Collaborating to Find Developmental Genes

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00:00:13.12 Hello. I'm Ron Vale
00:00:14.17 and today I have the pleasure to be
00:00:15.25 speaking with Dr. Christiane Nüsslein-Volhard
00:00:18.25 and Dr. Eric Wieschaus
00:00:20.18 who worked together as junior faculty
00:00:22.22 between 1978 and 1981
00:00:26.02 and made historic discoveries about genes
00:00:28.15 that are involved in controlling
00:00:29.27 embryonic development. Work that lead
00:00:32.13 to the Nobel Prize in 1995.
00:00:34.24 So thank you very much for joining us
00:00:37.15 today and perhaps we can begin
00:00:39.10 by describing some of the work
00:00:40.24 that you did and the discoveries that you made.
00:00:44.01 Nüsslein-Volhard: I started working with flies with the idea to
00:00:46.20 find morphogens by mutations in their genes.
00:00:54.02 At the time, people were trying to isolate
00:00:57.08 factors which would alter or change
00:01:00.08 embryonic development and they did that
00:01:04.20 by cutting and slicing experiments, essentially.
00:01:08.26 Transplantation. Centrifugations. All these things.
00:01:12.22 And all these experiments had lots of artifacts
00:01:15.26 and at the time, in our institute, they were
00:01:19.17 people who did genetics, in bacteria,
00:01:22.24 trying to identify genes involved in
00:01:25.17 DNA replication and I figured if
00:01:28.00 one would try the same methods
00:01:29.26 to development: making a mutation
00:01:34.12 in a gene which is really important
00:01:36.22 for embryonic development
00:01:38.09 then you should see it in
00:01:39.14 phenotype and the gene would
00:01:41.20 be encoding something we are looking for.
00:01:48.06 I mean, drosophila genetics
00:01:49.27 had been done but mostly on
00:01:51.14 the structures of the adult fly.
00:01:53.01 Only very few people looked
00:01:54.17 at embryos at the time.
00:01:56.17 And Eric was one of them.
00:01:58.08 Wieschaus: Yeah.
00:01:58.28 Nüsslein-Volhard: I met Eric in Walter Gehring's lab
00:02:01.18 in Basel where he was already
00:02:04.09 finishing his thesis on
00:02:05.29 Drosophila embryology
00:02:08.08 and I found that extremely exciting
00:02:11.11 and learned a lot from him.
00:02:12.13 And then we joined later.
00:02:13.26 Wieschaus: Yeah. I think you've,
00:02:17.13 your sense of the problem was a
00:02:19.21 bit more, was actually really directed
00:02:22.02 towards morphogens. Whereas
00:02:24.18 I came into the field, I think,
00:02:28.08 because I had, as an embryologist,
00:02:32.09 didn't have the molecular training,
00:02:34.25 even the genetics training,
00:02:36.28 In a certain sense, I had.
00:02:39.01 I worked on flies all my life
00:02:40.14 but what really fascinated me was
00:02:43.26 watching embryos develop,
00:02:47.24 and that these things happen
00:02:51.19 that are reproducible and
00:02:56.03 mysterious but in some way had,
00:03:01.16 by that time, we knew, had to
00:03:03.26 depend on specific proteins
00:03:07.01 and therefore specific genes.
00:03:08.20 If genes are important
00:03:10.12 for morphogens, if they are important for
00:03:12.00 everything an embryo does,
00:03:13.07 then if you knocked.
00:03:16.07 If you set up a program where
00:03:17.21 you are going to randomly
00:03:19.24 mutagenize genes, knock them out,
00:03:23.04 in set of little inbred lines because flies are diploid,
00:03:27.13 and then look at the consequences of
00:03:30.05 thousands and thousands and thousands of mutations
00:03:34.04 to identify which mutations
00:03:37.22 in which genes therefore affect processes
00:03:41.10 that are discrete and understandable in the embryo.
00:03:44.23 Just about what we did.
00:03:45.25 We struggled to do it for several years
00:03:48.27 to figure out how we could do it.
00:03:49.25 Nüsslein-Volhard: It took some time until we
00:03:51.06 focused in on this project.
00:03:53.06 Wieschaus: And how to do it.
00:03:55.00 Because people had that mutagenesis.
00:03:57.01 Ed Lewis had figured out how to use EMS
00:03:59.24 to induce mutations. That was a huge, wonderful thing
00:04:02.26 about flies. People had worked on them
00:04:04.24 so we knew how to do stuff.
00:04:05.23 But how to do it on the scale that
00:04:11.14 we thought was necessary to actually
00:04:16.08 to get enough of the pieces of the puzzle
00:04:19.00 to get a picture of what was
00:04:21.19 really happening was hard.
00:04:23.07 Nüsslein-Volhard: One of the things we did
00:04:24.25 which contrasted the previous work
00:04:27.11 is that we figured that the result of
00:04:30.17 embryonic development would the larva
00:04:32.03 and not the fly so we should
00:04:33.19 look at larval structure and not at fly structures.
00:04:36.02 And this is what he did in his
00:04:37.19 thesis and then we turned to
00:04:39.17 developing methods.
00:04:41.13 How you could really see the segments
00:04:43.15 in a living embryo and also in a
00:04:45.17 prepared embryo and use
00:04:47.16 this pattern of the cuticle
00:04:49.03 which is displaying the segmentation
00:04:51.25 as landmarks for identifying mutants.
00:04:54.27 We established 12,000 inbred lines
00:05:00.00 which had on average had 1 or 2 mutations
00:05:02.27 in them and looked at the consequences in the
00:05:06.07 embryonic pattern in the larva, in the cuticle
00:05:11.24 and we discovered 120 new genes
00:05:15.04 which when mutated, caused strong
00:05:19.17 changes. Distinguishable, visable changes in the pattern
00:05:24.28 which was a small fraction of the entire
00:05:27.07 genome, about 1% or so.
00:05:29.08 Wieschaus: So we were lucky there.
00:05:30.13 Nüsslein-Volhard: Most of the genes, when mutated,
00:05:33.05 don't cause any morphological
00:05:35.12 visible alterations. Embryos just die.
00:05:38.09 They look normal. But we'd pulled out
00:05:40.24 those that did not look normal.
00:05:43.10 Wieschaus: After that initial screen,
00:05:45.11 to bring most of those loci to a point of
00:05:50.14 publication still took 3 or 4 years.
00:05:55.08 To go from, we did the screens,
00:05:58.03 we published an initial paper in Nature
00:06:00.10 on the small class that affected segmentation
00:06:03.19 but the broad group of 120, 130
00:06:08.27 genes that affected all aspects of
00:06:11.21 embryonic development, to map,
00:06:14.27 to characterize, to assign to complementation groups
00:06:17.05 all of that took 3 more years.
00:06:21.07 Vale: So the two of you worked very closely
00:06:23.10 together during this time
00:06:25.11 and I'm curious: what features of
00:06:28.22 about you as scientists were similar
00:06:30.23 that allowed you to really synergize in the
00:06:34.13 type of work you did and
00:06:36.01 in the discoveries that you made?
00:06:37.14 :Nüsslein-Volhard: We share one feature which is
00:06:40.19 important. We are very good
00:06:41.28 observers, both. I think, hardly anyone who can...
00:06:50.07 Wieschaus: It was terrible. It was wonderful but I mean
00:06:52.29 Nüsslein-Volhard: We really matched up on
00:06:54.24 this and it's rare that you match up
00:06:57.13 with other people in this special
00:06:59.06 quality that you really
00:07:00.24 recognize minute details
00:07:03.10 and I think we are equal
00:07:05.27 in this respect and it was
00:07:07.23 maybe really exceptional that
00:07:10.15 two people who are so
00:07:12.09 good in observing shared
00:07:15.12 this project. We had this
00:07:17.13 dissection scope where we looked
00:07:19.01 in from two sides on the same
00:07:21.14 embryos and then we
00:07:22.22 and one said "Ah look. Look at this!"
00:07:25.29 and then "Yes I've seen it already." This kind of thing.
00:07:28.05 We really, we had some phenotypes
00:07:31.17 which were so subtle and we both
00:07:34.09 saw them and then we discussed
00:07:36.17 is it worth keeping?
00:07:38.12 Is it not worth keeping?
00:07:39.23 We had to kind of have these cut off
00:07:41.07 criteria where one bristle too little or
00:07:44.09 one hair too curled?
00:07:47.15 Is it enough to be significant?
00:07:49.16 We did agree in most cases.
00:07:53.25 Wieschaus: There was of course a kind of
00:07:55.21 not quite a comp...
00:07:58.17 well maybe yes, a competitive
00:08:00.01 element in that because we were
00:08:02.20 so equally matched in the ability to see
00:08:05.29 phenotypes that were phenotypes
00:08:09.21 that, you know, you have this huge
00:08:12.04 mound of slides and you are looking
00:08:13.17 through them one at a time
00:08:15.16 and most of slides are garbage
00:08:17.08 because you just did embryos
00:08:20.08 from mutagenized stocks and so
00:08:22.07 the whole trick was to sort,
00:08:24.00 put the slide on and look at
00:08:25.26 it and recognize that there was a
00:08:27.14 quarter of the embryos that showed a
00:08:29.19 discrete phenotype. It could have
00:08:33.10 happened that either one of us was,
00:08:35.09 despite of our observational abilities,
00:08:38.14 could have been temporarily distracted
00:08:41.05 and the other would see the
00:08:43.18 phenotype first.
00:08:45.10 Nüsslein-Volhard: That kept us awake.
00:08:48.21 It was very important.
00:08:49.14 It's a tough job and it is extremely tiring.
00:08:54.12 When you look all the time.
00:08:55.05 It's like when you are in a museum
00:08:56.14 and you are there in the museum
00:08:58.04 and you are content. But when someone
00:09:00.11 goes with you and says
00:09:01.05 "Look at this, look at this"
00:09:02.18 then its much, much easier.
00:09:04.16 Wieschaus: And you did actually
00:09:06.13 develop a special relationship
00:09:09.06 to those loci that are mutant lines
00:09:13.24 that you saw, that I saw, first
00:09:16.16 and she didn't see until three seconds later
00:09:20.06 on the slide. So those became really
00:09:23.21 like they were mine and you also have.
00:09:28.05 These will stay secret. These are genes that
00:09:33.07 are out in the public domain now and so
00:09:35.18 you don't necessarily want to know
00:09:36.22 who are Janni's special children and who
00:09:40.01 are my special children in that respect.
00:09:42.01 Vale: So Janni, I was struck by one of the
00:09:44.18 the quotes in your Nobel Prize biography,
00:09:47.05 which said that "We realized the screening
00:09:51.20 for embryonic mutants would be very rewarding
00:09:54.05 and that we were the only people
00:09:56.10 in the world that could do it, "
00:09:57.22 and I’m just curious what that
00:10:00.00 meant and if you could elaborate on that?
00:10:02.17 Nüsslein-Volhard: True. No?
00:10:04.10 Wieschaus: At the time, certainly
00:10:08.02 but that is the kind of statement
00:10:11.28 you have to justify so now is your moment.
00:10:14.22 [Nüsslein-Volhard] You mean it's too arrogant
00:10:16.03 in such a biography?
00:10:17.14 No, it was strange. Listen Ron,
00:10:20.07 I remember when we had done the screen
00:10:23.26 and we were thrilled and we thought
00:10:25.18 "Shesh this is exciting" and we had
00:10:27.01 a poster of 48 pictures of
00:10:30.15 these mutants on the
00:10:31.23 second chromosome and
00:10:34.01 they were extremely significant,
00:10:35.16 the phenotypes, and
00:10:37.10 we knew that we couldn't
00:10:39.07 interpret them properly but
00:10:40.09 we knew each of them has
00:10:41.18 to be explained and put
00:10:43.27 into some framework before
00:10:45.12 we understand how embryos are made.
00:10:47.15 So it was a great achievement
00:10:50.17 we were sort of proud about it, sure.
00:10:53.05 And we presented this in a
00:10:56.00 drosophila meeting where there
00:10:59.13 the biggies of the field were
00:11:01.09 present and they stood in
00:11:03.25 front of this poster and "Oh, what's this?"
00:11:07.11 and then they turned around
00:11:09.20 and went away.
00:11:11.02 They couldn't understand it.
00:11:13.05 They didn't even
00:11:14.29 They had no…they didn't even say "Wow! Oh!"
00:11:20.18 I mean some hostile. Others
00:11:25.29 were completely insecure,
00:11:28.03 didn't know what to say
00:11:29.19 And this was the response.
00:11:31.03 And this was sort of...
00:11:36.01 This is why we say "Well,
00:11:37.21 only we could have done it."
00:11:38.25 I mean, if no one can
00:11:40.06 understand it, it means no one else
00:11:42.28 could've done it too.
00:11:45.05 Vale: So I gather that the two of
00:11:46.13 you first met in Walter Gehring’s lab although
00:11:49.24 you only overlapped for a short period
00:11:51.22 of time. Was there something
00:11:53.24 about when you first meet
00:11:55.08 each other that you realized you had
00:11:56.23 similar interests or similar intellectual curiosities?
00:12:01.03 Nüsslein-Volhard: So I went to work
00:12:02.18 in Walter Gerhring's lab actually
00:12:04.06 Wieschaus: In January.
00:12:05.20 Nüsslein-Volhard: In January 1975
00:12:10.17 and Eric had just finished his
00:12:13.01 thesis and that was full of
00:12:16.04 people who came to work with
00:12:18.22 drosophila without having
00:12:20.29 worked on drosophila before
00:12:22.24 and Eric was one of the
00:12:24.01 very few people in this
00:12:25.04 lab who knew something
00:12:26.13 about embryos. He
00:12:27.22 knew something embryos
00:12:29.00 and it was another woman,
00:12:30.15 Jeanette Holden, who
00:12:31.23 knew drosophila genetics
00:12:33.10 and so I tried to get as much
00:12:36.29 out of them as I could.
00:12:38.06 Jeanette left after half a year
00:12:40.16 later and Eric left a couple
00:12:43.26 months. He had already started to
00:12:45.23 move to Zurich but I tried to
00:12:47.22 and he came back because he
00:12:49.05 had a collaboration with
00:12:49.28 people and I just tried to get
00:12:52.08 as much knowledge out of him
00:12:53.26 as I possible could and
00:12:56.12 that was a time for me, for which I was
00:12:58.28 eagerly picking up whatever I
00:13:01.13 could get and it was
00:13:03.00 so exciting. I dreamt of flies
00:13:05.15 when I closed my eyes I saw
00:13:06.21 fly embryos.
00:13:11.09 Wieschaus: We used to met and eat
00:13:12.17 dinner together and talk
00:13:15.04 about stuff. I think we talked about
00:13:18.14 science. We talked about art.
00:13:21.00 I was, you know because I grew up in
00:13:22.20 in Alabama, I was like...
00:13:23.19 Nüsslein-Volhard: I knew nothing about
00:13:24.04 imaginal discs. I had a hard time
00:13:26.16 understanding your thesis and was so...
00:13:29.04 Wieschaus: I had a hard time understanding my thesis!
00:13:34.02 Nüsslein-Volhard: But we had common interests too. I
00:13:36.23 I mean music and drawing and arts.
00:13:39.28 So both of you then did your postdocs
00:13:42.20 and then you both got hired
00:13:45.08 at pretty much the same time at
00:13:47.01 the European Molecular Biology Lab.
00:13:49.04 Was that just a coincidence or was
00:13:52.00 there some planned synergy
00:13:53.24 that brought the two of you together?
00:13:55.22 Nüsslein-Volhard: I was looking
00:13:56.12 for a job after two years in
00:13:57.22 Walter's lab. I had an EBMO fellowship
00:14:00.10 which run out and he and I
00:14:03.04 didn't hit off together too well
00:14:06.00 actually and I wanted to leave but I
00:14:11.09 didn't have a place to go
00:14:13.02 so I applied to the EMBL,
00:14:15.13 which was new at the time,
00:14:17.25 it was the second year or so,
00:14:19.19 and I didn't get a job because
00:14:24.21 people said "Well maybe she
00:14:26.12 can't do that alone,
00:14:27.16 she is just started working with
00:14:29.26 flies and in case some other fly
00:14:33.06 people come to the lab
00:14:34.09 yes, maybe but not alone."
00:14:36.25 And then I first got a
00:14:41.08 another fellowship and went to
00:14:42.27 Freiburg and spent a year in
00:14:45.20 Klaus Sander's lab and
00:14:47.00 embryologist, insect embryologist,
00:14:49.19 and then I got the offer from the
00:14:52.16 EMBL and they had in the meantime
00:14:54.21 asked Eric. You had been asked hadn't you?
00:14:57.27 Wieschaus: I was asked to...
00:14:59.05 Nüsslein-Volhard: You hadn't even applied.
00:15:00.07 Wieschaus: I hadn't applied.
00:15:00.21 Nüsslein-Volhard: He didn't have to
00:15:01.13 apply. He just was asked
00:15:03.05 would you be interested in
00:15:05.01 coming to the EMBL.
00:15:07.24 What a luxury!
00:15:09.08 Wieschaus: Yeah, it was pretty cool.
00:15:11.02 Nüsslein-Volhard: I was struggling and I dreamt of
00:15:13.19 being out of unemployment and
00:15:15.16 didn't know what to do and I wrote
00:15:17.02 letters to people I didn't really
00:15:18.28 respect and begged them to
00:15:20.22 give me a job. It was really
00:15:22.00 tough because I had
00:15:23.19 started working with flies
00:15:25.06 only when I was the age of 32.
00:15:27.26 I had done a long PhD,
00:15:29.00 a good, interesting PhD, on
00:15:31.01 bacteria genetics, no, bacterial
00:15:32.29 molecular biology and then
00:15:35.17 switched to flies with great
00:15:38.07 enthusiasm but in a short time
00:15:40.15 in the lab and in Walter's lab, I had
00:15:43.18 published a paper in contrast to
00:15:46.02 all these other brilliant
00:15:47.07 postdocs who took them much
00:15:49.19 longer to publish something
00:15:50.20 but I didn't get a job for that
00:15:53.05 because this was not a field for which
00:15:55.18 it was not a big field and people were...nah.
00:15:59.06 I didn't get credit for what
00:16:01.01 I had done before so
00:16:02.11 for me it was a tough time
00:16:03.15 I must say. And then
00:16:05.21 when I got the job at EMBL
00:16:07.05 I was of course thrilled and
00:16:08.19 together with Eric, oh great fun, yes!
00:16:10.26 But they treated us in a very
00:16:12.19 "maybe we can take this risk
00:16:16.04 it's not so expensive. let's take
00:16:17.20 these two guys and put them in
00:16:19.08 the smallest lab" and a very
00:16:20.25 small, we had a...
00:16:22.23 an office space together
00:16:25.05 two by two meters.
00:16:27.01 Wieschaus: We discussed a lot.
00:16:31.16 Nüsslein-Volhard: But not in this phase.
00:16:34.19 The lab was really so small that
00:16:36.10 it was a bit hard but we didn't
00:16:41.21 bother to much and we just tried to
00:16:43.16 to get our microscopes working and
00:16:44.28 going and we got a technician,
00:16:47.03 shared technician, and a
00:16:49.03 girl who took care of the
00:16:53.15 flies and then we had a good set up.
00:16:56.17 we had no students. It was also no
00:16:59.11 discussion of whether you get
00:17:01.04 PhD students. We just were
00:17:03.03 on our own. So we were
00:17:04.17 a two headed group without a body, essentially.
00:17:10.01 Wieschaus: Essentially for us,
00:17:11.08 being in the lab, having the
00:17:14.10 facilities that were available
00:17:15.27 at the EMBL, not having to worry about
00:17:19.00 teaching, not having worry about
00:17:20.22 money, being in this small group
00:17:23.26 where the most obvious thing for us
00:17:26.07 to do was to push forward
00:17:28.29 this common experiment.
00:17:31.13 That was enough! I mean
00:17:34.04 there we were and we could talk.
00:17:38.03 We talked with each other a lot
00:17:42.20 and then it we went off and you knew
00:17:48.14 other people. It wasn't totally enough
00:17:50.22 and it wasn't that we were totally
00:17:52.03 isolated but the reason why it worked
00:17:55.26 was that we were intellectually
00:17:57.25 dependent on each other.
00:17:59.01 Vale: So I was wondering how you're
00:18:02.04 experience might be relevant
00:18:05.09 for young people today who
00:18:08.08 are obviously trying to start their own careers
00:18:10.00 and achieve their own independence
00:18:12.08 but also want to collaborate with
00:18:13.25 one another?
00:18:14.29 Wieschaus: The good thing about
00:18:16.06 obviously the good thing about
00:18:17.09 collaborations is when they work
00:18:18.21 is that you do have
00:18:21.01 two people, that if they are
00:18:22.27 really good and they, even
00:18:26.15 if it's not truly yin and yang,
00:18:30.02 complementary, it is an overlapping
00:18:38.03 synergism that is hard to predict
00:18:39.28 but I think that's why you want to
00:18:41.15 why you are really lucky in your
00:18:45.07 career if you are able to collaborate.
00:18:49.29 Nüsslein-Volhard: And in this case,
00:18:51.09 I think that none of us could have done
00:18:53.12 this project alone and it got much richer
00:18:57.23 with two of us. Also the quality of the
00:18:59.28 analysis, I think, is not just
00:19:01.20 maybe could have discovered
00:19:05.06 120 genes but how you describe them
00:19:07.21 and how you put them in order.
00:19:09.09 I think that was really much,
00:19:12.01 much, much better with us
00:19:14.17 two together compared to each of us
00:19:17.27 singularly and I think it's the best
00:19:20.12 project I’ve done in my life.
00:19:24.05 Wieschaus: I have to obviously say
00:19:26.05 that it was the great time in my own career.

This Talk

Speakers: Eric Wieschaus, Christiane Nüsslein-Volhard

Audience:

Educators of H. School / Intro Undergrad
Student
Educators of Adv. Undergrad / Grad
Researcher

Recorded: July 2013

Talk Overview

While working together as junior faculty at the European Molecular Biology Laboratory (EMBL) from 1978 to 1981, Christiane Nüsslein-Volhard and Eric Wieschaus made groundbreaking discoveries about developmental genes in fruitflies. In this interview, Nobel Laureates Nüsslein-Volhard and Wieschaus reminisce about their early experiments, successful collaboration, and what it was like to work in a field in which very little was known at the time.

Speaker Bio

Eric Wieschaus

I grew up in Birmingham, Alabama and did my undergraduate work at University of Notre Dame. During my graduate work at Yale University, the professor I was working with (Walter Gehring) decided to return to his home country of Switzerland and I followed him and completed my Ph. D research in Basel, Swizterland. After doing… Continue Reading

Christiane Nüsslein-Volhard

Christiane Nüsslein-Volhard is the Director of Genetics at the Max Planck Institute for Developmental Biology. Throughout her career, Nüsslein-Volhard has studied the genetic basis of development and morphological variation using Drosophila and zebrafish as model systems. She was awarded the 1991 Albert Lasker Award for Basic Medical Research. Continue Reading