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00:00:00 My name is Hans Clevers, I have been working in Utrecht for a long time.
00:00:03 First I worked at the teaching hospital...
00:00:08 and since 2002 my laboratory is at the KNAW Hubrecht Institute.
00:00:13 Over the years I have tried to answer the question
00:00:21 of how we succeed to become ourselves out of one singular cel,
00:00:26 the fertilized ovum.
00:00:28 This is the science of developmental biology,
00:00:33 it has taken us on a journey through many different fields of study.
00:00:37 We started as immunologists,
00:00:38 the study of the body's defence system.
00:00:41 We've occupied ourselves with frogs and fruit flies and worms.
00:00:44 For the past fifteen years we've primarily worked on adult stem cells,
00:00:49 we've done a lot on mice
00:00:51 and for the last couple of years, since we know more about how it works,
00:00:55 we've also done this with human stem cells.
00:00:58 That's quite a story, I'm going to split it into smaller parts.
00:01:06 But it's good you mentioned all of it. What is your field of study?
00:01:16 My field of study is medical biology,
00:01:20 everything that has to do with animals an humans,
00:01:24 how we come into existence, how we enduringly stay healthy,
00:01:27 but also how we become ill, and how we eventually repair damaged tissue.
00:01:33 What does you research concentrate on? What is your domain in this area?
00:01:45 We've never allowed ourselfs to be restricted by scientific disciplines.
00:01:51 We've frequently crossed borders,
00:01:55 but the unifying factor is technology, it has been a lot of DNA technology,
00:02:01 which went through an explosive growth since the '80.
00:02:04 Every time a technical step was taken, we could take up new questions.
00:02:09 That is actually what we do,
00:02:11 whether it concerns a fruit fly or a human, doesn't really matter to us.
00:02:16 And what is your speciality?
00:02:18 At the moment it is stem cells and cancer research,
00:02:22 in particular the link between the two. A cancer cell is actually a derailed stem cell.
00:02:28 Really, is it that simple?
00:02:30 Yes, well...
00:02:33 What does a stem cell, the way we sit here, do?
00:02:36 So not the stem cells that we are made out of very early on in our existence, three days after fertilization,these exist shortly,
00:02:43 then they dissapear.
00:02:45 But the way I sit here, every organ has it's own specialized stem cells.
00:02:51 What are these stem cells good at? They lay low when they are not needed, they don't devide themselves.
00:02:55 But when tissue is damaged, they renew the tissue,
00:03:02 they can resist a lot of radiation and abuse.
00:03:08 That's exactly like cancer cells, they can handle anyting, cystostatics, radiation,
00:03:14 they can sleep for years before becomming active again.
00:03:17 But they've lost the brake to stop once they should be done.
00:03:21 So the cancer cell is like a natural enemy for the stem cell?
00:03:24 It's the doctor Hyde... What are they called?
00:03:29 Dr. Jeckyll and Mr. Hyde.
00:03:32 It's the downside of having stem cells, they sometimes go astray,
00:03:39 and become our worst enemy.
00:03:42 So if you compare it to good and evil....?
00:03:46 That comes very close, we all struggle with aging.
00:03:51 Can we only live till we're eighty, or is there no limit to aging?
00:03:55 I'm convinced we've been designed to live for about eighty, ninety years.
00:03:59 That's plenty of time to bring children and grandchildren into the world.
00:04:05 But then it's time to step off the stage, evolution must be able to do it's work,
00:04:09 which means selected generations eventually need to dissapear.
00:04:13 We're not built to live longer than eighty to ninety years,
00:04:16 on average our stem cells are capable to repair our organs over that period of time,
00:04:23 but in the end they wil start making mistakes and finally we will all encounter cancer.
00:04:28 Yes, yes...
00:04:30 I can explain it simpler and shorter, but that's actually...
00:04:35 What isn't done very much, we study healthy stem cells, and how they aid in staying healthy over time,
00:04:43 as well as the malignant stem cells.
00:04:46 They are so much alike, from each one you learn about the other,
00:04:52 it works both ways. We simultaneously do cancer research and stem cell research.
00:04:56 Everytime we make progress in one field, we can translate it to the other field.
00:05:01 For example, how does a stemcell in the intestine regenerate?
00:05:04 A cancer cell turns out to use the exact same process as the normal cell, but has lost the off switch.
00:05:14 So it's the like the naughty child?
00:05:17 Yes, yet in my experience a child can be controlled,
00:05:24 but cancer cells have lost the ability to be controlled.
00:05:28 And then, what can you do?
00:05:31 Designing therapies to battle cancer is very complicated,
00:05:38 because almost any other disease comes from the outside.
00:05:42 Aids is a good example, unknown in 1980 and resolved by 1985.
00:05:48 An exernal disease-causing agent,
00:05:50 completely different from anyting in our body.
00:05:53 It's not that complicated to rapidly develop a few drugs
00:05:56 that at first may not be excellent but are quickly much better
00:05:58 at combatting the virus, but not you own cells.
00:06:02 A cancer cell is you, yourself.
00:06:06 Our genetic information consists of three billion letters, Gs As Ts and Cs.
00:06:11 It only takes three to four errors in those three billion letters for a normal cell to turn into a cancer cell,
00:06:19 that's a tiny difference, enough for the cell to keep growing, but very difficult to target with therapy.
00:06:26 If you aim a little too wide, you target every cell in the body,
00:06:31 you have to try to aim at those few little mistakes that distinguish the cancer cell from your normal cells.
00:06:38 That is a huge challenge.
00:06:40 Are you kind of like a cryptologist?
00:06:43 We do a lot of DNA analysis,
00:06:47 other colleagues do this more in-depth, we mostly use it,
00:06:52 and it is indeed like decoding a book.
00:06:56 A book we now know has more than one code, maybe three or four or even many more.
00:07:02 Codes we didn't even suspect existed.
00:07:05 Interestingly physicists approximately know what they don't know,
00:07:08 the dark matter, eighty percent of the universe.
00:07:11 We don't know what we don't know,
00:07:14 every few years a new system is discovered, one we never needed to explain the way that things are.
00:07:20 A new principle emerges, which turns out to be half of biology's foundation, but we never missed it in our explanations.
00:07:28 This has already happend three or four times.
00:07:29 It's usually a code in the genetic information we hadn't seen.
00:07:36 So there many you don't know of yet?
00:07:40 There used to be talk of one or two percent serious code
00:07:44 and 98 percent "junk DNA".
00:07:47 By now we can probably understand about ten percent,
00:07:51 but in the other 80 percent there is undoubtedly much more hidden we still need to discover.
00:07:57 Let's get back to the stem cell research you do, what is that like?
00:08:07 The research or the stem cell?
00:08:10 The research of the stem cell. I have no...
00:08:16 You can't imagine... Let me try to explain how it's done.
00:08:21 Everyone knows, if you hurt yourself, if you have a scrape wound, it heals.
00:08:29 If you look at it with a microscope, you see many cells are dead or gone, and they are replaced.
00:08:37 After two to three weeks the skin is healed.
00:08:42 Most of our organs can do this,
00:08:44 we are still searching for stem cells in the heart,
00:08:46 it's unclear of they excist, there are even stem cells in our brain.
00:08:49 What a stem cell does, in theory,
00:08:52 many haven't been discovered yet,
00:08:53 but they can repair damaged cells, they can replace lost tissue.
00:09:09 So that's my definition, this field is quite young,
00:09:13 there are many dogma's that turned out to be wrong.
00:09:19 We try to stick to this: which cell, in a surtain organ, helps this organ to replace cells and tissue.
00:09:29 How do you recognize those cells?
00:09:31 Yes, then the next question is how to recognize them.
00:09:32 First off, they need to be able to multiply,
00:09:34 that is what they do when they are active.
00:09:36 That is is way to spot them.
00:09:38 the very strong convictions on how a stem cell should look were problematic for us,
00:09:46 they would be very rare, extreemly small,
00:09:50 they never or rarely multiplied, their offspring would multiply a lot.
00:09:57 So they were defined as cells that you would hardly be able to find.
00:10:02 Nowadays we can use many genetic tricks.
00:10:07 We can replace the genetic code in mice, while sitting behind a computer.
00:10:15 We can change or improve it.
00:10:17 That way we can make a mouse that has exactly the alteration in it's code we need.
00:10:22 For example, if we see a surtain type of cell,
00:10:28 in the mouse's intestine and we think it might be the intestine's stem cell,
00:10:33 that is how we started,
00:10:35 we can make a mouse who's stem cells lights up.
00:10:38 It's a hereditary trait stolen from fire flies
00:10:44 we write an email to the man in Califonia who discovered this,
00:10:48 he puts some of this DNA on a coffee filter, sends it to us by fedex,
00:10:53 we put in in a tube with water, and then we have the DNA code for giving off light.
00:10:58 We can place it in the mouse, it's not that simple,
00:11:02 but we do it in such a way that the cell will light up.
00:11:08 That makes it much simpler, we can easily spot them,
00:11:13 we can take them out of the mouse, because they light up and the other cells do not.
00:11:16 Back then we used a second trick,
00:11:20 from the outside, we can inject a three to four months old mouse with something
00:11:27 and we activate something else we built in,
00:11:30 then only the permanent cells can give themselves a colour.
00:11:35 They light up, but if they are no longer stem cells they won't light up anymore,
00:11:38 when we colour a cell, every cell that comes from that cell, will have the same colour.
00:11:48 so you can wait for a year, after a day you see one blue cell,
00:11:54 but after a year you see a whole part of the intestine had coloured blue,
00:11:58 that way you see the cell indeed is a stem cell,
00:12:03 you have formal evidence.
00:12:04 Those are the tricks we can use in mice.
00:12:10 And do you think that when a stem cell has multiplied, the new cell has stem cells?
00:12:15 Well, that was also a dogma,
00:12:17 once a stem cell multiplies it makes one new stem cell and a daughter cell,
00:12:20 the daughter cell goes futher through the system, but has a short life.
00:12:23 But we see this isn't true.
00:12:26 If you loose many stem cells, the remaining stem cells immediatly replenish the shortage.
00:12:32 And if you loose all of you stem cells, cells that were on their way out can turn back and become stem cell.
00:12:42 It's a very artificial system,
00:12:44 we didn't know this,
00:12:45 the dogma was that it didn't work this way,
00:12:47 it was a challenge to dismiss these convictions I had been taught since elementary school,
00:12:53 to look at those stem cells in a different way.
00:12:57 What is your field, what in you research makes you a front runner, what discoveries enjoy international interest?
00:13:28 If I look at the subjects I'm asked to speak about at conventions, it started about fifteen years ago,
00:13:36 by accident we discovered how colon cancer arises,
00:13:41 we became interested in the intestine's stem cells,
00:13:43 we discovered that in the '60 it was described as the most active stem cell in our body,
00:13:48 we thought this would make it the easiest to study, we just needed to find it.
00:13:52 That took a while, but when we found the intestenal stem cell,
00:13:57 we discovered nothing that was known about stem cells was actually true.
00:14:01 For example, I think this is what we are most know for,
00:14:05 a very powerful dogma was that a healthy cell,
00:14:09 put onto a petri dish with a culture medium would die after a few days.
00:14:19 The only cells that would grow well were cancer cells.
00:14:23 All the research on cells, outside of the body of humans or mice, has been on cancer cells.
00:14:31 Almost all discoveries within the biomedical science, are based on cancer cells.
00:14:35 Because you can endlessly multiply them.
00:14:38 How is that possible? I don't understand. How come healthy cells die after a few days, but cancer cells don't?
00:14:46 That was the observation, from the '60 people tried to cultivate cells
00:14:52 after a few attempts it turned out to be quite easy to keep tumor cells alive,
00:15:04 tumor cells look a lot like the tissue they originate from, they are like malignant stem cells.
00:15:12 That was a dogma, you would read is was impossible to keep healthy cells alive for more than a few days.
00:15:20 But when we made the stem cells visible in mice,
00:15:23 using the trick to let them light up, we could see that they split every day.
00:15:28 However, it was thought they multiplied just once a year.
00:15:31 We thought, if they split every day,
00:15:34 they will do this a thousand times in a the lifetime of a mouse, about three years.
00:15:40 We have to be able to recreate this in a lab.
00:15:43 If you understand it, nothing is impossible within biology.
00:15:47 Eventually it turned out to be quite simple, the hardest thing was convincing someone in my lab that we needed to do this.
00:15:55 Everyone was convinced it would be a waste of time and effort.
00:16:00 A japanese scientist, TOSHIRO SATO, started working on it, and accomplished it in a couple of months.
00:16:06 What did he do exactly?
00:16:07 What you need...
00:16:09 Can you briefly explain?
00:16:12 He extracted those luminous stem cells from the mice,
00:16:16 everyone knew this was possible,
00:16:18 what the cells need to grow in culture are the right nutrients.
00:16:22 Epo is what bicyle racers take, it activates the stem cells in you bone marrow,
00:16:27 they in turn make red bloodcells, so you can cycle faster.
00:16:29 We thought we needed substances like that, and we discovered which ones.
00:16:33 A combination of three substances was added to the stem cell and it never stoped growing.
00:16:39 It grows ten times bigger each week.
00:16:41 If we had saved all that tissue we could have filled the whole universe.
00:16:46 A physisist could calculate it...
00:16:50 It grows endlessly?
00:16:51 Yes, it grows endlessly, you can see it grow under a microscope.
00:16:56 We can film it if you like, it just never stopped.
00:17:00 The first mouse we used has been dead for three years, but the cells continue to grow.
00:17:05 So we thought it must have turned into cancerous cells...
00:17:09 Wait a moment, so you have found something that doesn't die?
00:17:18 Isn't that sort of a code of life you have found? Eternal life?
00:17:26 Yes, well, let me finish the story, you'll be better able te understand.
00:17:35 The stem cell of the intestine was the most active,
00:17:39 so at first people told us it could not be the stem cell because it didn't fit the criteria.
00:17:46 It does grow the intestine, so it must be the stem cell.
00:17:52 It took a couple of years before people accepted this.
00:17:55 Then we thought, it splits so fast, we must be able to copy that.
00:17:58 It was thought to be impossible, healthy cells could not survive outside the body,
00:18:03 however it did turn out to be possible.
00:18:05 We became facinated with this possibility and thought, what about other tissue,
00:18:12 tissue that doesn't devide so quickly.
00:18:14 Your intestine devides every day, but not much happens in your liver.
00:18:18 Or in your pancreas, prostate or lungs.
00:18:23 But they can repair themselves, if you binge on alcohol,
00:18:28 your liver is damaged, your stem cells are activated and repair the damage.
00:18:32 TOSHI had the mice in front of him and tried it with their pancreas, and it also grew.
00:18:41 This was a stem cell that is usually very quiet,
00:18:44 one that is only temporarily active and then sort of goes to sleep again.
00:18:47 So that opened the floodgates, we could try it for all the organs, we just needed to find the right nutrients.
00:18:55 And soon we could do the liver, prostate, lungs, kidneys.
00:19:00 We can cultivate kidney cells out of the urine of children.
00:19:05 Kidney tumor cells, right out of a tube of urine.
00:19:09 Out of a bit of saliva we can cultivate lung cells.
00:19:11 I'm trying follow, it's going quite fast. So in the intestines you found something that could live outside of the body, and even continues to grow.
00:19:20 It makes miniature intestines, we thought, if we succeeded we would make a lump of stem cells.
00:19:27 But it turns out they form a miniature version of the intestines.
00:19:32 It is shaped like a ball with protrusions, you can shape it like a tube.
00:19:39 So we can make two centimeters of intestine out of one cell.
00:19:44 And all of it is under a microscope, we can film it.
00:19:47 I would like to see that!
00:19:50 You can really just do that?
00:19:52 Well... not me, but...
00:19:54 You said it can be filmed, so when we're at the lab...
00:19:58 You can see those miniature organs with your bare eyes,
00:20:02 but they don't have a blood supply, so their growth is limited,
00:20:06 they need to have oxygen and nutrients, and waste needs to be filtered out.
00:20:12 These things are called organoids,
00:20:16 the past couple of years a whole new field developed, I think we were one of the two founders, SASAI, whom I previously mentioned was the other.
00:20:25 So now we are trying to make the organoid more complete,
00:20:30 with blood vessels, white blood cells, gut flora for the intestines, to see if it will function the same.
00:20:39 It is a whole new technology.
00:20:42 It's the cell by cell construction of organs and maybe even more?
00:20:46 The main idea is, this is long term research, but we think it will be possible,
00:20:51 that we won't need organ transplantations anymore,
00:20:55 you can take tissue from a living donor, cultivate it to be much more,
00:21:02 then freeze it, you can freeze cells and keep them for years.
00:21:05 And when someone needs a new liver, and the liver's infrastructure is present,
00:21:10 but the cells are ill, in theory, and in animal testing,
00:21:15 you can place a couple of stem cells from a living voluntary donor, which you can keep in the freezer,
00:21:21 and a stemcell will repair the liver.
00:21:25 It would take a while, but you could use stem cells to make someone repair his own damaged liver.
00:21:33 So that would be possible?
00:21:34 We can already do it in mice.
00:21:37 To be allowed to test it in humans is very complicated and the logistics... it would not be cheap.
00:21:43 But the proof of principle exists, we've supplied it, as have others.
00:21:50 So is it's just a matter of time?
00:21:50 Yes, and a large number of funds.
00:21:56 To translate such an insight into a therapy, you'll need corporations, it's not possible in an academic setting.
00:22:05 Yes, but it is possible, you've proved it...
00:22:09 The most important thing we've proved is that
00:22:13 the way people thought stem cells looked,
00:22:17 that they were undetectable, is all wrong.
00:22:20 They are easily detectable, if you search well and know what to look for.
00:22:24 We've clarified many things, but with our mice, the luminated ones, other laboratories have found other stem cells.
00:22:33 In the inner ear for example, if you lose those you become deaf.
00:22:37 Tasting buds on the tongue, a lab in the United States... all the same type of stem cells.
00:22:43 So that was the first, find the stem cells, if you know what they look like, you can learn to manipulate them.
00:22:49 The second thing is we countered the belief that it would be impossible to multiply them outside of the body.
00:22:55 The third thing is, they actually make a miniature version of the organ, we were surprised about this as well.
00:23:01 It is very interesting to see how they do this, we can see that they do it,
00:23:05 and we pretend we discovered it all.
00:23:08 We just give them a nudge in the right direction and they start to make the organ, but we have no idea how.
00:23:13 What happed to you when you saw that?
00:23:18 Well the first time...
00:23:20 People often talk of their eureka moment, it's the same,
00:23:23 the belief that something is correct grows,
00:23:25 Toshiro, the Japanese colleague,
00:23:28 when he came in he had ruined a piece of equipment.
00:23:31 His colleagues were temporarily not very fond of him, he became a bit isolated.
00:23:35 I hadn't talked to him much.
00:23:36 One day I walked into the lab, and asked him if the cells were growing, and he replied "Yes!"
00:23:41 And I asked him for how long they'd been growing, and he told me for about three months!
00:23:45 I asked him why he didn't tell me, he replied "You didn't ask."
00:23:49 I looked throught the microscope, I could see the cells were healthy, it was just beautiful!
00:23:57 I still have the images...
00:23:59 How big were they?
00:24:01 Large under the microscope, but about two, three milimiters in real life.
00:24:05 But if you've studied cells before, you can just see it, they were very healthy.
00:24:09 The cells had been growing for three months, while they should have been dead after a day.
00:24:15 Could you believe it?
00:24:16 Yes, immediatly. That wasn't a problem.
00:24:19 What did you do?
00:24:22 I told the others in the laboratory of course.
00:24:25 TOSHI deserved to have a different position in the lab.
00:24:29 And we tried to show as many people as possible.
00:24:34 In a scientific career... Then it's locked down, you have the evidence. You must celebrate this, I assume?
00:24:49 Yes, but you know it's not finished yet.
00:24:51 You need to build the story.
00:24:54 You need to convince other colleagues, that was the hardest.
00:25:01 We tried to publish our paper, and encountered many difficulties.
00:25:08 The first was people thought they already knew how it was done,
00:25:09 that is wasn't possible,
00:25:12 so it wasn't exactly new, and it wasn't deemed possible.
00:25:16 It took one an a half years to get the paper published.
00:25:21 Then people read the paper and think, yeah, they might have done it, but still have their doubts.
00:25:28 It takes a couple more years before others try to do it themselves, it's not simple,
00:25:32 you need to have a numbre of things in order.
00:25:34 For the past three or four years people are starting te realize it is in fact quite easy,
00:25:40 you need some experience, but you can do it with any organ.
00:25:46 It is possible with any organ, you did it with the intestines, those cells were easy to find. But you can do it with any of your body's organs?
00:25:59 Outside of the body? -Outside of the body.
00:26:01 We usually first try it with mice, then with humans.
00:26:07 Humans are a bit more complicated, it grows a little slower compaired to the tissue of mice.
00:26:11 But so far we've succeeded with every organ we tried.
00:26:15 The criterium is they need to be able to grow for at least a year.
00:26:19 And at the end of the year they need to be normal.
00:26:22 You can read the DNA material, the fear is there will be a mutation, a cancer.
00:26:28 You can regognize those, but we never find them.
00:26:31 The cells really stay healthy, it's like you literally took them out of a body.
00:26:36 So in you lab, you have department with living tissue...
00:26:45 Human living tissue, yes.
00:26:48 And is that personal or not?
00:26:53 To us, no. They are just cells.
00:26:56 But it has a lot to do with ethics of course.
00:26:57 we get all the human tissue from hospitals.
00:27:02 We deal with many regulations, informed consent, medical ethical committees are involved.
00:27:08 We are constucting large bio banks, we can do it with healthy tissue, but also with many forms of unhealthy tissue.
00:27:15 Interessting to research, interesting for the development of medication.
00:27:20 But what we are expanding on at the moment is using someone's sick cells to find the best personal medicine.
00:27:30 We're doing this for cystic fibrosis, there are a couple of drugs, that are very expensive, and it is unclear who will respond well to it.
00:27:36 All the patients want it, there is nothing else.
00:27:40 We now have a test that can see it this drug, that costs half a million a year, for eighty years, if it works their life expectancy is normal.
00:27:51 In our lab we can see, within a week, which drug will or will not work for you.
00:27:57 We're doing this, a great number of patients can't try these drugs, their insurance will not pay for it.
00:28:07 But when can prove it will work for the patient, then the insurance will cover it.
00:28:12 Now there are a few children walking around with the results of our organoid tests.
00:28:21 That is a wonderful application.
00:28:26 And it is easier than giving the stem cells to the patient.
00:28:30 we've shown we can take stem cells from a cystic fibrosis patients, hereditary disease, DNA error.
00:28:37 We can repair it using the CRISPR-Cas9 technique.
00:28:44 You can repair it from behind you computer, we already did this three years ago.
00:28:49 We cultivated stem cells for two patients, found repaired the error.
00:28:54 Then checked the whole DNA sequence.
00:28:59 We now have those cells.
00:29:01 If we would return the cells to the patients, the illness would be cured.
00:29:06 We still have a long way to go, doing this is not allowed yet.
00:29:09 But is is promising for the future.
00:29:11 If it would be allowed, this is what would happen?
00:29:12 It depends, not every organ is easily transplanted using stem cells.
00:29:17 The liver would be easy,
00:29:18 the lungs would be more difficult.
00:29:20 However we think this is the best way to attack hereditary disseases.
00:29:28 Repairing stem cells outside of the body.
00:29:31 I'm still stuck in you lab, where you've collected cells and issue that won't die. It's facinating, isn't it?
00:29:47 Well, we already knew, stem cells can keep our tissue intact for a long period of time.
00:29:58 What we've shown is you can take stem cells and multiply them outside of the body.
00:30:05 And in theory you could endlessly renew organs.
00:30:11 Like replacing parts on a car.
00:30:17 Over time we'll be able to do it for every organ,
00:30:21 In the end the question is, what will stand inbetween us and eternal life.
00:30:28 For me, that's our brain.
00:30:31 Where all your emotions and memories are stored.
00:30:37 You can't replace that with stem cells.
00:30:40 But you don't know yet?
00:30:42 There are science fiction writers...
00:30:45 There isn't that much information stored in your brain.
00:30:48 I think a large USB memory stick or hard drive could store it.
00:30:53 When we know how our brain works,
00:30:58 you could download everything, get a new brain and upload it again.
00:31:03 Sciencefiction...I think it would be very complicated ethically.
00:31:09 I understand, but if everything if made up of stem cells...
00:31:17 And is replacable...
00:31:19 What is interesting, we used to be taught you're born with a fixed amount of brain cells,
00:31:27 which are made in your first year.
00:31:32 But now some parts of the brain, like the hippocampus, have stem cells.
00:31:37 The memory department, keeps making new cells, keeps storing new memories.
00:31:45 No one knows what the relationship is, but it's the primary location of human brain stem cells.
00:31:54 Large parts of the brain probably don't have stem cells.
00:31:58 So what you have is what you've got.
00:32:01 So in the worst case, you're really stupid?
00:32:08 If you don't have a brain? You must be.
00:32:11 You wouldn't be able to do much...
00:32:13 The brain is quite important for controlling the body.
00:32:17 I've asked this before, but we didn't get to it. It sounds like you are occupied with the code of life.
00:32:27 Yes, yes. In my opinion the border of the individual being becomes a bit vague.
00:32:36 It generates many ethical questions.
00:32:40 If you think about species, my DNA code is mine, but it's not very different from yours,
00:32:47 and even less different from my parents'.
00:32:50 The DNA code is what makes our species.
00:32:54 Passed down from generation to generation. It hasn't been changed much for over three thousand years.
00:32:59 My body is just the carrier, the DNA gets passed on.
00:33:04 With our technology it's not just the code which is abstract, but parts of my body...
00:33:10 I just told you about that mouse. It died three years ago, but it's stem cells keep growing.
00:33:17 So the end of the life of most organ, turns out not to be so definite.
00:33:26 What does that mean?
00:33:29 Medically, it means you can keep people healthy for a longer time.
00:33:35 If you contemplate what you really are, I arrive at the things that are in my head.
00:33:45 Not much else about me is unique. My DNA code.
00:33:51 But in my body everything can be replaced. Like we now know how to do.
00:34:06 I think that's exeptional.
00:34:10 In biology, my life is just information.
00:34:17 The information stored in my brain,
00:34:22 and the information in my DNA. Given to me through evolution.
00:34:27 But my matter is completely replacable.
00:34:31 So you're a piece of information.
00:34:36 Do you understand?
00:34:38 Yes, I do. We're a code that can be programmed.
00:34:54 The code can be programmed. We've known this for a long time.
00:34:56 There is great amount of resistance, ethical obstacles.
00:35:00 But we've know for a long time.
00:35:01 We only know a small part of the code,
00:35:03 but in biology, discovering something can be hard,
00:35:09 but it is always easy to understand.
00:35:12 If you understand the principle, you can apply it. You can do it in the lab.
00:35:17 I'm convinced that we can understand and copy everything nature does.
00:35:24 We can even change it, but in the distant future.
00:35:29 But it won't become more abstract or complicated.
00:35:31 We learn more and more, but we always still comprehend it.
00:35:40 I feel that is different in physics and mathematics.
00:35:43 The further you go, the less comprehendable it becomes.
00:35:48 In biology, you can always explain things.
00:35:51 You explain it very well. It's really facinating,
00:35:57 your body is your vehicle, broken parts can be replaced. Like car parts.
00:36:18 It sounds like science fiction. But is isn't.
00:36:21 We regularly do organ transplantations, but not often enough.
00:36:27 We've been doing blood transfusions for eighty years or so.
00:36:32 This is more complex, but it is not different.
00:36:37 I am diabetic. My pancreas has sort of stopped working. Can that be solved?
00:36:50 You're probably a type 1 diabetic, so you don't have any beta cells.
00:36:56 There a huge field of research on making new beta cells. Cells that make insulin.
00:37:03 For some reason it works up to the last step, but then something is missing.
00:37:14 You could do it with your cells.
00:37:17 We could do it in my lab, with cells from your pancreas. Also, we could use a trick, using your skin cells, turning them into pancreas cells.
00:37:26 You can instruct them to produce hormones.
00:37:29 But what we can't do yet, is the final step. We can't place them back.
00:37:39 When you start making beta cells, they'll be destroyed.
00:37:45 For some reason you immune system thinks of the beta cell as it's enemy.
00:37:49 So that is a second obstacle, protecting the cells from your immune system.
00:37:55 You need to keep the immune system away from the cell,
00:37:58 or change the cell so it won't be seen as an enemy.
00:38:04 I don't know how to do it, but you say eventually it will be possible.
00:38:07 Not at the moment. But when I see how easy it is to make other tissue It'll just be a matter of time.
00:38:14 A lot of time?
00:38:18 Predicting science is always hard.
00:38:21 I think it really just takes one more discovery. It could be tomorrow.
00:38:30 But maybe they're not thinking of the right thing, of the right thing isn't available yet.
00:38:36 It might take ten years.
00:38:38 What do you dream of?
00:38:39 Regarding my own work...
00:38:43 Doesn't matter, about anything...
00:38:45 I hope to continue doing this for a long time, that's my biggest dream.
00:38:52 That I can experience from up close,
00:38:55 how biological science is exploding into a wealth of knowledge,
00:39:01 we wouldn't have dreamed of thirty years ago.
00:39:03 And that I can contribute.
00:39:06 I don't feel like I have to solve a big problem all by myself,
00:39:11 I'm part of an international community, with my lab.
00:39:16 To be able to help to take some of these steps, that's the dream.
00:39:20 That's what you're already doing!
00:39:22 Yes, maybe.
00:39:25 So then it's not really a dream anymore.
00:39:27 Well I must admit, thirty years ago, when I just started, while I was studying,
00:39:32 I was always going somewhere.
00:39:36 A family, a home, children. The kids need to go to school...
00:39:43 In my work I haven't had that feeling, for the past fifteen years.
00:39:46 I want to keep things the way they are. In my lab things have become easier, more succesful.
00:39:57 Isn't there something, something you know is possible, something you want to achieve?
00:40:05 Maybe I need to tell you how we work.
00:40:08 Many people thing scientist pose a question, then formulate an answer, a hypothesis.
00:40:21 And see if it's correct. But in our field, that doesn't work at all.
00:40:30 In reality we are like historians.
00:40:32 We try to find out how evolution overcame obstacles.
00:40:36 If a fish is swiming in water, and want to come to land. You can come up with many solutions.
00:40:45 The fish needs feet and lungs.
00:40:47 But I could've come up with completely different things.
00:40:51 I can't just imagine the way it happened, like Einstein.
00:40:55 I need to look at what evolution did.
00:40:58 It is a search for the solutions evolution came up with, by coincidence.
00:41:09 They might not be the best solutions, but they work.
00:41:12 Then it's embedded in DNA and every living being carries the solution.
00:41:17 It's completely random.
00:41:22 You ask a question, you don't know it it's the right one.
00:41:27 If you can even answer it using the current technology.
00:41:31 I think it is arrogant to think you can just figure out, what happened thirty five million years ago, somewhere on this planet.
00:41:41 Something that changed us from the way we were thirty five million years ago.
00:41:46 What works much better, is studying a system, like the intestine,
00:41:53 poking it left and right,
00:41:57 you must precisely measure and observe,
00:42:00 keep an open mind, just collect observations,
00:42:08 at a certain moment you'll see a pattern, this is dangerous,
00:42:11 those patterns usually don't exist, like in aboriginal art,
00:42:14 those patterns don't exist, you make them up.
00:42:17 cause and effect, typically associated, we automatically turn it into a story.
00:42:23 This caused that...
00:42:25 When you start thinking like that, you need to prove it.
00:42:30 I go wrong there all the time, people in my lab as well.
00:42:33 Keep observing until you discover a natural law.
00:42:40 Then you test it, but many people don't do this.
00:42:46 It's very hard to design a test that challenges your own hypothesis.
00:42:56 That's another problem.
00:42:58 If you're wrong, this is usually the case, you let the idea go and start to observe again.
00:43:05 Then people tend to make the idea more and more complex,
00:43:10 until it doesn't explain anything anymore.
00:43:13 This way many people reach a dead end.
00:43:16 For myself and in my lab I try to keep an open mind.
00:43:20 Attach importance to something that is at odds with what you observe.
00:43:31 You're inclined to see confirmation, and ignore contradictions.
00:43:36 That is very difficult for the human mind, to let things go.
00:43:43 We don't know how it works and take a step back.
00:43:45 Isn't that also evolution? Confirmation after confirmation...
00:43:53 Yes, well... INAUDIBLE.
00:44:02 Returning to the way we work, we ask very superficial questions, like how does this work,
00:44:13 you talk about it, read about it and as long as you design a good system,
00:44:20 in our case often with mice that have new traits, so we can clearly see something and study it.
00:44:27 Then a moment comes and you know how something works.
00:44:32 At that point you switch from being intuitive, the first fase is completely intuitive and associative,
00:44:38 you feed off of things you remember.
00:44:48 Then you recognize a pattern, you want to see if it's correct, and you test it.
00:44:55 How do you call that quality, this ability to see connections?
00:45:01 I'm not sure how it's described.
00:45:03 I feel like a scientist needs to have productive intuition.
00:45:11 It isn't imagination.
00:45:13 No, it's intuitive and subconscious thinking and relating.
00:45:20 Then you need luck, you need the associations you come up with to be productive.
00:45:27 I think for an artist the process is the same, but what you creatively come up with doesn't have to fit into reality.
00:45:42 If you're not creative you can't do this.
00:45:44 You need to use unexpected angles, memories, conversations an observation.
00:45:55 We talk about this a lot, everyone has their own way,
00:46:01 but often ideas often come from your subconscious mind.
00:46:06 You need some sort of censorship...
00:46:08 When do you get these ideas, when you're sleeping...
00:46:12 It often happend to me while I was running, while working out. Now it often happens...
00:46:17 Can you tell me how that works?
00:46:19 If you run fast you're not really thinking anymore.
00:46:22 But most of the time, after working out, you just get an idea.
00:46:30 Then you think it must be wrong, seven years ago we saw this...
00:46:35 I can feel it isn't right somehow, but I don't know why.
00:46:40 In my lab there is always someone else who feels the same.
00:46:43 And when you discuss it you think, seven years ago, darn I always knew.
00:46:51 And then you abandon the idea and start over.
00:46:55 It is productive creativity, you let things from your subconscience surface,
00:47:04 it can't be too much or too little.
00:47:13 You need to find a balance.
00:47:15 And you need a switch, you need to know when it's enough.
00:47:21 You take what seems right and start testing the idea.
00:47:25 At that moment the lab changes, everyone starts planning what to do.
00:47:32 Then within a week you know whether or not is't correct.
00:47:36 You know when everything you predict, works.
00:47:40 At the first try.
00:47:42 In that moment, what do you feel?
00:47:45 The whole lab becomes stoked, it's a lot of fun.
00:47:51 The advantage of having dutch people in you team, is that you experience it as a group.
00:47:58 In the United States people kept it for themselves, it was your personal succes.
00:48:05 I think that's the strength of our lab, everybody teams up, we work though the whole process together.
00:48:18 That is something you can learn.
00:48:22 I'm an experienced scientist, especially experienced in that process.
00:48:26 Turning that switch when you have enough and getting it out.
00:48:40 Can you try, as a scientist, to make a prediction?
00:48:46 You usually don't do this, but for this program,
00:48:51 the mind of the universe, we're looking for prospects, what can we expect from science in the future?
00:49:14 I can try.
00:49:18 What I know for certain, I'm not sure how long it will take,
00:49:30 but we will know exactly how our body constructs itself, and how it sustains itself.
00:49:35 That means we'll be able to repair any unhealthy organ, pobably using your own cells.
00:49:46 We'll be able to use your cells, outside of you body, to determine what drug is best for you.
00:49:54 Maybe even design better drugs.
00:49:57 Eventually, this leads to great ethical challenges,
00:50:05 we'll probably be able to optimize every individual's genetic code.
00:50:11 You can delete hereditary diseases, which isn't a major ethical problem.
00:50:19 But you could also change people's appearance, we can already do this, but we don't want to.
00:50:30 I think in the near future, we'll understand many hereditary traits
00:50:37 and we'll be able to manipulate them.
00:50:45 t's possible, but will it really happen...
00:50:49 It's not up to us.
00:50:52 I would like you to tell me about the aboriginal art, about the other things you study.
00:51:19 What is the opposite of your research?
00:51:25 The opposite of my work has always been sports.
00:51:29 And I've always read a great deal, I'm not good at doing nothing.
00:51:38 But recently I've become interested in the art of painting,
00:51:43 especially in Australian aboriginal art.
00:51:49 The history behind it this art came into existence like an explosion.
00:52:00 The aboriginals who had been painting on tree bark for fourty thousand years, suddenly had modern painting tools,
00:52:08 and started a huge art movement within fifteen years.
00:52:17 They create symbolic painting, usually big and colourful.
00:52:24 Patterns, depicting their genesis,
00:52:30 or maps showing where water was or where ceremonies where held.
00:52:36 When I look at it, I don't see what the story is, it is too strange.
00:52:46 But I can see the patterns,
00:52:48 how the painting brings about all kinds of associations in my mind.
00:52:56 It works exactly the same when we look at a image through a microscope.
00:53:01 Or a set of numbers.
00:53:03 And all kinds of patterns surface in our mind, and we have to wonder if they are in fact real patterns.
00:53:12 Does it fit into the whole of the painting, or the tissue?
00:53:17 I use the same creative processes... It's nice that it doesn't have to lead to a discovery.
00:53:28 You don't need to score, you can just enjoy it.
00:53:31 But it's very similar.
00:53:35 You look for a genetic code in their culture.
00:53:40 Yes, a code.
00:53:45 The genetic code is the start of everything in biology, it sets everything in motion.
00:53:52 You also find that in the art.
00:53:55 There literally is a code, using ancient symbols.
00:54:01 Of which I am now trying to understand the meaning.
00:54:06 It is a funny resemblance. What was it like, when first saw such a painting?
00:54:12 I was familiar with similar art from New Mexico, Native American art.
00:54:24 About five years ago, when I saw a painting that is currently in Amsterdam.
00:54:36 I became interested and discovered it was like the counterpart of what I do during the day.
00:54:46 You immediatly feel engaged, it's different from other art.
00:55:00 What does that say about art and science?
00:55:04 Art and science are much more related than most people think.
00:55:10 You can hear it in the words we use: passion, talent, enthusiasm.
00:55:16 Artists and scientists are facinated with the human being, our surroundings, our planet.
00:55:27 They ask and answer questions. They investigate and describe the world.
00:55:33 ninety percent of that process is the same,
00:55:38 the big difference is, an artist creates something unique,in any shape or form
00:55:48 But we produce the correct description of what the planet had created through evolution.
00:55:58 Although we can be creative, we are restricted by the truth.
00:56:07 It's not about what could be possible.
00:56:09 I think that's the big difference between art and science.
00:56:13 If we succeed to replace anything in our body, once it stops working, we can live forever. Right? What is stopping us?
00:56:24 There is one part of our body that can't be replaced, our brain.
00:56:29 I think, who I am, is in my brain.
00:56:37 It holds my emotions, my memories, me.
00:56:40 The way I see it every other part of you body is replaceable.
00:56:43 Is that your spirit?
00:56:45 You could call it that. Not a religious spirit, but it's me.
00:56:53 That's up here. I am my brain,
00:56:56 I'm convinced of that.
00:56:58 If I replace my brain, the hardware,
00:57:03 everything that is stored up there would be gone.
00:57:07 I'm not my brain's matter, it's the information in my brain.
00:57:18 Stem cell scientists won't solve that problem.
00:57:24 It's like software?
00:57:26 Yes, data, stored in your brain.
00:57:33 An operating system?
00:57:38 It's more like a hard disc.
00:57:40 Everything you've seen, learnt and experienced is stored in your brain.
00:57:46 Together, that is who you are.
00:57:53 It works like a computer, your brain is the hardware that is fed with external data.
00:58:04 Images, experiences, emotions.
00:58:07 That isn't something tangible you can transplant.
00:58:13 I think it is fine, it's not my goal to become one hundred twenty years old.
00:58:20 I think humans are built to live eighty to ninety years.
00:58:25 Yes, but we can replace everything...
00:58:32 The most common age related disease is cancer,
00:58:35 we'll eventually conquer this.
00:58:40 The stem cells make a mistake when rewriting the code,
00:58:45 if the mistake is in an unfornunate place, it becomes a cancer cell.
00:58:48 That's a disease you need to get rid of.
00:58:51 The wear and tear on bones needs to be solved.
00:58:57 In the end you can't replace the brain.
00:59:01 After puberty, your brain cells don't renew.
00:59:11 It doesn't work that way in a computer either.
00:59:16 If the brain is damaged, for example by a stroke, you can't just place stem cells and make it work again.
00:59:26 You can do it with any other organ, but not with the brain.
00:59:28 Becaus vital information is lost.
00:59:36 Does anything scare you?
00:59:40 No, not really.
00:59:45 When you're working on something do you ever get scared by the possibilities?
00:59:52 No, I don't think I've ever been scared.
00:59:56 But we're very aware, that when we take steps in our research,
01:00:03 it has implications we can't always foresee.
01:00:09 It has become an important step to us,
01:00:14 after overcomming a technological obstacle we ask ourselves, do we want this, what do we want to use it for.
01:00:22 That is not something a debate by myself, of with my colleagues.
01:00:26 The debate takes place in society.
01:00:29 But I'm never afraid of things we discover, because we are a product of nature.
01:00:35 When we discover something, it is natural.
01:00:38 It's not something to be afraid of.
01:00:41 Well, nature can be frightening.
01:00:43 That's true. But we can't be more frightening than nature.
01:00:51 If I assume everything you have discovered is true, aren't there other parties interested in that knowledge?
01:01:06 The knowledge is so precious, yet so explosive.
01:01:18 Does that bother you? Is the knowledge protected, is it safe?
01:01:25 Do you mean in the wrong hands...
01:01:29 I can think of Dr. Frankensteins that would be interested...
01:01:34 It is possible, with the work of some of my colleagues.
01:01:41 As we speak there are experiments mixing human stem cells with an animal's embryo, with a mouse or a pig
01:01:49 You get an individual that is part human and part mouse.
01:01:55 It is allowed on mice in England. Up to about two third of the mouse's pregnancy,
01:02:00 then it has to be terminated.
01:02:03 But that little mouse, after fourteen days, is part mouse and part human.
01:02:10 I don't do those kinds of experiments, I wouldn't want to.
01:02:14 But in England they are allowed.
01:02:17 In that direction, you can imagine quite scary things.
01:02:23 At the moment, something governments are backing,
01:02:28 if you have diabetes and you want a new pancreas
01:02:33 there are experiments farming pigs, pigs don't have a pancreas,
01:02:43 but are given human stem cells right after fertilization.
01:02:48 That way you get a pig with a human pancreas, and some other random human cells.
01:02:57 In Japan and Spain they are working on farms with pigs,
01:03:04 that can give people with diabetes a new pancreas.
01:03:10 The farming of organs, it's happening right now.
01:03:16 What do you find inspiring?
01:03:20 Looking at when I come up with an idea, it's either after an intense workout, or at conventions.
01:03:41 I travel al lot, when it's not my turn to speak at a convention, I sit at the back of the room,
01:03:47 many things happen around you, and out of nowhere an idea pops up.
01:04:03 Or while I'm on an airplane, not really focussed on anything, ideas tend to come up.
01:04:24 Have you even had an idea while looking at the aboriginal art?
01:04:30 No, no...
01:04:34 Can you imagine it happening?
01:04:40 When I look at the aboriginal art, I can feel the same things happening in my mind, the same enjoyment.
01:04:59 But I don't think the answers to my questions can be found in the aboriginal art.
01:05:04 It's the same pattern, it might be some kind of exercise.
01:05:14 But I don't think the answers are concealed within the art.
01:05:18 In your field of study, what is the magic word?
01:05:24 I don't understand...
01:05:26 What is the magic word for your field of study?
01:05:31 The magic word? I would think the discovery.
01:05:38 To have an insight no one has had before.
01:05:46 But there is no magic formula.
01:05:52 Beautiful, to discover something no one has seen before.
01:06:00 Maybe someone did see it, but didn't recognize it. That's also a possibility.
01:06:06 Well, in our work, evolution is history.
01:06:11 I've found an image, a drawing of stem cells, from 1888.
01:06:19 With an arrow, and a letter S,
01:06:26 I thought it stood for stem cell, but it meant small cell.
01:06:35 We watched the intestines for twenty years and couldn't find the stem cells until they lighted up.
01:06:40 And this man already saw them 150 years ago.
01:06:48 In 1960, a Canadese scientist spotted them again and predicted everything we've discovered.
01:07:02 We read about this afterwards,
01:07:05 everything was already known, it just needed to be proved.
01:07:12 These cells have been dicoverd three times, but now we were able to show what they are and what they can do.