Sir John Gurdon, a Nobel Prize-winning biologist whose experiments in the field of cloning laid the foundation for modern stem cell research, visited the USC Health Sciences Campus on May 16. He met with faculty and friends of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC for a casual conversation during a coffee break before presenting a public lecture, “Nuclear Transplantation to Prospects for Cell Replacement.” He was then interviewed by Madeline Andrews, a PhD student who conducts research at the center.
Madeline Andrews: When did you become interested in science?
John Gurdon: I had a very checkered background in a sense that at my time in school, there was no science until the age of 15. When I did one term or semester of that, they said, “This is absolutely not your subject.” So, I was removed from science completely for the next few years and started ancient Greek and Latin. Later, my parents could see my actual interest was in biological things. So, I had to get back into it, having given it up first. That was rather complicated, but it did work out.
MA: Who are your scientific heroes?
JG: One such person is Max Perutz, who was the head of the MRC [Medical Research Council] molecular biology lab in Cambridge, [Mass.,] for many years. I think you might say it’s the most successful research lab there’s ever been. It wasn’t a very large lab, but they, I think, accumulated 17 Nobel Prizes. That’s more than most countries. He was the mastermind behind that, and he got his Nobel Prize for working out the X-ray crystallographic structure of hemoglobin.
MA: What initially sparked your interest in nuclear reprogramming and animal cloning?
JG: That’s because my eventual supervisor offered to have me be a graduate student with him. I was struggling to find anyone to let me be a PhD student with them. I was rejected for entomology, which I was quite interested in.
My eventual supervisor asked if I’d be interested, and he put me on a rather routine project for about three months. Then he said, “Have you thought about taking an interest in this nuclear transplantation work?”
I said, “Oh, that sounds very interesting.” It then started working. That was, of course, the critical thing.
MA: What made you continue the nuclear transfer experiments in light of what Robert Briggs and Thomas King published — that they believed it is impossible to produce a clone from the nucleus of an adult cell?
JG: They’d published a paper, and it was a very nice paper. There were two possibilities at that point. Either what they said is correct, in which case, the next question is, why is it that a somatic nucleus [the nucleus of an adult, differentiated cell, such as skin or intestine] cannot generate normal embryo development?
If they weren’t correct, then you have a whole field in front of you as to what is correct. It was a strong incentive to go on.
MA: After you had successfully transferred a somatic nucleus, did you have any kind of disbelief at what you were seeing because how contradictory your result had been?
JG: First thing, you say is, am I wrong? You have to consider that. The main likelihood of being wrong is that, when you inject a nucleus into an enucleated egg, the enucleation has not worked. So, all you’re really doing is activating the egg’s own chromosomes to develop. That would be the most obvious artifact.
But then, we had this amazing nuclear marker, which seemed to rule that out. That meant it probably was right. If you get a result that questions what everyone else thinks, there’s a very strong incentive to pursue that and see what is the right answer.
MA: How can our current understanding of nuclear reprogramming be applied clinically?
JG: If you regard nuclear programming as being the resetting or rejuvenation of an adult cell or nucleus back to the beginning of life, then it means that you can make any kind of cell out of any other kind of cell. The clinical application would be that if you want to replace some part of the body, which is — either through age or disease — not functioning properly, a very good way to do it would appear to be to take something accessible like skin or blood and make new heart or brain or eye out of that.
In the talk I gave this morning, I was quoting the case of the eye. That’s because many older people suffer this age-related macular degeneration by which the central vision gets clouded. You can only see the periphery. Then, eventually, that goes too. So, you have no vision. If someone has lost their vision, it would make an immense difference to their life to regain some of it, as you can imagine.
MA: What is the most difficult intellectual challenge that you’ve had during your career, something that you struggled with, that you had a hard time understanding?
JG: For a long time, I’ve had difficulty understanding how transcription factors might work to activate a gene. For example, a gene-specific transcription factor means the kind of protein that sits on a gene and enables it to be functional, to make transcripts. We know some examples of those, one being MyoD. It’s a muscle-inducing factor.
MyoD molecules, proteins, in the cell have to find their downstream genes, that’s to say, the genes that those factors work on. You might imagine when they find such a gene, they sit there long enough to make the gene transcribe. But you have to remember that most transcription factors recognize only about 10 nucleotides — quite short. And for every 10 nucleotides that they recognize, there may be many others in the genome.
A transcription factor will bind tightly to its own designated sequence. It also binds less tightly to every other sequence. There’s a hundred million excess of the wrong DNA. So, most of the time, this molecule like MyoD will be sitting on the wrong piece of DNA. How does it ever find the right DNA? We don’t really understand how that works.
MA: Do you have any advice for young scientists [and] current students who are struggling with their own research?
JG: My own background is that I was extremely unsuccessful early on. Everything went wrong. And so, one piece of advice would be: Don’t give up too early.
MA: What would you consider your biggest accomplishment?
JG: I think, to a large extent, when you do your experiments in the lab, you have to have luck. I’ve been extremely lucky and things that needed to work did actually work.
So, you might say, which experiment do I most like? Certainly getting normal adult animals out of an intestine nucleus has to rank very high, but the other one was injecting messenger RNA into an egg.
We take that for granted now that that works, but at the time, it was extremely unlikely to work because the egg is full of ribonuclease, the enzyme that destroys messenger RNA. If I’d gone for a grant and said I wanted to try injecting messenger RNA, they’d have said it couldn’t possibly work. Luckily, I didn’t need to apply for a grant. And amazingly, it worked incredibly well.
The idea seems to be that an egg is full of ribonuclease if you grind it up, but if you inject something carefully into the egg, it’s not that different from a sperm entering an egg. It doesn’t break these particles in the egg, which contain the ribonuclease. That wasn’t predictable, and it did work astonishingly well. So, I always regard that as one of the most amazing experiments I’ve had that worked.
MA: You were saying earlier that you still do lab work. What experiments do you like doing in the lab still?
JG: I still do the injection experiments, injecting things into eggs or oocytes. That is the one I specialize in. In fact, my colleagues usually ask me to do theirs if they can. I’ve done so much, I like to think I’m reasonably good at it.
MA: What are your hopes for the next generation of scientists? What are the big questions that you anticipate will be answered?
JG: In the field where I work, I think cell replacement is surely going to work in some cases. Perhaps it’ll work in many others too, as we find ways of doing things better.
In the talk I gave this morning, I mentioned that when you have beating cardiomyocytes [heart muscle cells], they don’t integrate properly into the heart. I’m sure that will be soluble, and that will make a big difference. So, when you have cells or tissues working well in the laboratory, you can then transplant them into a host and even the brain. That would be fantastic if one could do that.