Monday, November 18, 2013

PAST 90: IMMUNOLOGY — A Return Journey

Past 90 (8)

Now long after retirement, I have all but lost connection with my years of research and teaching in immunology, the molecular and cell biology of the immune system. Once in a while I feel pangs of nostalgia and regret that I have allowed so significant a separation from my long and memorable active years on the UC Berkeley faculty.

That’s the background for my impulse to “catch up” when I heard about a new book: The Compatibility Gene: How Our Bodies Fight Disease, Attract Others, And Define Ourselves, Daniel M. Davis (Oxford University Press). My comments here are not directed at suggesting that most of my op-ed friends should read the book. It’s never easy to make a complex area of science accessible even to interested “outsiders”. But for me, the book served as an intellectual and emotional reawakening to the remarkable advances in our understanding of the immune system.

By the time I got involved in immunology, beginning as a chemistry graduate student in1958, what Davis calls a “scientific revolution” was underway. In the early 1950’s, Watson and Crick revealed the double helix structure of DNA, an event that ushered in the era of direct study of genes and impacted virtually every area of research in biology. At about the same time, Peter Medawar in Britain and Macfarlane Burnet in Australia each made seminal contributions that revolutionized our understanding of the immune system and led to a remarkable expansion of fruitful research in immunology.

The two fundamental riddles that the immune system presents are:

How can it recognize and respond specifically to an almost infinite array of antigens (bacterial, viral, even synthetic molecules)?

How does it normally avoid responding to “self”, that is, to antigens in one’s own make-up, while rejecting those from another individual?

Burnet and Medawar opened the way to answering both questions. Remarkable contributions by many outstanding researchers have since proven them correct and revealed vital, previously unknown, features of our immune system. In proof of Burnet’s “clonal selection” theory, it has been shown that each of our many billions of immune cells is restricted to making a unique antibody molecule or antigen-binding site. When activated by a particular antigen, the cell multiplies, resulting in a clone of cells that that will respond when exposed to the antigen. Medawar (and Burnet) also postulated “acquired tolerance” to “self”, whereby cells that could target self-antigens are destroyed in early stages of development. Indeed, as later discovered by Miller, that’s exactly what happens in the thymus, an organ whose function had been a mystery. Medawar’s experiments and insights paved the way for significant medical advances, including in organ transplantation.

Very exciting things happened during my almost thirty years in immunology. Some I recognized and marveled at as they unfolded. Some I took note of, but underestimated. In fact, the Davis book is most inspired by an area of research whose initial phases I found confusing and tended to overlook: the very intriguing and important place of variable histocompatibility sites on cells of the immune system and possibly the brain.

My intent here is not to attempt an even meager review of progress in immunology during and after my active connection. I only want to share some reflections.

I’m struck by the enormous creativity in scientific endeavor, no less than in art. The difference from at least most great art is that creative achievement in science is a collective experience, more than the imagination and genius of any one brilliant talent. Big ideas and small by many, many investigators, and lots of hard work, go into every important discovery and its verification. When the pieces come together, from many people in many lands, it’s a thing of beauty and a triumph of human creativity. The canvas is vast and the minor brush strokes by most contributors are soon lost from view.

My colleagues and I shed a little early light on the make-up of an antibody combining site, not of lasting consequence once the full picture emerged after it became possible to work out the complete structure of genes that code for an antibody molecule. That was achieved by Susumu Tonegawa, a Japanese scientist. Yet we had our moments and I can still feel each thrill. Of course, there is also chagrin when I think of a smudge or two we added inadvertently to the canvas by misinterpreting an experimental result.

Back to the Davis book, much about the significance of compatibility genes was new to me and impressive. Things have come a long way since Zinkernagel and Doherty discovered in 1974 that, in order to kill a virus-infected cell, an immune cell (a T cell) had to recognize both a viral antigen and the targeted cell’s major histocompatibility marker. The implications of this finding have become increasingly important in medical and genetic research into patterns of susceptibility to certain diseases.

Davis is most excited by the discovery that histocompatibility genes function in brain. That was bound to evoke great interest in further research and a lot of speculation as well. Davis and others are especially fascinated by a so-called “dirty T-shirt” experiment, where women are turned on by smell to the discarded undershirts of men with appropriately matched or unmatched histocompatibility genes. Davis embraces with enthusiasm the possibility that sub-conscious responses to histocompatibility types may be determining whom we choose to love and other fateful decisions.

Forgive me for being old fashioned, but this isn’t our first exposure to absurd theories of genetic determinism.

Still let’s not on that account minimize the established importance of compatibility genes. I should probably maintain humility regarding some (not all) speculation on connections between the immune system and the brain    — after all, during my time in immunology, I regretfully managed not to be much distracted by significant phenomena like histocompatibility, NK (natural killer) cells, and more.

So, thanks to Davis for making my fond ties to immunology vivid once more.

1 comment:

  1. Leon, as probably the most un-scientific minded individual who reads your blog, I have two comments: First, I admire your enthusiastic embrace of new developments in your profession and wonder whether the "auto-immune" diseases of which we still hear will ever be conquered, and second, what nostalgia I felt reading about women turned on by the smell of their partners' used clothing! Many years ago I was amazed at such a reaction in myself when on a cool day in Santa Cruz I went to fetch a jacket for my beloved out of our car trunk and noticed that it must have been his smell on the clothing that provoked this reaction. So I vouch for that research finding personally!