Unit One: Candace Pert
The Chemistry of Life

Interview: Candace Pert

Biology and chemistry are allied sciences. Even our thoughts and emotions are based on chemical events in the brain. Candace Pert and Solomon Snyder revolutionized neurochemistry in 1972, when they discovered opiate receptors in the brain. These receptors, molecules on the outer membranes of brain cells, are the sites where morphine, heroin, and other opiate drugs bind and trigger their effects on behavior. The receptors normally function as binding sites for molecules called endorphins, opiate-like substances that the brain itself produces. Opiates evoke euphoria by mimicking the brain's natural pleasure-promoting substances. Pert and Snyder had identified the first step in a chemical pathway that leads to a change in emotional state.

Candace Pert was educated at Bryn Mawr College and Johns Hopkins University, where she earned her Ph.D. in pharmacology in 1974. Dr. Pert continued her neurochemistry research at the National Institutes of Health (NIH) in Bethesda, Maryland. She recently left NIH to devote herself full time to AIDS research as scientific director of Peptide Design, a biotechnology company. In this interview, Dr. Pert describes how her interest in the behavior of humans led her to study the behavior of molecules.

Dr. Pert, what attracted you to science and, more specifically, to neurochemistry?

The truth is, I grew up thinking of myself as more of an English literature person. The first science that attracted me was psychology. I believe I was interested in psychology because I'm very interested in people—in human behavior. Then in college, when I saw that there was a field called psychology, that was as far into science as I wanted to go. But then I wanted to get to a more scientific basis for behavior. I wanted there to be a field that looked for the biochemical substrate of psychology. That field didn't really exist at the time. But I began to search for it, and it began to exist.

In fact, you helped invent that field, which is sometimes called "molecular psychology." What does the term mean?

It's the idea of finding the chemical basis of human behavior. You can ask what chemicals make up the brain. You can measure those chemicals. You can study how those chemicals change and what chemicals are released in different mood states and different behaviors. And you can ask how different drugs affect behavior by binding to certain receptor molecules in the brain— receptors that normally bind to internal chemical signals in the brain. These are some of the questions of neuroscience and what I've been involved with for 20 years.

You and Solomon Snyder pioneered the field in the early 1970s when you demonstrated the existence of receptor molecules in the brain that bind to opiates such as morphine and heroin. Can you retrace that key discovery?

I was trying to follow from psychology and behavior to an understanding of what's actually going on inside of the black box, the brain. But I had only been exposed to experimental psychology, things like operant learning. So I actually chose Dr. Snyder to work with because he was one of the first to be looking at the biochemistry of the brain, to be grinding up brain and measuring chemicals.

And I fell in love with the idea of searching for an opiate receptor as a long-shot project. People have used opiates for thousands of years. The ancient Sumerians had a written symbol for opiates, a combination of two characters: one means "joy," and the other means "juice." The topic of opiates appealed to my interest in emotions. My library research had me really believing that there had to be receptors in the brain for opiates: molecules on certain brain cells that could recognize and bind to the drugs. I was looking for the experimental approach that would be able to demonstrate these receptor molecules. It was my fascination with the topic that kept me working very hard, probably past the point where it was sensible to keep working on the problem. I was really hung up for quite a while and not making any progress, until there was a breakthrough experiment. Then the whole thing opened up.

And what was that experiment?

It was on October 22, 1972, and I have it in my lab notebook. I had been trying to find opiate receptors by adding radioactively labeled morphine to suspensions of membranes collected from brain cells. The drug is tagged with radioactive atoms so that you can detect its presence if it binds to receptor molecules on the brain cell membranes. At first, the experiments with radioactive morphine were unsuccessful. Then I switched to radioactive naloxone. Naloxone is an opiate antagonist, a drug that reverses the effects of opiates. It was thought that naloxone competes with opiates by binding to the same receptor molecules in the brain. And it was believed that naloxone and other opiate antagonists stay stuck to the receptor, unlike opiates, which bind less tightly. I said: "Oh, if this idea is right, I should be using an antagonist to find the opiate receptor." And so I obtained radioactive naloxone, purified it, and it worked. It stuck to receptors on the brain cell membranes. It was a "Eureka!" moment. And later, by adjusting the salt concentration in our experimental mixture, we showed that morphine binds to the same receptors.

How did it feel to publish such an important discovery?

Absolutely great! The first excitement was really just sharing it with Dr. Snyder, sharing it with my close colleagues in the lab at Johns Hopkins. I think that's probably 90% of the fun. I mean you really do it on some level for yourself. There was finally a method for getting data on the molecular targets of a drug's action. Then we published in the journal Science.

And the news media picked up the story?

My theory is that there was not much news at the time. It was a very dull time, right before Watergate had broken and right after Vietnam had died out. You know—'72. There just wasn't much news. So our discovery wound up on the front pages all over the place. It's almost arbitrary what discoveries get promoted. I think I've had other discoveries that are more important, but they didn't get promoted as much as the discovery of opiate receptors in the brain.

Have you been able to determine which regions of the brain are enriched in opiate receptors, which regions are most affected by the drug?

In the beginning, we did crude things. We just divided a brain up into chunks and measured the concentration of opiate receptors. But about seven years later, when I went to NIH, a colleague named Miles Herkenham and I developed a method for actually slicing the brain and visualizing the receptor's distribution. It was most concentrated in parts of the brain which are believed to be involved in emotions. So the opiate receptor did lead me to what I'm really interested in, which is emotions. These chemicals can affect mood by binding to receptor molecules in certain parts of the brain.

Why would the brain have receptors that recognize opiates, which, after all, are chemicals produced by poppy plants?

After we discovered the receptor, other researchers found internal opiate-like molecules in the brain that are called endorphins. Endorphins are one of several classes of molecules, called "peptides," that function as chemical signals within the brain. Cells have receptors that recognize certain peptide signals, such as endorphins. I guess the idea of receptors for internal opiates led to the discovery that there are natural chemical mechanisms that produce pleasure in some way. There's great survival and hence evolutionary value in rewarding certain behavior with pleasure, so animals will seek to repeat these behaviors. There is now a whole literature showing that endorphins are associated with eating, sexual behavior, and bonding, for instance.

So these "feel good" substances and other brain chemicals that affect emotions not only reinforce survival behavior but play a role in our social development as well?

We learn to control our emotions. We are capable of self-control. For example, there's just the simple thing of training a child not to do certain things, like shouting, disrupting others, or beating up on other children. Maybe this translates as not letting certain chemicals develop to too high a concentration. I don't know what control is on this level, but we do have the potential for altering our brain chemistry and body chemistry.

Is there any validity to the idea that the high some joggers experience from running is associated with elevated levels of endorphins?

The answer's yes. Experiments definitely show that some of the endorphins do increase in the bloodstream under these physically stressful conditions. The increase people have been able to measure is actually quite small, maybe a twofold difference in endorphin levels in the blood. But that's OK, because measuring brain chemicals in the blood is like trying to understand a family by studying the concentrations of wastes in the fluid running in the gutter outside their house.

In the case of runner's high, the real action would be at certain receptor sites within the brain. And maybe there, endorphin concentrations have increased much more than what we observe finally coming out in the bloodstream. There's definitely a scientific basis to runner's high. But as with other emotional states, endorphins are probably only part of a more complex story. There are many other brain peptides. Certainly different emotions and physiological states are going to reflect combinations of these things. But people have probably focused a little myopically on the endogenous opiates because it's such a sexy area of research. It may turn out that some brain chemical that hasn't been discovered yet is the main factor in runner's high.

Has research on endorphins and opiate receptors in the brain provided new insights about drug addiction?

This is a tricky area. It's almost like it's political. There is this rationale that if we're funding opiate research, we're going to learn about the biochemical basis of addictive behavior. And I think there are experiments that show that if someone takes external opiates chronically, then the body stops making internal opiates. And then with withdrawal of the drug, the body has to "relearn" how to make endorphins again. The same seems to be true of many other drugs, Valium, for instance, which also mimics a certain brain peptide. But I don't think there's any evidence that certain people are predisposed to drug addiction because they naturally have less endorphins or fewer receptors for these internal opiates than do other people. Social factors and social conditioning are probably more important.

What do you think has been the most important contribution of endorphin research?

It led to the discovery of many other brain peptides. It turned out that almost every biological peptide anybody ever looked at, whether they got it from the skin of a frog or from the gut, is found in the brain also.

The brain is a microcosm of all the chemical signaling that goes on throughout the body?

You've got it! What we experience as emotions depends on the fact that everything going on in the body somehow feeds back into these major parts of the brain. Thirst is an example. You can think of feeling thirsty as a mood. It's a blood molecule called angiotensin that makes us feel thirsty. You drop angiotensin into the brain of a rat, and that rat will start drinking water, no matter how much water it had previously. And if you drop angiotensin on the kidney, the kidney will start to conserve water. So here is one chemical which, in a holistic way, unites the animal into, "Let's get as much water as we can and save as much water as we can."

Are there health implications of the integration of mind and body?

This realization has certainly transformed my own beliefs about myself. The idea that the mind is not confined to the brain has lots of implications. For instance, some of the brain peptides communicate with the immune system. Different kinds of personalities and attitudes can affect both the onset of diseases like cancer and the progression of those diseases. When we start thinking about the mind extending throughout the body, this puts us in the same camp as advocates for a more holistic approach to health care, and that's really outside the Western tradition of medicine. But the basic ideas are actually ancient in almost every other culture.

Speaking of medicine, your interest in peptides and their receptors has led you into a new area of research, the use of a chemical called peptide-T as a potential treatment for AIDS. What is peptide-T, and why do you think it may help people infected with HIV, the AIDS virus?

Peptide-T is a small piece of the envelope that covers the HIV virus. It's the part of the virus that is probably on the tip of a larger molecule that actually binds to a receptor on the surface of a cell. That's how the virus gets into cells within the human body. We have evidence that purified peptide-T prevents viruses from getting into cells by blocking the receptor sites on the cells. And peptide-T also reduces the toxic effects of the viral envelope. It turns out that many of the symptoms of AIDS are due to the viral envelopes floating in the person's bodily fluids. From the trials just getting under way, it looks as if there's a lot of evidence that peptide-T reverses the symptoms of the disease. It makes people feel a lot better.

How long has this research been going on?

The first work was in 1985. There have been tests all along the way. There was a whole year of lab tests. Then you had to put peptide-T into animals. And finally, the clinical trials with humans. This is like nothing I've ever done. As a scientist, the smartest experiments you try to do are the quick, simple ones that give you results in one day. Nothing like these clinical trials; it takes months just to negotiate who's going to pay for what, and there are all these legal considerations. It's an amazing amount of effort. But I'm doing this research with a group of people. I'm very much into group process and discovery.

On the other hand, there is a competitive side to science.

Yes. I really have mixed feelings about this. In some of my best work, I really got moving because I was in personal competition with someone else in the lab. So I know how competition can be motivating on some level. But I've really come to see it as a destructive force overall, because I think science at its best is a creative process that prospers when as many people as possible can contribute and come together. It's best if the competitive element can be minimized. I think I was successful at NIH because I could build groups of people working together who hadn't worked together before. Maybe women tend to work better in groups, tend to be less competitive and struggle less than men for recognition. And I think this is good for science. Competitiveness is pretty destructive.

What other encouragement can you offer to women who are considering careers in science?

That I think women are naturally really superb scientists, because they have curiosity and observational powers and good communication skills. And they have the kind of minds that like to consider lots of different things at once and from many angles. Analytical minds. So I think women may even be innately well qualified to be scientists. And girls, you're allowed to have babies, and get married, and still be scientists.

Any other advice for students?

Study hard! But don't underestimate how the health of your whole body affects your mood and mental state. If you go away to college, think carefully about how your exercise and diet might change, and how this can really affect the way you feel and how well you do with your studies. Good health should be at the top of your list.

©2005 Pearson Education, Inc., publishing as Benjamin Cummings