Thu September 27, 2012
British Scientist Driven To Find 'Spark Of Life'
Originally published on Tue October 2, 2012 12:47 pm
One night in 1984, British scientist Frances Ashcroft was studying electricity in the body and discovered the protein that causes neonatal diabetes. She says she felt so "over the moon" that she couldn't sleep.
By the next morning, she says, she thought it was a mistake.
But luckily, that feeling was wrong, and Ashcroft's revelation led to a medical breakthrough decades later, which now enables people born with diabetes to take pills instead of injecting insulin.
"I don't think people realize the excitement of being a true discoverer," Ashcroft tells Fresh Air's Terry Gross. "There are no new places to discover on this Earth, but there are many, many new ideas to discover — new things to find out about the way the world works."
Ashcroft says she grew up wanting to be a farmer's wife but later became fascinated with studying electrical impulses in the body. Her new book The Spark of Life details how electricity drives everything we think, feel or do through ion channels that are found in the membranes of each of our cells.
"Your ability to hear me now is because there are cells in your ears that are converting sound waves into an electrical signal, which is what the brain can interpret as sound," Ashcroft says.
Ashcroft is a professor at Oxford University and the winner of the L'oreal-UNESCO Award for Women in Science. She is now working on trying to see a particular protein at atomic resolution and on understanding why people become overweight.
On discovering the protein that causes neonatal diabetes
"Diabetes happens when you have too high a blood sugar concentration, and that usually happens because you don't have enough of the hormone insulin, which is the only hormone which can lower your blood sugar concentration after a meal. So every time you eat a Mars bar or Hershey bar, what happens is your blood sugar level will go up, insulin will be released from the pancreas, and that will cause the blood sugar to be lowered.
"This doesn't happen in diabetes. And what I was interested in understanding is how the rise in blood sugar causes insulin to be released in the pancreas. And it turns out — this is what I discovered late one night — that this is down to a whole complex series of events.
"But one of the crucial events, the little bit in the jigsaw puzzle that I discovered, is a protein that acts like a tiny hole in the cell membrane. And when this little pore is open, ions can go through it, so they carry, in this case, an electric current. And when the pore is shut, the ions can't go through, and the movement of the ions triggers a series of events that influences whether insulin is secreted or not. So, very simply put, when the pore is open, insulin is not released. And when the pore is shut, insulin is released. And glucose, or the rise in blood sugar, stimulates insulin secretion by closing these tiny pores. And what we found, together with a wonderful colleague of mine, Professor Andrew Hattersley, is that mutations, genetic defects in the gene that makes this tiny pore, cause it to always be open, so of course no insulin is ever released."
On the difference between electricity in wires and electricity in bodies
"Bioelectricity is similar but not identical to the stuff that's in sockets. Both are electrical currents, and, in both cases, the electrical current is nothing more than a flow of charged particles. But the stuff in our houses is carried by electrons whereas the stuff in our bodies is carried by ions — salt such as sodium chloride, common salt, in other words, the stuff you put on your meat. The second thing is that the speed is very different. So electricity in wires is carried at the speed of light, which is around 186,000 miles a second, whereas that in our bodies is very, very much slower."
On how electricity drives the way our bodies and bats sense heat
"Whenever you feel something that's burning hot — this is detected by this particular ion channel. It's sensitive to heat. And it fires off a signal that goes up your nerve cells. And it's exactly the same ion channels that are stimulated by chili peppers. So the reason that chili peppers taste so hot is that they stimulate the same ion channel, and the brain interprets them both as the same thing. And interestingly, they have been modified in vampire bats to detect the body heat of their prey. So that's how they can pick up the fact that your big toe is sticking out of a mosquito net, so they can come and suck your blood."
On how she became a scientist
"Well, I wanted to be a farmer's wife because I wanted a pony, and that was the only way that I thought I could ever get one. I think it's very interesting that I was educated to believe that I would not be the farmer but only a wife.
"However, I became very interested in natural history. I fell into a green lane one day — that's an old lane which has never been tarmac-ed over but was still used as a lane — and it was full of the most exquisite wild orchids in Britain. So I fell in love with them and I became a naturalist. I used to trek around the fields looking at plants and animals.
"And then when I went to university — I went to read natural sciences at Cambridge — and there was a choice of doing many different things. And somehow or other, ecology and nature conservation, which is what I thought I'd work in afterward, wasn't as exciting, wasn't as stimulating as the pure sciences and, in this case, biophysics ... because you can ask questions that are so well-defined that you can actually get an answer. You can do that now in the fields that I didn't take, but at the time, you couldn't."
On how science and scientists work
"Scientists are just like novelists in a way. We're all trying to tell a good story that explains how the world works, and we're interested in understanding how it works in exactly the same way that perhaps the early philosophers were. But we have much better tools with which to dissect it and understand it today. And the thing about science is it's always based on the facts. So if facts change and you discover new ones, or many more new facts don't fit the old ones, then you have to change the story. That's how major scientific revolutions happen, as, for example, when people suddenly realized that the Earth goes around the sun. So science is indeed a theory. But I really like what the very famous American physicist [Richard] Feynman said. He said, 'Science is imagination in a straitjacket.' We are constrained by all the things which we already know, so you can't simply conjure a story out of the air. It has to explain all the current facts and the new ones that have just been discovered. And it has to make predictions that can then be tested to see whether in fact that story continues to hold when we know even more information."
TERRY GROSS, HOST:
This is FRESH AIR. I'm Terry Gross. You probably don't think of yourself as powered by electricity - but you are. Everything we see, hear, think and speak is a result of electrical activity in our nerve and muscle cells. The new book "The Spark of Life," is about electricity in the human body.
The author is my guest, physiologist Frances Ashcroft. Her 1984 scientific breakthrough involves electricity in the body. She discovered what triggers the electrical impulses that control the secretion of insulin, in people who were born with diabetes - a type of diabetes that is very rare. Her discovery opened the door to further research and now, most people born with diabetes can be treated with pills instead of insulin injections. Ashcroft is a professor of physiology at Oxford University.
Frances Ashcroft, welcome to FRESH AIR. So just give us a little bit of an overview, of a few of the ways that electricity functions in the human body.
FRANCES ASHCROFT: Well, I think one of the most interesting things is that absolutely everything that we see or hear, or think or feel or do, is down to electrical impulses that are taking place in the nerve cells of our brain, and the muscle cells of our bodies; so that your ability to hear me now is because there are cells in your ears that are converting the sound waves into an electrical signal, which is what the brain can interpret as sound. And the person that you are, is down to the electrical signals that are occurring in the nerve cells in your brain. So everything is down to electricity.
GROSS: So how does electricity in the body, compare with electricity that powers our appliances and our computers?
ASHCROFT: Well, I would say that bioelectricity is similar, but not identical, to the stuff that's in the sockets. Both are electric currents and in both cases, the electric current is nothing more than a flow of charged particles. But the stuff in our houses is carried by electrons, whereas the stuff in our bodies is carried by ions; salt, such as sodium chloride - common salt, in other words; the stuff you put on your meat.
The second thing is that the speed is very different. So electricity in wires is carried at the speed of light, which is around 186,000 miles a second; whereas that, in our bodies, is very, very much slower.
GROSS: So you've done groundbreaking work about neonatal diabetes, people who are born with diabetes. It's a relatively uncommon form. But your breakthrough relates to electricity. So could you just describe how electricity functions, in this form of diabetes?
ASHCROFT: So let me begin by saying, this is an extremely rare form of diabetes. It's not at all related to juvenile diabetes, which is the form that's normally found in children. This is a rare form, where you're actually born with the disease. But what's been marvelous about this is that having identified the cause of it, we've been able to offer a different therapy for people who are born with this disease.
Diabetes happens when you have too high a blood sugar concentration. And that usually happens because you don't have enough of the hormone insulin, which is the only hormone which can lower your blood sugar concentration after a meal. So every time you eat a Mars bar - or a Hershey bar - what happens is, your blood sugar level will go up; insulin will be released from the pancreas, and that will cause the blood sugar to be lowered. This doesn't happen in diabetes.
And what I was interested in understanding, is how the rise in the blood sugar causes insulin to be released from the pancreas. And it turns out - this is what I discovered late one night, you know - that this is down to a whole, complex series of events but one of the crucial events - the little bit in the jigsaw puzzle, that I discovered - is a protein that acts like a tiny hole in the cell membrane.
And when this little pore is open, ions can go through it. So they carry, in this case, an electric current. And when the pore is shut, the ions can't go through. And the movement of the ions triggers a series of events that influences whether insulin is secreted or not. So very simply put, when the pore is open, insulin is not released; and when the pore is shut, insulin is released.
And glucose - or the rise in blood sugar - stimulates insulin secretion by closing these tiny pores. And what we found - or, together with a wonderful colleague of mine, Professor Andrew Hattersley, is that mutations, genetic defects, in the gene that makes this tiny pore cause it to be always open. So of course, no insulin is ever released.
GROSS: Now, how does this relate to electricity?
ASHCROFT: Ah, it relates to electricity because the current that flows through those tiny pores, those channels - which is what we call them - is actually an electric current. It's just that this time, it's carried by potassium ions - not by electrons. And it generates electrical impulses in the pancreatic cells, and that's what's necessary for insulin release. So these cells fire electrical impulses in just the same way as your nerve cells do.
GROSS: And through your research - as a result of your research, now, people who are born with this type of diabetes - neonatal diabetes - they can take pills to regulate their diabetes, as opposed to self-injecting. And that's an extraordinary change in their lives, thanks to you and your research partners. When you first made the discovery, what happened in the lab? Just tell us about that moment of breakthrough.
ASHCROFT: Well, of course, there were many steps on the way. But the first step - when I actually discovered this particular, tiny little pore in the membrane that conducts electricity, it - I was working all on my own, late in the night - about 8 o'clock, I think; and I was looking to see this tiny pore close, in response to an increase in the sugar concentration in the solution around the cell. And so I was recording these tiny little electrical currents and hoping that they'd go away.
And when they did go away, I actually thought that there was something wrong with the experiment. I didn't, at the time, realize that what I had predicted might happen, had happened. And so it wasn't until I took the sugar away again - and the tiny, little current blips came back - that I realized, actually, this was what had happened. And I was unbelievably excited.
I don't think people realize the excitement of being a true discoverer. That's one of the wonderful things about being a scientist. There are no new places to discover on this earth but there are many, many new ideas to discover; new things to find out about the way the world works. And for me, that's the incredibly exciting thing about being a scientist. So you can imagine, I was over the moon. I couldn't sleep. By the next morning, of course, I thought it was all a mistake.
GROSS: Why did you think that? Why were you ecstatic... one day and then you were - you just didn't believe it the next?
GROSS: ...one day, and then you were - you just didn't believe it, the next?
ASHCROFT: I think the thing is, you always think that you've made a mistake; that something must have gone wrong in the experiment; that this wasn't actually a real breakthrough because breakthroughs happen so rarely; that I'd done something wrong in the experiment. So you have to do what everybody does - who's a scientist - and that's repeat the experiment again and again and again. And I was lucky. I was right. And the experiment has been repeated many hundreds of thousands of times, by different people throughout the world, and it always is the same.
GROSS: You print in your book something that somebody told you; somebody who was born with diabetes and as a result of your research, can take pills instead of self-injecting insulin. And she says, "Thanks to you, I can wear a dress. I no longer need a skirt, or trouser waistband, from which to hang my insulin pump." I mean, that sounds like a trivial thing. But that sounds like, on the other hand, it meant so much to her to be able to live life without the encumbrance of an insulin pump.
ASHCROFT: It's not trivial, if you think that you're an 18-year-old, and you want to wear a slinky, sexy dress.
ASHCROFT: What do you do with your insulin pump - for her prom? She had to strap it to her leg with - sort of package tape. That's not very comfortable when you're dancing. So you can see, it does matter. And it also matters if you're wearing a pump, and you want to go swimming. You have to take it off, and then put it back on again. It's not very nice every time you put the needles in, just injecting yourself every day - especially if you're a parent who's got to inject a tiny baby several times a day. That's not so easy. So I think for them, it has actually been liberating. And for me, it's been such a privilege to meet these people. I've been fortunate enough to meet some of the people who Andrew's work and mine has been able to help. And that's been a very - a very, very emotional experience. It's not usual. Most scientists will never see their work help people in their own lifetime. I've been lucky.
GROSS: So your work in understanding neonatal diabetes, had to do with ion channels; these - like, proteins that electricity passes through. And these kinds of ion channels are involved in basically, all of our functions in the body. Could you talk about that, a little bit?
ASHCROFT: Ion channels are little pores that are found in the membrane - the envelope - around each of our cells. And they're found in every cell of the body, and in every organism on Earth - from the smallest bacterium, to the redwoods of California. And they're important for everything that we do. I suppose one of the ways in which ion channels can be seen to be important, is by what happens when things go wrong.
So your heart is controlled by electrical impulses which determine the rate at which it beats, and ensure that each beat is coordinated so that it functions as a pump. And these electrical signals originate in the pacemaker area of the heart. And they are down to the activity of ion channels, these tiny pores. And if there are genetic defects in these pores, then things go wrong; and you are susceptible to cardiac arrhythmias. And a particular example of this, is a disease that goes by the strange name of long QT syndrome. And what happens here is that a particular ion channel doesn't work properly. And the consequence is that people with this disease can have a cardiac arrhythmia, and simply die as a consequence of being startled or excited or even - in one case - laughing too much. So there are sad tales of people who've died as a consequence of being too excited, watching a TV show, being told off, dying of fright.
GROSS: So since we were talking about electricity in the heart, why don't you explain the principle of how defibrillators can save somebody who - well, tell us who it can save. And defibrillators are those two pads that you see a lot in crime shows and hospital shows; where, like, if somebody's had a heart attack or something, the defibrillator pads are put on the heart; they turn on the button and there's like, shocks that are delivered and - you know, maybe it saves the person, maybe it doesn't. But we've all seen that a lot in movies and television - and hopefully, not too much in real life.
ASHCROFT: Very often, what people think is that the heart has actually stopped, and the defibrillator is being used to shock it into action. That's not actually the case. What's happening is that the heart is fibrillating - that's why it's known as a defibrillator. And fibrillation means that the heart is no longer beating in a coordinated, synchronized fashion - which is necessary, if it's to act as a pump. Instead, it's become rather like a quivering jelly; Vesalius once called it a quivering bag of worms. So you can imagine that if that happens, the heart can't work as a pump anymore. No blood is going to come out. And that's the reason you die - because the brain isn't getting any oxygen; and neither is the heart, of course. So what the defibrillator does is, the shock stops the heart. And then the hope is that it will restart automatically but this time, in a synchronized fashion.
GROSS: So it's not - it's not unlike when your computer crashes; and you turn it off, and then turn it on again?
ASHCROFT: It's exactly like that, in a way. It's pressing the reset button. I have to say, in Australia, they have a wonderful name of Packer whackers. And that's because a millionaire philanthropist donated a lot of money to ensure that the defibrillators were carried in every ambulance, in one of the states of Australia, because he was fortunate enough to be saved by the presence of defibrillator in an ambulance, when he had a heart attack.
GROSS: Let's talk a little bit about electricity and pain. Pain signals are communicated with the help of electric impulses, yes?
ASHCROFT: Yes, that's right. So what happens is, there are sense organs; very often, these are just pure - just the ending of the nerves in your skin, that detect pain. They detect a - they detect a signal; and then that's translated into an electrical signal, which is sent up specialized nerve fibers - known as sensory nerve fibers - to the brain; which then interprets it as pain, and enables you to do something about it. And what is fascinating is that ion channels - these important proteins - are also involved in the sensation of pain.
And one of the ones I think is very interesting, is an ion channel that goes by the name of TRPV1. And this is very important for detection of noxious heat. So whenever you feel something that's burning hot, this is detected by this particular ion channel. It's sensitive to heat, and it fires off a signal that goes up your nerve cells. And it's exactly the same ion channels that are stimulated by chili peppers. So the reason that chili peppers taste so hot, is because they stimulate the same ion channel, and the - you know, the brain interprets them both as the same thing. And interestingly, they have been modified in vampire bats, to detect the body heat of their prey. So that's how they pick up the fact that your big toe is sticking out of the mosquito net, and they can come and suck your blood.
GROSS: Hmm. Does knowledge of how electricity works in sensing and communicating pain - might that lead to breakthroughs in controlling pain?
ASHCROFT: That's certainly the hope, so that there are - certain number of people working now, very hard, on seeing if they can find blockers of ion channels that specifically target ion channels found in the sensory nerves. At the moment, every time you go to the dentist, you will have a local anesthetic. And that will numb your mouth so that you don't feel any pain. But it will also numb the motor nerve fibers that go to the muscle fibers. So not only will you feel no sensation, but you'll also have a kind of paralyzed jaw. And what's happening there is that the drug you're taking - which is usually Lidocaine - actually is inhibiting the sodium channels. It's blocking the sodium channels in both the sensory nerve fibers and the motor nerve fibers; those which feel pain, and those which cause muscles to contract.
What people are now looking for are drugs which will only work on the ion channels that are found in the sensory nerve fibers. And happily, there are some ion channels which are specific to the sensory nerves. So in the future, maybe, we can look forward to having an anesthetic which doesn't give us a lumpen jaw.
GROSS: Well, wouldn't that be nice?
ASHCROFT: It would be wonderful. There are, unfortunately, some poor people who have mutations in some of these ion channels that are specific to nerve fibers. And in some cases, these knock - knock out the function, so they can't feel pain at all. And that's really, really a tragedy because unfortunately, it means that they can suffer broken bones; they can burn their hands on a hot pan; and they don't notice it. And so they actually can suffer dangerous lesions, dangerous wounds, without realizing it.
And then there are people who have the opposite. And I have no idea which is - you know, which is worse to have because they feel - they feel pain much more sensitively. So they are often in considerable pain, as a consequence of the fact that their ion channels are operating all the time. And so they get - they say that walking is like walking on hot coals all the time.
GROSS: So what you're saying about ion channels is that it tells us that pain really is subjective, in part because of different physiologies.
ASHCROFT: Well, that's actually very true. And in fact, some people may, indeed, be more sensitive to pain - not just these very specialized people, but you and I - because there are variants in the gene that codes for this particular ion channel, that's found in the general population. And it looks as though some of them actually enhance sensitivity to pain, in some people; and reduce it, in others.
GROSS: Something that you bring up in your writing is that people who are skeptical about, like, say, global warming or evolution, say - with accusation - "it's just a theory," and "there's questions about it." But you point out, like, all of science is theory.
ASHCROFT: Well, I think scientists are just like novelists, in a way. We're all trying to tell a good story that explains how the world works. And we're interested in understanding how it works, in exactly the same way that perhaps the early philosophers were; but we have much better tools with which to dissect it, and understand it, today. And the thing about science is, it's always based on the facts. So if the facts change, and you discover new ones - or many, many more new facts don't fit precisely with the old ones - then you have to change the story.
So science is, indeed, a theory. But I really like what the very famous American physicist Feynman said. He said, "Science is imagination in a straitjacket." There are - we are constrained by all the things which we already know. So you cannot simply conjure a story out of the air. It has to be - it has to explain all the current facts, and the new ones which have just been discovered; and it has to make predictions that then can be tested, to see whether, in fact, that story continues to hold - where we know even more information.
GROSS: So another thing I want to ask you about, is Botox. A lot of people get Botox treatments as a form of surgery-free cosmetic - surgery.
GROSS: And Botox is botulinum. It's a poison from spiders that's one of the most powerful, naturally occurring toxins that we know of. [POST-BROADCAST CORRECTION: Botulinum is made by a bacterium.] And it paralyzes facial muscles so that the muscles that we use to wrinkle our brows, can't wrinkle the brows anymore because they're paralyzed. So what's going on, in terms of electricity - in terms of the kind of thing that you're writing about, and researching - with a Botox injection?
ASHCROFT: Oh, well, it's very interesting. What you're doing is, you're paralyzing the muscle. And the way you are doing that is, you're preventing this chemical signal - that travels from the nerve, to the muscle - from leaping the gap. So what happens when a nerve impulse fires off and runs down the nerve, to tell a muscle to contract, is when it gets to the end of the nerve cell, it's got to somehow or other signal to the next cell in the chain - the muscle cell - that the muscle cell must twitch. But the electricity cannot jump the gap between the two cells.
And what happens is that the nerve releases - when the electrical impulse gets to the very end of the fiber, it releases a chemical signal - a chemical messenger - that travels across the very tiny gap to the muscle fiber, where it binds to receptors on the muscle cell membrane. And then that opens more ion channels, and triggers an electrical impulse in the muscle fiber that then causes it to contract. So what happens is that Botox blocks the transmission of those chemical signals so that the nerve isn't able to signal any longer to the muscle fiber; and so the muscle fiber is always relaxed. And that's how Botox works.
GROSS: So what's the downside of injecting minute amounts of this incredible toxin that's messing around - between the communication of nerve and muscle?
ASHCROFT: So the downside, of course, is that you inject too much and then, of course, you get a frozen face. Your facial muscles are so frozen that you can't smile or laugh. But tiny amounts injected are fine because they're very localized, and they don't move very far. But if you inject a little bit too much, then you could paralyze the muscles that are involved in smiling, or facial expressions. And that's a downside from having a Botox injection into your face.
GROSS: So where are you in research now? What are you working on?
ASHCROFT: Oh, well, we're doing a number of different things. One of the things we're doing is trying to actually see the particular ion channel that I work on, the particular protein. We want to do that at atomic resolution, which means that we have to grow crystals of it - crystals, like salt crystals - and put them in a huge synchrotron, which shoots X-rays at it and allows us to see what it looks like. Another thing we're trying to do is understand why some patients who have mutations in the particular protein I work on - don't just have diabetes from birth; they also have neurological problems. They don't walk and talk at the right age; they're very delayed. That's what I'd really like to be able to understand, and also to understand how we can help them.
And the third thing I'm interested in is trying to understand why people get fat. I think it's a hugely important problem. And we're looking at a particular gene, which goes by the wonderful name of the fat mass and obesity related protein; which is the gene that is the most common cause of obesity in the general population. And nobody understands how it works, and so we're trying to figure it out.
GROSS: Thank you so much for talking with us. And for all of our sakes, I wish you really good luck with your research.
ASHCROFT: Thank you very much.
GROSS: Frances Ashcroft is the author of "The Spark of Life: Electricity in the Human Body." You can read an excerpt on our website, FRESH AIR.NPR.org.
Coming up, actress Amy Adams. She's starring in two new films, "The Master" and "Trouble with the Curve." This is FRESH AIR. Transcript provided by NPR, Copyright NPR.