‘‘Genetic probes ideal for early detection of cancer’’
Dr R S K Chaganti is the founder of Cancer Genetics Inc headquartered in Milford, Massachusetts which has recently entered Indian healthcare sector through the launch of ‘Genetics Specialties Pvt Ltd’ for marketing their probes. Dr Chaganti left for the States after completing his B Sc Honours and M Sc from Andhra University. He pursued his PhD in biology and genetics from the Harvard University in Cambridge, Massachusetts. He is the recipient of Fellowship of the American Association for Advancement of Science and Founding Fellowship of the American College of Medical Genetics. Dr Chaganti was professor of Genetics of Pathology, Wiell Medical College of Cornell University, professor of cell biology and genetics, Graduate School of Medical Sciences, Cornell University.In an exclusive interview with R Baby Manoj, he discusses various facets of the genetics of cancer, emphasising the usefulness of ‘probes’ in its early detection. Excerpts:
Could you throw some light on the breaking of chromosomes and its impact on developing cancer?
I have spent 13 years of my life in finding out which genes are involved in these breaks. And why do they break? What causes the break? What is the relationship of the change in the gene to the formation of cancer? Now if a gene is broken up and become a problem in some way, clearly that has to do with the development of that cancer. How it behaves? Using molecular cloning techniques, we pull out those genes from the arrangement. If the gene product is linked with the development of that cancer, we can use the information of that product to develop new drugs to treat that cancer.
Could you site some examples of oncogenes?
Several genes identified that cause cancer. BCR and ABL is one such pair. These are two genes at two positions on chromosomes that break into a range. In the case of ABL (a gene that normally works for the development of the body by aiding the formation of various bio-molecular products), when its job is done it does not make any more product. But in a cancer cell, when these two genes come together, BCR makes ABL active by virtue of a re-arrangement and this becomes active and that causes cancer.
Are there drugs to prevent this activity of BCR/ABL pair?
There is a drug called imatinib mesylate (Gleevec) which has been recently developed. This is a blocker of the product of this gene combination. Until imatinib mesylate has been introduced, treating cancer using drugs was a near impossible proposition.
What are the other popular oncogenes?
Imatinib mesylate comes directly from the discovery of yet another oncogene ‘HER 2 new’ that causes breast cancer. HERB is another oncogene. Lot of rapid research has been going on to take clue from these abnormalities and develop therapeuticals. There are certain other genes identified in breast cancer. Involvement of genes in the case of chronic myelogenous leukaemia is also established. For the past twenty years, we have discovered genes responsible for inducing cancer. And we developed agents to find the genetic lesions. Now we are going to identify what is behind those lesions. Can we develop therapeutic products based on the identification of the lesion? That is a big question.
What is the consequence of the re-arrangement taking place in genes? What types of genes are involved? What is the impact of that on the cell/cancerous cell? How lack of self regulation among genes brings about cancer?
It seems that in cancer, there is a general loosening of the entire genome and is predisposed to what we call ‘instability’. Sometimes, this will provide ‘selective advantage’ to the cell.
We are interested in knowing how and when cancer comes about and how we can kill it. Cancer can happen in any of the five basic types of the cell line in the human body – blood, brain, bone, skin, germ and epithelial cell types. As far as genes in which re-arrangement happens, for example, in normal human beings we do not know what BCR does. But what ABL does is, during embryo development and later on during developmental processes it regulates certain functions.
Those genes are not continuously stressed. They come on and go off. Their expression comes on when it is required. BCR/ABL fusion does take away the ability of ABL gene for self regulation and BCR goes on continuously expressed. That is what it makes oncogenic.
Are probes available for all types of cancer?
The probes were not developed for all types of cancers. They were first developed for probing haematopoietic (blood cell forming) tumours, leukaemias and lymphomas. For solid tumours, we don’t have genetic probes mainly because of insufficient information gathered. However, now there is a breakthrough. We are just introducing probe for treating solid cell cancer. Abnormal cells from the pap-smear of a woman called ‘aplasia’ cytologists can recognise different grades, SIN1, SIN2, SIN3.
SIN3 is highly suggestive of possible cancer. But it is not necessary that every body who has SIN 3 may not develop cancer. Sometimes, a base C (cytocin, a nitrogenous base, others being adinine, thymine and guanin), becomes T and the whole structure of the gene is changed. It leads to an abnormal RNA and an abnormal protein. That abnormal protein is oncogenic.
What is special about the probes launched by Cancer Genetics Inc?
The probe that we have designed can tell about the presence of lesions. If the number of SIN lesions positive with the probe, are two or three, then the chances that the lesion is cancer is more than 95 per cent. At that point, if you treat those lesions, which is very easy, you can be sure it can be killed before it gets started.
Can drugs used to treat cancer, induce cancer in healthy cells?
Theoretically, if it is used high enough, it could. Because, not only can these drugs kill cancerous cell, in high doses they can induce mutations as well. Certain drugs used in breast cancer for example, can induce leukaemia in the same patients, two or three years down the line. There is some evidence that drugs can cause cancer.
What role does genetic probe play in treating genetic birth defects?
Probes can identify genetic defects. That genetic defects are the cause of mental retardation, infertility, reproductive wastage, was well known before, the recognition that they also cause cancer is recent.
When you talk of genetic defects, different kinds of mutations need to be dealt with. For example, thalassemia and hemophilia are two genetic defects in which mutations play an important role. There is yet another category called ‘chromosome abnormality’. There are 46 chromosomes (XX pair in female and XY pair in male). It was discovered in 1959 that in ‘down syndrome’, chromosome no. 41 is present in three copies instead of two copies. This gives rise to 47 chromosomes. There are several defects that can develop from genes.
In females, instead of the regular 46 X chromosomes, if one X chromosome is missing, it results in a condition called Turner’s syndrome.