA,’ is composed of genes that can jump from one place to another.”
As far as what this means for the functioning of a body, he explained, “When they jump, they can activate genes and they can also inactivate genes, and it’s a random process. Actually, when I was PhD student in ’82 at the Weizmann Institute, I found the first example of such an event in mammals.” And, he added, “We were also the first to show the role of such events in cancer.”
Rechavi explained, “In cancer, there is a set of genes called oncogenes, genes that usually are normal genes in our genome but, when they are over-activated or activated in the wrong cell or at the wrong time, they can push the cell to proliferate and can cause cancer.”
Now, he said, many years later, using advanced technologies based on whole genome sequencing, they have found that, “in a variety of neurodevelopmental disorders, such as autism and Rett syndrome and similar diseases, there is a basic gene defect in the family or in the affected child. However, the clinical presentation can differ even between identical twins. Nobody understands why the same genome and the same genetic background will result in such a difference, one patient will be affected by epilepsy, the other one by autism or mental retardation.
“The mechanism that we show is that, in the brain, there is, normally, a constant level of jumping of such genes and, probably, it’s essential for diversity of neurons and brain plasticity and activity.”
This is happening all the time in neuronal stem cells, he said. “During the differentiation of neuronal stem cells … there is a very precise time window of 48 hours when such transposition events can take place. And, probably, it’s essential, because you find it in mice, in monkeys and in humans. However, in all the diseases that we are studying, there is over-activation of the mechanism, so you have many more jumping events.”
We have neuronal stem cells dividing in the brain our whole life, said Rechavi. “In the past, we used to think that all of the neurons are created during pregnancy or soon after, but now, in the last 20 years or so, we know there are also adult neuronal stem cells. When you do gymnastics or when you take Prozac, there are more neuronal stem cells. And, in these neuronal stem cells, these transposable elements – jumping genes – are jumping and probably contribute to brain function.”
The process seems to be quite regulated, he said. “The mechanism we suggest, we call it the ‘lightning rod’ mechanism or hypothesis.”
He explained, “The majority of jumping events occur in sequences in the genome where integration will not cause harm. So, in a normal level of jumping, we expect it will be beneficial, and the chance for damage is low. Although, if, in a variety of diseases, there is uncontrolled activation of this mechanism, so there are many more jumps, then it can saturate the lightning rod safeguard mechanism and then affect genes that are relevant to neuronal diseases, and we have a lot of examples where such things happened.”
To study this, said Rechavi, they sequenced the genomes of 100 samples, which included normal, diseased and control brain samples. “We were able to show that there is a particular normal level of transposition … and, then, over-activation, with many more transposition events, in the brains of disease-affected children.”
From these results, he said, we know that “the genes affected by such insertions from these transpositions, you see that many of them are relevant to neuronal functioning, neural development and a variety of neuronal disorders, such as autism and schizophrenia.”
By understanding the biochemical mechanism in these patients, what activates the jumping, “then you can intervene,” said Rechavi. For example, perhaps a drug could be developed that would decrease the level of transposition.
“This is the next step,” he said. “Now, we have several patients where we know the gene defect involved in the syndrome and, therefore, is involved in the enhanced transposition, so now we have to find a way to shut it off, to lower the activity.”
Rechavi said his lab is researching these jumping genes and their effects in both cancer and neuronal disorders, and that they are currently looking for funding to study the involvement of such genes in Alzheimer’s and in aging.
The purpose of the jumping genes is not certain. “What people suggest,” said Rechavi, “is that it has to do with diversity.” Recalling that it is a random process, he explained, “So, instead of having all the neurons in a particular part of the brain being identical, now you have diversity and probably the diversity increases the efficiency of the brain circuits, etc. It can also be relevant to plasticity. We know that specific brain regions can take over following damage or following a kind of environmental influence and change the activity and perform new activities. So, maybe the ability to create diversity in the brain is an advantage.
“A similar model has to do with the immune system,” he added. “With the immune system, we know that there are genetic mechanisms that increase diversity and, then, the cells of the immune system of an individual can respond to any virus and any bacteria.”
The main focus of his lab at Sheba Medical Centre, he said, is to find new genetic and epigenetic mechanisms, “and then to ask, what is their relevance to normal physiology and what’s their relevance to diseases. That’s how this story that started with cancer research turned out to be very relevant to neuronal disorders and psychiatric disorders.”
Rechavi said the phenomenon of jumping genes, or transposable elements, was first identified by American scientist Barbara McClintock (1902-1992) in experiments with maize. (She won the Nobel Prize in 1983 for this and other contributions to the study of genetics.) “She found it in maize,” he said. “We found it in mammals.”
Conferences like the one Rechavi was attending in Vancouver when he spoke to the Independent by phone Jan. 23 from his room at the Fairmont Hotel Vancouver, where the conference was being held, are useful for several reasons.
“Some people, after my talk, came and they wanted to collaborate, they want to learn the methodologies. Some people suggested samples we could analyze…. This is the basis for scientific collaboration, the main reason to do scientific meetings. You can read everything on the internet,” he said, “but when you discuss with people the findings and you drink coffee together and discuss the details, you can get new information, new non-published information, and also collaborations and friendships.”
Sheba Medical Centre doesn’t have many partnerships with Canadian institutions, said Rechavi. The centre’s main collaboration in Canada, he said, is with Toronto’s Hospital for Sick Children, especially in the field of brain tumours, because one of Rechavi’s former trainees, Dr. Uri Tabori, went to SickKids to study such tumours and stayed there.
Before obtaining his PhD at the Weizmann Institute of Science, in Rehovot, Rechavi earned his doctor of medicine at Tel Aviv University’s Sackler School of Medicine. He is a professor of hematology at Sackler School and heads the Cancer Research Centre at Sheba Medical Centre, the largest hospital in Israel, which serves as a university teaching hospital (affiliated with Sackler) and as a tertiary referral centre. He has published more than 450 scientific papers.
In addition to treating some 1.5 million patients annually, Sheba Medical Centre has 75 laboratories and more than 2,000 ongoing clinical trials; 30% of Israeli medical research is performed at Sheba, which files, on average, 15 biomedical patent applications per year.
In October 2017, Sheba Medical Centre inaugurated the Wohl Institute for Translational Medicine. The idea, said Rechavi, is to take the “findings emerging from basic research and try to translate it into taking care of patients; to better diagnose, to [develop] better treatments.”
* Methylation, explained Dr. Gideon Rechavi, “is the addition of a chemical group known as methyl on the four basic letters of the genetic material (DNA and RNA) to generate a new expanded ‘alphabet.’”