I think it’s simply a reflection of the importance of these seven-membrane-spanning receptors and, obviously, of people’s interest in them. These receptors are pervasive. There’s no field of biology or medicine that’s not impacted by them. We cloned the first of these receptors in 1986, the beta(2) adrenergic receptor, and in the years since then about 1,000 genes for these receptors have been identified. They all share this structure in which the peptide chain runs across the plasma membrane back and forth seven times. By far this is the largest, most ubiquitous family of receptors that exist. And this family includes a huge diversity of receptors—virtually all sensory receptors, hundreds of smell receptors, dozens of taste receptors. Their properties are so universally conserved. By and large all the central principles of receptors have been worked out on these beta adrenergic receptors. The work has a lot of generality and that’s why people cite it so frequently. What’s more, the drugs that target these receptors account for 60-70% of all the prescription drugs used in the world. Any antihistamines, for example. Anything that targets serotonin receptors. Opiates. And on and on.

Well, this was based on work we had done showing that certain mutations in receptors led to what is called constitutive activity. Receptors are switches. The key to being a switch is to be off to begin with and then only turn on when occupied by a stimulant—adrenaline, for instance. In constitutive activity, the receptor, due to some mutation, is turned on to begin with, without a hormone or drug on it. It turns out to be very interesting from a basic science point of view. It also turns out that it is a fairly general phenomenon and we now know of a number of such mutations that occur spontaneously and cause diseases. Let me give you an example. One involves a hormone called LH, which stands for luteinizing hormone. That’s a hormone secreted by the pituitary gland, which tells the ovaries to ovulate. In men it’s important in the development of certain reproductive functions, as well. It’s like just about everything else in the world in that it works through seven-membrane-spanning receptors. It turns out that some families will inherit a mutation in the LH receptor that turns it on. It becomes constitutively active, which leads to familial male precocious puberty. Normally, puberty in girls has its onset because two hormones start getting secreted at a certain age. They need both: LH and follicle stimulating hormone. Boys only need LH. But in boys who inherit this mutation, their LH receptors are on all the time. They don’t have to wait until they’re 11, 12, or 13 to start secreting it. They develop precocious puberty at a few years of age. That research was published a few years ago. I didn’t discover that. What I discovered was the basis of constitutive activity of the receptors.

As soon as we published that JBC paper, people started looking for this constitutive activity in various disease states. Another example, and one of the first ones discovered, was in the thyroid. Normally, thyroid stimulating hormone (TSH) is secreted by the pituitary gland and it goes to the thyroid gland, where it binds to a seven-membrane-spanning receptor and tells the thyroid to do things and make thyroid hormones. Researchers discovered what’s called hot nodules, which are little tumors in the thyroid gland that secrete thyroid hormone. Ninety percent of these tumors arise from somatic mutations in the thyroid, in the TSH receptors, such that they’re constitutively active. So now any cell with such mutation thinks it’s being stimulated. It isn’t, but it thinks it is. It causes these hyper-functioning thyroid nodules. There’s a growing list of these diseases, probably up to a dozen now.

  Did you expect that paper to be so highly cited?

I’m actually surprised that that particular paper is that highly cited. You can’t always predict these things.

  Why do you think it might have transcended your expectations?

Well, there’s some very interesting theoretical material in that paper, some interesting mathematics and theory. That’s of interest above and beyond the clinical aspects. My guess is that this probably accounts for more of the citations than the clinical stuff.

  Which of your more recent work would you rate as equally or more significant?

Another big area that we initiated, in a sense quite by accident, and which we no longer really pursue is what are now called orphan receptors. An orphan receptor is a receptor that you know exists because you’ve cloned a gene and that gene tells you there’s a protein somewhere with a seven-membrane span, and it has these particular amino acids, but you don’t know what that receptor does. With the solving of the human genome, we know of about 1,000 or more of this family of seven-membrane-spanning proteins. Of those only about 200 are functionally defined. So of the 1,000 such genes in this family, 800 encode proteins for which we have absolutely no idea what the ligand is. It’s a fascinating opportunity for therapeutics, as well as a great opportunity to dramatically increase our understanding of the relevant physiology.

We actually cloned the very first orphan receptor back in 1987, right after we cloned the beta adrenergic receptor. That’s an interesting story. We cloned the beta(2) receptor, and then immediately figured we could pull out closely related receptors by homology techniques. So we took a probe for the beta(2) receptor, pulled out what seemed to be the most closely related other gene that existed. We were sure we had the so-called beta(1) adrenergic receptor, because that was functionally very close. When we sequenced it, it was very close to beta(2), but when we expressed it in cells, it failed. It didn’t do what beta(1) receptors should do. It didn’t bind the right drugs. We had no idea what it did. So we published it as the first orphan receptor. Now there are 800 more.

  Do you know what that receptor does now?

Yes, it turned out to be a serotonin receptor.

Yes. People call that de-orphanizing. Every drug company now has a program trying to de-orphanize receptors.

Like everything else, when you look back it looks like it flowed so quickly. Still there are two types of obstacles in all research: conceptual and technical. The technical obstacles were the biggest ones for us, especially in the 1970s and 1980s: figuring out how in the world to deal with these molecules. How do you solubilize them? How do you purify them? How do you ever get enough of them to work with because they are so rare in the cell? These were just huge technical obstacles. That’s not to say there weren’t conceptual obstacles: a lot of people, for instance, just didn’t believe these things really existed. People change their minds slowly in science. And then there’s another problem: as soon as you discover something and think you understand it, it limits your ability to go to the next step. Take arrestin molecules. They are so named because they stop signaling. But in the last five years, we realized they don’t just stop signaling, sometimes they facilitate it. So even the name "arrestin" is limiting your thinking.

  Do you find it increasingly difficult to continue to play a leading role in the research considering how extraordinarily hot this is all is now?

Well, it’s interesting. I obviously can’t lead in all areas just because the field is now so diverse. But my main interest during this phase of my career is still on basic signaling mechanisms and the regulation of signaling by receptors. There we have been able to continue to lead. Other areas—orphans, for instance—we’re just not doing that. How long we’ll be able to continue to lead, I don’t know. I remember when I was told that I was ESI’s most-cited researcher in biology and biochemistry, I had this big rush of ego, and then I thought "Holy cow, the only way to go from here is down."

So I suspect it won’t go on forever, but I have trained a huge number of people and they’re now truly the leaders in this wide field of research. They are my greatest source of pride. When I go to certain conferences, it’s not unusual for a significant number of the speakers to have trained with me. There are so many other things in this field going on and people I trained are doing a lot of it. One of my former fellows, Steve Liggett, was on the front page of the New York Times a few months ago. He found polymorphisms in genes for the beta(1) adrenergic and alpha(2) adrenergic receptors, which seem to correlate with the risk of developing heart failure. I don’t do that kind of research. He started that work just as he was leaving my lab. He’s just one example. There are many others like that. The lead guy in orphan receptors is a guy who trained with me, Brian O’Dowd. There’s a whole field called dimerization of receptors, which I haven’t mentioned. People believe that in order to function these receptors have to form dimers. The leader in that field is a guy who trained with me, Michael Bouvier. By myself I can only lead in one or two areas now.