By David N. Leff

Dictionaries define the word "id" as one of the psyche's three notional components - the other two being the ego and the superego. "Id," they tell us, "is the unconscious source of uninhibited impulses and demands for immediate satisfaction of primitive needs - notably, the libido."

Curiously, this lexical rap sheet could characterize the human id gene, which perches on the short arm of chromosome 2. Here's how research pediatric oncologist Antonio Iavarone, at the Albert Einstein College of Medicine, in New York, characterizes the id gene and its uninhibited Id2 protein:

"'Id' stands for 'inhibitor of differentiation'. Id2 is the protein expressed by the id gene. It has a fundamental role in making brain cells during normal mammalian embryonal development. This same protein at some point shuts down its function when the normal number of brain neurons has been reached.

"Now if in the presence of extremely high levels of Id2 during normal development these cells do not become neurons yet, they keep on proliferating - growing. And if the Id2 protein stays at very high levels, then you get cancer, derived from the nervous system. The type of cancer we have been studying is called neuroblastoma, which is a highly malignant pediatric tumor. By itself, it's the third-most-frequent tumor in children. It's not by itself a very frequent disease, but among kids it is. Pediatric cancer is indeed the first cause of death in children, after accidents. Neuroblastoma is probably one of the big killers in children. Definitely one of those that gives most of the worrying to the pediatric oncologists.

"Usually it is diagnosed in younger children," Iavarone noted, "around four or five years of age. It has always been thought that this cancer arises during embryonal development. So as the fetus grows, these cancer cells already start to come up."

Loose-Cannon Protein Piles Up In Body

"Our studies, in fact," he said, "are providing the molecular explanation of this hypothesis. We think the reason these tumor cells originate during development is because the most important factor that is required to allow proliferation of brain cells during development is deregulated, with Id2 kept at very high levels, when instead it should shut off. So this factor, we believe, is why these kids get neuroblastoma.

"This solid tumor," he added, "is usually first manifested as an abdominal mass, although it can occur anywhere in the body. It originates from the peripheral nervous system, from neuronal ganglia, which are present in virtually every tissue of the body. And unfortunately, in advanced cases, neuroblastoma is metastatic, and leaves very little hope for the child who carries this tumor, because there are no effective therapies at the moment."

But the cancer-causing Id2 protein doesn't run amok unaided. Two other molecules - the retinoblastoma and myc genes - join it to form a trivalent gang of three, which makes neuroblastomas happen.

Iavarone is senior author of a research article in today's issue of Nature, dated Oct. 5, 2000, titled: "Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins."

"Retinoblastoma - Rb - as mentioned here," Iavarone explained to BioWorld Today, "does not refer to the Rb ocular tumor itself but rather to the Rb gene. This gene, together with the Rb protein it encodes, constitutes the most important so-called tumor suppressor gene - on a par with p53. That means it has the fundamental function of preventing tumors in humans.

"In order for a tumor to arise," he continued, "this Rb gene needs to be inactivated. And what we report is that the mechanism of Rb protein inactivation is through the elevation of very high amounts of Id2. What happens is that in normal development, the Rb protein has to keep down the Id2 function. There is a dialog - a sort of crosstalk - between the Rb protein and the Id2 protein. So as soon as the normal number of brain cells is reached, the Rb protein basically tells the Id2 protein to shut off.

"In cancer instead, in neuroblastoma disease, the amount of Id2 becomes so huge, so unlimited, that it completely overcomes - totally bypasses - the tumor suppressor function of the Rb protein. So basically, Id2 is there to negate the function of the most important tumor suppressor pathway in humans - the RB pathway."

Rounding out this sinister trio is the myc oncogene, a transcription factor strongly implicated in driving cell proliferation. "Its job," Iavarone noted, "is to turn on the Id2 gene, which is a downstream effector of myc function. In the absence of Id2, myc doesn't function, doesn't trigger neuroblastoma. So Id2 is the crucial effector for myc to cause cancer."

Antisense Sequence Makes Small-Molecule Inhibitor

"Having found that Id2 is so important for development of this childhood malignancy," Iavarone said, "our next goal now is to provide a potential therapeutic approach, where we hope to inactivate Id2 selectively in this cancer. We are now doing experiments in our laboratory for this purpose to remove Id2 protein, using small molecule inhibitors - antisense oligonucleotides, that we have synthesized, which in fact can prevent the cells from growing.

"This antisense," he recounted, "is a small piece of DNA that is synthesized based on the DNA sequence of the Id2 gene. It anneals with the Id2 and the messenger RNA, which codes for the protein. So it goes to inactivate the mRNA, which is degraded and removed. It's extremely specific in targeting the Id2 gene and nothing else.

"And in this case, it's the method of choice, with implications for real therapy, to design drugs that will counteract the id gene - first in mice, then hopefully in humans."

At present, he and the Medical College are exploring the prospect for filing to patent this finding, Iavarone allowed, "particularly the idea of using Id2 not only as a therapeutic tool - that's really the major hope of course - but in addition the much quicker possibility of applying it for diagnostic purposes - to stage neuroblastoma prognoses and outcomes.

"If there was a biotech or pharmaceutical company expressing an interest," he concluded, "I would gladly be available to talk and see what we can do together."

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