Aging Begins at 30

Interferons

In 1956 my classmate, neighbor, and friend Alick Issacs, added heat damaged flu virus to a tissue culture. If he added undamaged infectious flu virus 2 to 6 hours later the virus multiplied much less than it did in cultures that had not been treated first with the damaged virus. In other words the pretreated cells produced something that interfered with the growth of the second virus. He called the hypothetical substance that did this "Interferon." He showed that it was a substance secreted into the tissue culture fluid by the cells. The fluid could be applied to other cells and make them resistant to infection too. Unfortunately, my friend died in 1967 at age 46. If he had lived, I believe he would have been a candidate for the Nobel Prize in Medicine.

Cells can also be stimulated to secrete interferon if they are stimulated by double stranded RNA or by the toxins (poisons) made by some bacteria (for example gram negative bacteria of the gut). Interferon belongs to a family of small proteins called cytokines (chemical messengers) that carry signals cell to cell. The Interferons (we know there are several now) can inhibit bacteria, parasites viruses, and cell growth so they have wide application in the treatment of infections and cancer. The FDA has approved them for the treatment of chronic hepatitis, genital warts, Kaposis (cancerous), sarcoma, multiple sclerosis, hairy cell leukemia, laryngeal and genital papillomas. They are being studied for their effects on non-Hodgkin's lymphoma and a variety of other tumors (malignant melanoma, renal cancer, multiple myeloma, urinary bladder tumors, and ovarian cancer).

The interferons are made by recombinant DNA techniques. That is by putting genes for interferons into bacteria so that the bacteria with grafted genes act as interferon factories. We know now that there are five classes of interferous alpha, beta gamma, mega, and tau, each with particular properties.

So interferon has demonstrated new physiologic mechanisms in the body. The interferons are species specific that is monkey interferon protects monkey and human cells but has no effect on chicken cells.

Not all treatments with interferons are benign. Headaches, muscle aches, fever, rapid pulse rate and generalized feeling of unwellness or malaise can occur. Patients getting interferon treatment feel as if they have the flu. Indeed some of the symptoms of influenza may be due to interferon . At high doses of interferon confusion, loss of attention, paranoia and disorientation can occur. Side effects are readily reversible but 30% of patients withdraw from treatment because of the side effects.

Leishmaniasis is a tropical disease that is often very difficult to cure with older treatments. It can be treated with interferon. It makes parasite infected macrophages produce nitric oxide which kills the Leishmania parasites.

Alick Issacs opened a window on the extraordinary breadth of interferons immunologic repertoire. All interferons also enhance destruction of tumor cells by natural killer cells (lymphoid cells). So Alick's discovery will also improve the treatment of some cancers.

Intriguingly, the Trophoblastin that protects the corpus luteum and developing embryo in pregnancy is the interferon called tau.

What an incredibly complex business the interferons are. It is exciting that we are learning their structures and approximately how they work. Yes, I feel sure Alick would have won the Nobel Prize had he lived long enough.

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