SCIENCE / MEDICINE : INSIDER’S VIEW : Designing a Perfect Antibody Defender

Dr. Leroy Hood, a Caltech molecular geneticist, in September was one of three scientists to win the prestigious Lasker Basic Medical Research Award for helping explain how the immune system creates an almost endless variety of antibodies to protect the human body from foreign invaders.

The immune system is believed crucial to curing many of man’s diseases, a fact reflected in the number of Nobel prizes granted in this field. Two weeks ago, MIT geneticist Susumu Tonegawa, with whom Hood shared the Lasker Award, won the Nobel Prize for his work on antibodies. This week, Hood, chairman of Caltech’s biology division, explained to Times staff writer Jill Stewart what he has learned and how he discovered it .

The immune system is the major defense system we have against foreign invaders, viruses and bacteria, and to a certain extent against cancer. If one looks at modern medicine, the immune system impacts on virtually every single area. There is no fundamental discipline that is more integral to understanding the human body’s fight against disease.

But I suspect that what immunology has accomplished in the past will be trivial compared to what it will do in the future.

I believe that, within the next 10 years or so, we’ll have the fundamental insights that are required so we will literally be able to design antibody molecules to order--these molecules will be able to destroy any foreign invaders we wish. For example, we could design an antibody molecule, conceivably, to attack the AIDS virus.

Modern biology is in its golden period. We have this wonderful coming together of high technology and a new understanding, in enormous detail, of how the immune system works.

Indeed, the Lasker Award is a beautiful example of this expanding understanding because it was given for work that deciphered one of the major puzzles in immunology.

We asked the question: How is it that our antibody molecules, which protect us against foreign invaders, can protect us against any foreign invader that could ever be imagined? How can the immune system respond to millions, if not billions, of different foreign invaders, most of which the body has never seen?

Our results came out during a period of 2 1/2 years, and those were terribly exciting times. It was like being in a building with many, many rooms, and light bulbs were continually going on in different rooms. We could not completely see what was around us. Then when we looked back we could see, we came to understand the whole structure of this building as it became luminated.

What it comes down to is that for every different kind of disease or pathogen or cancer that your body can recognize and defeat, you have to have a different antibody molecule.

The three people that were awarded the Lasker prize received recognition for explaining the two key mechanisms that produce this incredible diversity of molecules.

The first mechanism I call the “jukebox strategy.”

Imagine a jukebox where you have 26 letters, A through Z, and say 26 numbers. Since each different letter/number combination, A1 or B3, specifies a different tune, the number of different tunes you can play is 26 times 26. Although you only have 52 basic elements--the numbers and letters--you can generate almost 700 different tunes.

The immune system does exactly the same thing. Its limited number of genes can create hundreds, if not thousands, of different molecular tunes that in turn create the diversity of antibodies that fight disease.

The second mechanism we discovered is what I call the “shotgun mutation theory.” Once the jukebox shuffling creates a particular molecular tune, you can actually create millions of variations on it by randomly changing a few of the tiny sub-units of each gene.

We know the human body has cells totaling 10 to the 14th power--that’s a 10 with 14 zeros after it. As it turns out, 10 to the 12th of those cells--or a 10 with 12 zeros after it--are immune cells. Each of these millions of immune cells can be directed by the genes to play a different tune, to respond to different invaders.

So if you’re a foreign invader in the body, you’d see the immune cells circulating around in the blood and in the connective tissue spaces. When you, as a virus, met a cell that played your special tune, you would interact with it. Suddenly, that cell would divide many times to make 10,000 or more identical cells, each with the capacity to destroy the virus. This is the basic process called vaccination.

Medicine will be revolutionized if man can learn to create these antibody molecules to fight a particular disease.

We’ve solved the antibody diversity puzzle in a general sense. What we do not understand yet are the rules that take us from the linear information carried by each antibody gene to a three-dimensional protein molecule called the antibody.

Proteins give your body size, shape and form. They are the essence of your muscles and your connective tissues and so on. We know that proteins begin as a linear string of beads, just like a string of pearls, and are made up of 20 different amino acid sub-units. Somehow, proteins literally begin to fold, and are transformed into a precise three-dimensional structure based on the order of those beads.

When proteins fold, they can create a building block for a muscle, or for the connecting machinery between neurons and muscles, or for whatever you need. Every protein must have a different shape if it is to carry out a different function.

That shape is the key. What we’d like to find out is: How do you create specific shapes, and how do the shapes go about carrying out their functions? We have known the shapes of some proteins for years now, but still we don’t understand quite how they function.

This mystery is one of the central problems in modern biology. It’s one that I predict will be solved within the next 10 to 15 years with the new technologies that are being developed. Once it is solved, we can tailor-make antibodies, a stunning idea.

I spend an enormous amount of my conscious time thinking about science. I try to view problems in many dimensions. Insight in science is very intuitive, subliminal, and not completely rational. You envision new ways of looking at things or new experiments to put all the pieces of the particular puzzle together.

Often all the key pieces will be in front of scientists for two or three years before somebody finally says, “Aha!” Talking with a scientist in Copenhagen for 15 minutes may give you an idea that will fundamentally change the direction of your research. So there’s always this possibility, just around the corner, that you’re going to have an idea that will unify and clarify.

Quite often, the critical experiments that unravel these problems do not come to me when I’m consciously trying to figure them out.

They come just when I’m reading a book or climbing a mountain or even talking with a friend about another subject. All of a sudden one will have an insight and realize that there is yet another way of tackling this particular problem.

In the end, the productivity of a laboratory is determined by the quality of the people it attracts. I have always had superb fellows and students. I also have a wonderful family who understands the demanding commitments of science.

However, for quite some years I have been convinced that we need new and better tools to explore the incredibly complex questions that modern biology poses.

I did my Ph.D. thesis work with Prof. Bill Dreyer at Caltech. He always had special insights into technology and instrumentation. Dreyer argued that what really dictates the pace of science in many cases is the development of new technology.

Bright scientists do carry out the experiments, but imagine climbing up a mountain, the mountain called biology. Lack of a particular technology may freeze you at a certain height. One reason biology is in its golden age is that a series of biotechnologies have helped us climb this mountain more rapidly and higher than ever before.

And this is where these instruments developed at Caltech enter the picture.

We now have machines that give us the ability to carry out studies in just a few days or weeks that once took months or even years to complete. They have allowed us to analyze ever-smaller quantities of material so that we can study rare proteins and genes that were just utterly inaccessible to biologists in the past.

Two of our machines synthesize proteins or DNA--that is, they actually permit us to build these molecules. The other two machines are sequencers--they tell us the order of the basic sub-units that make up proteins and DNA, giving us the recipe, if you will.

The synthesizers allow us to create large amounts of proteins and DNA in the laboratory. DNA synthesis allows us to make special genetic probes that carry out detective work by locating, in a test tube, the particular gene or protein we are interested in.

A probe is a small fragment of DNA, hundreds of thousands of times smaller than anything you could see under a normal microscope. The probe is only one part of a DNA molecule, and it naturally wishes to match up with its other half.

We put a radio tag on the probe and place it in a test tube with other DNA. When the probe finds its partner DNA, it tells us where the partner is located. Then we quite literally pull the DNA and the probe out of the test tube. Once we have located the particular DNA we are interested in, we can unravel its makeup on the sequencer machine. Then we can manufacture large quantities of it on the synthesizer, and study what it does.

Your body has enough DNA for 3 million genes’ worth of DNA, so to go into that soup and pick out the single gene that you are interested in, without the probe, would have been difficult for many genes.

The sequencer machine does something quite different from the synthesizer.

It is, in a sense, a pair of molecular scissors. It takes protein, which again is like a string of 20 beads of pearls, and snips the pearls off one at a time. The machine places each pearl in a separate test tube. From that we can determine the order of the different pearls on the chain, and this gives us the recipe we need. The process for DNA is similar.

One of our major accomplishments, in developing the protein sequencer, is that we have decreased the amount of material needed for our sequencing work by four orders of magnitude--that’s 10,000-fold.

Within the next year, we believe we’ll be able to decrease the amount we need by yet another three orders of magnitude. That means we’ll need 10 million-fold less protein, and that means we can study critical proteins of medical interest that we were never able to study before.

Interferon’s a good example of a very inaccessible and rare protein. It is secreted by just a few cells in the body and has an important role, probably, in fighting viral infections and some cancers.

Yet one had to process literally tens of thousands of outdated units of blood, over months of time, to obtain the very, very small amount of material necessary to sequence the interferon protein and eventually clone the interferon gene and discover what it was all about.

After scientists cloned interferon, they learned something I had always suspected--that interferon was not the general cure for cancer that its advocates hoped it would be. So these machines are saving us tremendous amounts of time we might, in the past, have spent following the wrong paths.

Even if interferon had turned out to be more promising, I am still far more excited about understanding the entire picture than I am about studying something so limited.

Our lab is particularly interested in the body’s T-cell system, a major part of the immune system which protects you against parasitic infections and cancer and causes organ graft rejection when the cells attack the foreign organ.

We are very interested in how T-cells are turned on and off in the body. We would like to be able to manipulate the structure of T-cells to make them work better or direct them to more effectively attack different kinds of foreign invaders.

My belief is that such global, general studies, where we attempt to understand how man’s immune system functions, pushes science to the point of curing disease faster than if one works with an extremely narrow focus, such as delving into a particular disease.

My philosophy of doing science is that it’s best to be up on the tops of peaks, able to see the whole landscape and the entire forest, rather than to be mired in the valleys, struggling to figure out the relation of one individual tree to another.