Highly technical science can often appear to have no immediate relevance to everyday life. But frequently it is breakthroughs achieved by the most esoteric research that yield the farthest- reaching gains, frequently offering practical solutions to a number of seemingly unrelated problems. That is because the systems that warrant this type of scientific interest are often so fundamental to all living things that when they malfunction, things can go awry in multitudes of different ways.

Take, for example, the hormones that regulate the transcription of DNA. It is these molecules that are the particular focus of Dr. Robert Haché, whose hope is that his investigation of nuclear proteins with deceptively cozy names like Ku and POU will lead directly to improved treatments for a whole host of diseases, including rheumatoid arthritis, breast cancer, T-cell lymphoma, and lung cancer.

Ku autoantigen (or "Ku" for short) is an important part of many DNA processes; consequently, Dr. Haché and his team are taking several different approaches to studying it, with the specific intention of showing it to be a sequence-specific DNA binding protein, or a transcription factor. In one project, they are investigating Ku's role in autoimmune diseases like arthritis. In such diseases, the body's natural defenses are somehow turned against the very body they are meant to defend. If the joints are what's under attack you've got arthritis. One molecule that may be involved in this betrayal is Ku. Although it belongs in the nucleus, if it somehow strays into the bloodstream or otherwise comes into contact with the immune system, the immune system fails to recognize Ku as part of the body, and goes on the offensive. Antibodies destroy the body's own protein, just as they would try to fight off a virus. Ku might well be the cause of this abnormal response in autoimmune disorders like rheumatoid arthritis, scleroderma, and lupus erythematosus. The precise role Ku plays in these diseases is not yet known, but it is present, in the wrong places, in patients with a variety of these diseases often in abundance. As Dr. Haché deepens our understanding of how this protein can lead to the initiation of the auto-immune response, a way to manipulate the status of the protein to prevent that response may well become evident with the result of eradicating, or at least improving treatment for, a whole category of autoimmune diseases.

Another aim in Dr. Haché's study of Ku is to identify which proteins physically bind with Ku, which will increase our knowledge of Ku's role in controlling nuclear events. Two of the proteins Ku binds with are already known protein phosphatase IIa and DNA-dependent protein kinase. But these are relatively rare nuclear proteins, while Ku is relatively abundant good evidence to suggest that it interacts with other not-yet-identified molecules. Also as part of the same endeavor, Dr. Haché is investigating whether Ku's interaction with phosphataseIIa has a direct effect on gene transcription.

In a separate venture, Dr. Haché and his team are using the mouse mammary tumor virus (MMTV) a retrovirus like HIV, the virus that causes AIDS as a vehicle to further study Ku. As it happens, Ku binds to a particular sequence of the virus's DNA. What's more, and particularly fascinating, is that although Ku will bind both to DNA ends and nonspecific sequences, it binds to this specific DNA site preferentially. That makes Ku unusual, as few DNA-binding proteins recognize both structure and sequence. Therefore, Dr. Haché intends to identify functional domains within the protein: where it binds, and why it prefers to bind to this particular sequence.

Another interesting aspect of the work with MMTV is that mice with this infection develop not only mammary tumors, but also T-cell lymphoma. Ku appears to inhibit the ability of MMTV to transform T-cells. Dr. Haché hopes to determine the mechanism for Ku's effect, and to learn why that effect is e xerted whether it's because of Ku's interaction with kinase, or its interaction with a different nuclear protein, or because it's a DNA helicase (a protein that unwinds DNA to gain access to the base-pair sequence), or for some combination of these reasons.

Another avenue of investigation has opened up for Dr. Haché with the recent discovery that Ku is required in the repair of double-strand breakage of DNA. Certain cancer therapies, especially radiation, are designed to introduce this kind of DNA breakage to halt tumor growth. One obvious question therefore arises: Is Ku a factor in cancers that resist this type of therapy? Could it be that the cells of these tumors contain more Ku, and therefore, more of an essential tool for the repair of the therapeutic DNA breakage? If that is the case, radiation therapy could probably be combined with an agent that specifically blocks Ku from helping to repair the damage. That could lead immediately to more effective treatments for tumors that resist radiation therapy.

In yet another project, Dr. Haché is taking a closer look at glucocorticoid hormone action, to learn how receptors function to activate transcription. For this investigation, he and his team are working with a class of proteins called POU factors. Already they have found that all nuclear hormone receptors so far identified appear to interact with a portion of the POU factors called the homeodomain. The glucocorticoid receptor that specifically interests Dr. Haché is a transcription factor that regulates gene expression through a DNA sequence element. Dr. Haché is using mutant receptors to learn how normal receptors function.

Dr. Haché has established several collaborations with other Loeb scientists: further investigating the glucocorticoid receptor with Drs. Yvonne Lefebvre and Peter Walker, studying neuronal development with Dr. Leo Renaud and plasminogen activator with Dr. Ben Tsang and, recently, devising a yeast two-hybrid screen for Ku binding proteins with Dr. John Ngsee.

It is basic investigations like these that will lead us to dramatic improvements in treatments in many different diseases ranging from arthritis to cancer and, ultimately, to their complete eradication.