New Drugs for old Bugs (Drug Development – Yonath & Kobilka)


We should all be worried by the growing number of antibiotic-resistant bacteria and we urgently need to develop new drugs, says Ada Yonath. She and Brian Kobilka won Nobel Prizes for using x-ray crystallography to understand cell structures that are vital targets for drug development. In this film, three researchers challenge the structural approach and propose alternative ways to find drugs; some cutting edge, such as computation, and some ancient, such as searching for chemicals deep in the rain forest. What is the best way forward? Or is a combination of techniques the most promising approach?

Neue Antibiotika durch Strukturbiologie – Tom Steitz und Ada Yonath

Ein Leitmotiv des diesjährigen Treffens ist die Frage, wie die Medizin der Zukunft aussehen könnte. Harald zur Hausen hat betont, dass möglicherweise in der Prävention von Krankheiten größeres Potential steckt als in der Entwicklung von Therapien. Martin Evans, der den Nobelpreis für Isolierung embryonaler Stammzellen erhielt, sprach die Möglichkeiten und Hürden der personalisierten Medizin an. Eine konkretere Antwort lieferte Tom Steitz. Er erklärte in seinem Vortrag, wie in seiner Arbeitsgruppe strukturbiologisches Forschungsergebnisse genutzt werden um neue Antibiotika zu entwickeln.

Steitz erhielt den Nobelpreis für Chemie 2009 zusammen mit Venki Ramakrishnan und Ada Yonath (die am Montag hier in Lindau einen Vortag hielt) für die Aufklärung der Sturkur und des Mechanismus des Ribosoms.

Ribosomenen sind große molekulare Maschinen aus zwei Untereinheiten, die jeweils aus RNA und Proteinen bestehen, und die sich nach Bindung der mRNA, also der zu übersetenden Information, zum fertigen Ribosom zusammenlagern. In einem komplizierten und trotzdem rasend schnell ablaufenden Prozess wird die mRNA durch das Ribosom geleitet, spezifische tRNAs erkennen komplementäre Sequenzen auf der mRNA und liefern die passenden Aminosäuren an, die dann am Ribosom zu Aminosäureketten verbunden werden. Die so synthetisierte Aminonsäurekette verlässt das Ribosom durch einen Tunnel in der Struktur des Ribosoms und lagert sich danach zu fertigen, funktionalen Proteinen zusammen. Ribosomen übersetzen also die genetische Information in Proteine.

Diese komplexen Maschinen kommen in allen lebenden Organismen vor – mit kleinen, jedoch sehr wichtigen Unterschieden zwischen den bakteriellen Ribosomen und jenen in menschlichen Zellen. Diese kleinen Unterschiede bieten die Angriffspunkte für rund 40% der gängigen Antibiotikaklassen: Chloramphenicol und Tetracyclin binden beispielsweise an der Stelle an der die tRNA an das Ribosom herangeführt wird und hemmen so die Proteinsynthese. Clindamycin verhindert die Bildung der Peptidbindungen zwischen den einzelnen Aminoäuren und Erythromycin blockiert den Ausgangstunnel, es kommt sozusagen zu molekularer Verstopfung.

 Blick in den Ribosomentunnel. Einige dort bindende Antibiotika sind farbig eingezeichnet

Blick in den Ribosomentunnel. Einige dort bindende Antibiotika sind farbig eingezeichnet

Antibiotika können therapeutisch eingesetzt werden, da sie aufgrund der kleinen Unterschiede zwischen bakteriellen Ribosomen und denen von Menschen, spezifisch die Proteinsynthese in den Krankheitserregern hemmen, die Funktion der Ribosomen in den körpereigenen Zellen jedoch nicht beeinflussen.

Gleichzeitig bergen die kleine Unterschiede zwischen den Ribosomen von Bakterien und Menschen jedoch auch die Gefahr für bakterielle Antibiotikaresistenzen. Beispielsweise reicht eine einzelne mutierte Aminosäure im Ausgangstunnel des Ribosoms aus, um die Bindung von Erythromyzin zu verhindern. Und genau hier ist der Punkt an dem biomedizinische Grundlagenforschung bei der Entwicklung neuer Antibiotika hilft.

Durch die Aufklärung der Struktur des Ribosoms durch Yonath und Steitz, buchstäblich bis aufs Atom, kann die Bindung der Antibiotika genau modelliert werden. Dadurch ist die Möglichkeit gegeben, bekannte Antibiotika zuerst am Computer so zu verändern, dass sie an neue, kritische Stellen spezifisch im Bakterienribosom binden, oder sogar ganz neue Antibiotika in silico zu entwerfen – basierend alleine auf der Kenntnis der Wechselwirkungen zwischen Aminosäureseitenketten des Ribosoms und den Bausteinen des Antibiotikums.

Es ist ein ständiger Wettlauf zwischen der Entwicklung neuer Antibiotika und der Ausbildung von Resistenzen in den Organismen, die damit abgetötet werden sollen. Durch die Ausnutzung der strukturbiologischen Kenntnis des Ribosoms hat möglicherweise wieder der Mensch die Nase vorne. Zumindest so lange, bis pathogene Bakterien sich wieder angepasst haben.

Hier eingebunden noch ein Video vom Prozess der Proteinsynthese. Es veranschaulicht die Komplexität und die Schönheit eines der grundsätzlichsten Mechanismen des Lebens. Das Video stammt von Venki Ramakrishnan, dem dritten Nobelpreisträger für das Ribosom 2009.

Noble Sätze – Verraten Original-Publikationen den Nobelpreis?

Wie alle Wissenschaftler publizieren auch zukünftige Nobelpreisträger ihre Forschungsergebnisse in peer-revieweten Wissenschaftsmagazinen. Ihre ursprünglich veröffentlichten Ergebnisse, Thesen und Ideen sind in den digitalen Archiven der Wissenschaftsliteratur auch Jahre und Jahrzehnte später konserviert, als wären sie erst gestern publiziert worden. 

Lucas Brouwers, der Kollege im englischen Lindau Blog und dessen Blogpost ich hier frei übersetze, hatte eine nette Idee: Er hat sich die Originalveröffentlichungen der Laureaten angeschaut und untersucht, ob dort bereits Spuren der tiefen Einsicht oder der gloreichen Entdeckungen erkennbar sind, die zum Nobelpreis führen sollten. Gibt es Absätze in den Papers, die den Erfolg, welche die Autoren Jahre später hatten,  vorwegnehmen?  Gibt es den einen nobelpreiswürdigen Satz?


Natürlich nicht. Es ist lächerlich zu meinen das der wissenschaftliche Fortschritt auf ein einzelnes Paper oder gar einem einzelnen Satz kondensiert werden kann. Wissenschaftliche Einsicht ist ein Prozess und sie kommt nicht als Geniestreich. Sogar die Laureaten bauen auf das Wissen der Forscher vor ihnen.

Ich denke dennoch, dass es interessant ist, wie die Nobelpreisträger, die dieses Jahr am Treffen in Lindau teilnehmen ursprünglich von ihren Ergebnisse berichteten. Ich habe daher deren Schlüsselpublikationen gelesen und die Sätze ausgewählt, die meiner Meinung nach die Idee, die zum Nobelpreis geführt hat, am besten repräsentiert.

Aus den Zitaten wird klar, dass es nicht den einen Weg gibt eine Entdeckung oder Erkenntnis zu veröffentlichen. Zum Teil sind es technische Beschreibungen, zum Teil sind es klare Worte. Manche sind im Aktiv geschrieben, andere im Passiv. Aber sie haben eines gemein: Alle sind ausgezeichnete Beispiele hervorragender Wissenschaft und Teil der Speerspitze unseres Wissens.

Unten die Beispielsätze mit Links zu den Papers. (eventuelle Fehler sowie mehr oder weniger gelungene Wahl der Schlüsselveröffentlichung sind Lucas zu zu schreiben! :-))

Peter Agre gibt die Entdeckung von Wasserkanälen in Membranen bekannt:
“Our observations strongly suggest that CHIP28 is the functional unit of the constitutively active water channels of RBCs and proximal renal tubules.” (ref)

Werner Arber liefert den Schlüssel, das Restriktionsenzyme spezifische DNA Sequenzen erkennen:
“It is concluded that host specificity is carried on the bacteriophage DNA.” (ref)

Elizabeth Blackburn beschreibt zum ersten Mal ein Telomer:
“The results described in this paper show that at each end of the palindromic, extra-chromosomal rDNA molecules there is a tandemly repeating hexanucleotide sequence.” (ref)

Aaron Ciechanover und Avram Hershko über die Entdeckung des Ubiquitin-basierten Proteinabbaus:
“We now report that the ATP-dependent cell-free system is composed of complementing species, and describe the properties of one of the components.” (ref)

Christian de Duve entdeckt das Lysosom:
“Acid phosphatase is attached to a special type of cytoplasmic granules, differing both from the [..] mitochondria and from the [..] microsomes.” (ref)

Sir Martin Evans beschreibt die erste Isolierung embyonaler Stammzellen von Mäusen:
“We have demonstrated here that it is possible to isolate pluripotential cells directly from early embryos.” (ref)

Edmond Fisher beschreibt die reversible phosphorylierung als Regulationsmechanismus:
“The activation and inactivation of muscle phosphorylase, which results from the interconversion of phosphorylases b and a, constitutes an important mechanism by which the metabolism of carbohydrate in this tissue may be controlled.” (ref)

Robert Huber und Michel Hartmut geben bekannt, dass sie die Struktur des photosynthetischen Reaktionszentrums gelöst haben:
“In this letter we report the spatial arrangement of the prosthetic groups in the photosynthetic reaction centre as the first result of our structure analysis at 3 angstrom resolution” (ref)

Sir Harold Kroto witzelt über den Namen “buckminsterfullerene” oder “bucky balls”, die er und sein Team synthetisiert haben:
“We are disturbed at the number of letters and syllables in the rather fanciful but highly appropriate name we have chosen in the title to refer to this C60 species” (ref)

Jean-Marie Lehn beschreibt die Synthese von Cryptanden:
“In previous communications, we described the synthesis of a macroheterobicyclical compound.” (aus dem Französischen übersetzt: Dans la communication précédente nous avons décrit la synthèse de composés macrohétérobicycliques.) (ref)

Anmerkung: Das ist die erste Erwähnung der Cryptanden die ich von Jean-Marie Lehn finden konnte. Der Satz enthält einen Literaturverweis, der aber nur als “previous communication” im Literaturverzeichnis ausgeführt wird. 

Ferid Murad beschreibt wie einfache Stickstoffmonoxidmoleküle die Aktivität eines Enzyms regulieren können:
While the precise mechanism of guanylate cyclase activation by these agents is not known, activation may be due to the formation of nitric oxide. (ref)

Ei-ichi Negishi beschreibt zum ersten mal die Bindung einer organo-zink Verbindung an ein Halogen mit Hilfe eines Palladium-Katalysators (diese Reaktion wird später die “Negishi-Reaktion” genannt):
“We now report that organozinc compounds readily participate in the Ni- or PD-catalyzed cross-coupling reaction.” (ref)

Erwin Neher und Bert Sakmann beschreiben zum ersten Mal das Verhalten eines einzelnen Ionenkanals:

“We have formed the following picture of acetylcholine receptors [..]: a channel opens and closes rapidly.” (ref)

Hamilton Smith entdeckt TypII Restriktionsenzyme:
“We have made the chance discovery of what appears to be [..] an enzyme in Hemophilus influenza which specifically degrades foreign DNA.” (ref 1 and ref 2)

Oliver Smithies schreibt, dass er mit Hilfe der homologen Rekombination erfolgreich ein fremdes Gen in ein Wirbeltiergenom eingeführt:
“The experiments reported here establish that the planned modification of a specific human gene can be accomplished in mammalian cells by homologous recombination without detectably affecting other parts of the genome.” (ref)

Thomas Steitz  über die Aufklärung der Struktur des Ribosoms:
“The analysis of the 50S ribosomal subunit structure presented here describes the overall architectural principles of RNA folding and its interaction with proteins, but many exciting details remain to be explored.” (ref)

Roger Tsien sieht die Zukunft fluoreszierender Proteine in der biologischen Forschung voraus:
“The availability of several forms of GFP [..] should facilitate two-color assessment of differential gene expression, developmental fate or protein trafficking.” (ref)

Torsten Wiesel beschreibt seine Experimente über die Prozessieung visueller Reize im Gehirn von Katzen:
“The present investigation [..] includes a study of receptive field of cells in the cat’s striate cortex.” (ref)

Ada Yonath über die Kristallisation ribosomaler Protein in thermophilen Bakterien:
“The  information obtained from the studies described in this paper will be a valuable contribution to the current investigation on the spatial  structure of  the ribosome by chemical, physical, and immunological techniques.” (ref)

Anmerkung: Ich habe erfolglos versucht die online-Version eines früheren Papers zu finden, das zitiert wird (1980, Biochemistry International).

Harald zur Hausen  isoliert humane Papillomvirus-DNA aus Gebärmutterhalstumorproben:
“The data thus indicate that HPV 16 DNA prevails in malignant [cervical] tumors, rendering an accidental contamination with papillomavirus [..] unlikely” (ref

Climbing the Everest with polar bears

In her lecture today, Ada Yonath compared her scientific quest to determine the structure of the ribosome to a climb of the Mount Everest. Time after time she thought that she had reached the peak, only to discover a taller summit. While her journey was long and arduous, Yonath eventually reached the top and was rewarded with a spectacular view of the ribosomal landscape. She shared some of those insights with her audience today. 

To solve the structure of any molecule, scientists first need to make crystals from it. The same is true for the ribosome, one of the cell’s most important molecules (it converts RNA into proteins). But crystallizing the ribosome turned out to be impossible using conventional methods. As unlikely as it sounds, Ada Yonath first found some evidence that ribosomes can crystallize in a paper about polar bears.

In that paper it was described how the ribosomes of polar bears become stacked when they go into hibernation. In this way, the ribosomes maintain their integretiy, Yonath explained. She saw a potential application in this finding: if under the right conditions ribosomes form some faint but detactable order by packing together, surely there must be a way to crystallize them as well?

This insight turned out to be a first glimpse of the mountain. It took many years of work before Yonath and her colleagues found out how she should convince the ribosome to form crystals. She was aon the right track by trying to crystallize the robust ribosomes from bacteria that live in extreme conditions, but even these sturdy molecules were destroyed by the X-rays that are used in the structural determination of proteins.

Yonath soon found the solution to this problem In 1984, she discovered that flash-freezing the ribosome crystals protected them from the damaging X-rays. With the ribosomes fixed at sub-zero temperatures, the analogy to hibernating polar bears is complete. Cryocrystallography, as the freezing treatment became known, was established as a routine procedure soon afterwards.

Now that the ribosomes had been crystallized, its structure could be solved. Still it would take almost two decades before the ‘final’ structures of the ribosome was published. Final, because these were the first descriptions of the ribosome at such a high resolution that the position of every single atom was known. ‘Final’, because there is not a single ribosome. The ribosome binds to molecules such as tRNAs, and all these binding events lead to different structures and crystals.

With the ribosome structure solved, there suddenly was a lot more to see. The molecular choreography of tRNAs, proteins and ribosomes could now be studied, for example. Yonath also showe examples how it became possible to study how bacteria resistant to the antibiotics that target the ribosome. She also mentioned tha the ancient RNA core of the ribosome hints at a world that was dominated by RNA instead of proteins. And perhaps the ribosome also holds the secret to the origin of proteins and the genetic code… One thing is certain: plenty of peaks await.

Sentences that win Nobel prizes

Nobel laureates, like all scientists, have published their findings in peer-reviewed journals. Their initial results, theories and thoughts in these publications have been preserved in the digital archives of the scientific literature, as if they have been frozen in time.

I thought it would be a nice idea to go back to these papers, and see whether they contain traces of remarkable insight or glorious discovery. Are there paragraphs that hint at the future recognition that its writer would receive?  Does the Nobel prize-winning sentence exist?
Of course not. It is ridiculous to suggest that the advancement of science can be captured by a single sentence, or even a single paper. Scientific understanding is a process, and does not arrive via a stroke of genius. Even the Nobel laureates have built on the knowledge of the scientists who came before them.

Still, I think it is an interesting exercise to find out how the laureates that will attend this year’s Lindau meeting initially reported their findings. I therefore reread their key papers, and picked out the sentence that I think best represents their Nobel prize-winning work.

The list makes clear that there is not one way to announce a discovery or insight. Some descriptions are technical, some are lucid. Some are written in the active, and some in the passive voice. But they do have one thing in common. They are all excellent examples of exciting science at the cutting edge of our knowledge. See for yourselves in the list below (any errors or poor choices are entirely my fault)!  

Peter Agre announces the discovery of water channels:
“Our observations strongly suggest that CHIP28 is the functional unit of the constitutively active water channels of RBCs and proximal renal tubules.” (ref)

Werner Arber provides a clue that restriction enzymes recognize specific DNA sequences:
“It is concluded that host specificity is carried on the bacteriophage DNA.” (ref)

Elizabeth Blackburn describes a telomere for the first time:
“The results described in this paper show that at each end of the palindromic, extra-chromosomal rDNA molecules there is a tandemly repeating hexanucleotide sequence.” (ref)

Aaron Ciechanover and Avram Hershko on the discovery of two-component ubiquitin degradation system:
“We now report that the ATP-dependent cell-free system is composed of complementing species, and describe the properties of one of the components.” (ref)

Christian de Duve discovers the lysosome:
“Acid phosphatase is attached to a special type of cytoplasmic granules, differing both from the [..] mitochondria and from the [..] microsomes.” (ref)

Sir Martin Evans describes the isolation of the first embryonic stem cells from mice:
“We have demonstrated here that it is possible to isolate pluripotential cells directly from early embryos.” (ref)

Edmond Fisher writes reversible phosphorylation is a regulatory mechanism:
“The activation and inactivation of muscle phosphorylase, which results from the interconversion of phosphorylases b and a, constitutes an important mechanism by which the metabolism of carbohydrate in this tissue may be controlled.” (ref)

Robert Huber and Michel Hartmut announce that the structure of the photosynthetic reaction centre has been solved:
“In this letter we report the spatial arrangement of the prosthetic groups in the photosynthetic reaction centre as the first result of our structure analysis at 3 angstrom resolution” (ref)

Sir Harold Kroto quips about the name of buckminsterfullerene, or ‘bucky balls’, which he and his team have synthesized:
“We are disturbed at the number of letters and syllables in the rather fanciful but highly appropriate name we have chosen in the title to refer to this C60 species” (ref)

Jean-Marie Lehn describes the synthesis of cryptates:
“In previous communications, we described the synthesis of a macroheterobicyclical compound.” (translated from French: Dans la communication précédente nous avons décrit la synthèse de composés macrohétérobicycliques.) (ref)

NOTE: This is the earliest mention of cryptates by Jean-Marie Lehn that I could find. The sentence contains a reference, but it is merely described as ‘previous communication’ in the reference list.

Ferid Murad describes how a simple nitric oxide molecule can regulate the activity of an enzyme:
While the precise mechanism of guanylate cyclase activation by these agents is not known, activation may be due to the formation of nitric oxide. (ref)

Ei-ichi Negishi describes the first coupling of an organozinc compound with a halide using palladium as a catalyst (this reaction would later become known as the Negishi reaction):
“We now report that organozinc compounds readily participate in the Ni- or PD-catalyzed cross-coupling reaction.” (ref)

Erwin Neher and Bert Sakmann describe the behaviour of a single ion channel for the first time:
“We have formed the following picture of acetylcholine receptors [..]: a channel opens and closes rapidly.” (ref)

Hamilton Smith discovers type II restriction enzymes:
“We have made the chance discovery of what appears to be [..] an enzyme in Hemophilus influenza which specifically degrades foreign DNA.” (ref 1 and ref 2)

Oliver Smithies writes that he has succeeded in inserting foreign genes into mammalian genomes via homologous recombination:
“The experiments reported here establish that the planned modification of a specific human gene can be accomplished in mammalian cells by homologous recombination without detectably affecting other parts of the genome.” (ref)

Thomas Steitz on solving the structure of the ribosome:
“The analysis of the 50S ribosomal subunit structure presented here describes the overall architectural principles of RNA folding and its interaction with proteins, but many exciting details remain to be explored.” (ref)

Roger Tsien foresees the future of fluorescent proteins in biological research:
“The availability of several forms of GFP [..] should facilitate two-color assessment of differential gene expression, developmental fate or protein trafficking.” (ref)

Torsten Wiesel describes his studies on the visual processing of the brain in cats:
“The present investigation [..] includes a study of receptive field of cells in the cat’s striate cortex.” (ref)

Ada Yonath on the crystallization of ribosomal proteins in thermophilic bacteria:
“The  information obtained from the studies described in this paper will be a valuable contribution to the current investigation on the spatial  structure of  the ribosome by chemical, physical, and immunological techniques.” (ref)

NOTE: I tried finding an online version of an earlier paper that is referenced (1980, Biochemistry International), but was unsuccessful

Harald zur Hausen isolates human papillomavirus DNA from cervical cancer samples: 
“The data thus indicate that HPV 16 DNA prevails in malignant [cervical] tumors, rendering an accidental contamination with papillomavirus [..] unlikely” (ref

Laying down the global health gauntlet

The panel on global health at the opening ceremony of the 61st Meeting of Nobel Laureates in Lindau well and truly laid the gauntlet down to young researchers from around the world. On the panel was: Bill Gates, chairman of Microsoft and co-founder of the Bill and Melinda Gates Foundation; Ada Yonath, Noble Laureate in Chemistry 2009 for her groundbreaking crystallography work revealing the structure and function of the ribosome; Sandra Chishimba, a malaria researcher from Zambia; and Jonathan Carlson, a researcher into HIV/AIDS at Microsoft Research.

Bill Gates said that we must pay more attention to the ‘silent voices’ in poor countries, who don’t have their medical needs met by funding from their governments or companies. It sounds unbelievable, but he told us that 10 times more research funding goes into finding a cure for male baldness than finding a cure for malaria – which kills 850,000 people a year.   

 

Global health panel opening ceremony

The panel (from l-r: Gates, Chishimba, the moderator Adam Smith, Yonath, Carlson), Photo: Rolf Schultes 

Gates asserts that doing basic research is really important to solving global health problems. He said that his foundation seeks out “people who are good imaging, people who are good at nanotechnology. Their basic thinking could apply to global health in the future.” 

Ada Yonath recommends first identifying a problem, if not in global health, then related to global health. She advises: “Look for some indications you are going to make it. If you stick to them [it could result in] a new drug, procedure or understanding or immune response.” 

Sandra Chishimba stressed the importance of scientific research to our well-being today. For instance, if someone had not worked on, and prioritised the smallpox vaccine, all of us would probably all have had it. Now, we need to prioritise malaria, she said. Her challenge laid down to the audience was simply: “We’ve all seen somebody suffering from a disease. So we should pay attention to such things as global health. We all need to be healthy.” 

Jonathan Carlson encouraged the scientific community to find a way to share data, because the potential to help people is huge. He said: “We have been generating vast amounts of data. In HIV [research], we are looking at tonnes of data for T cell responses, B cell responses, tonnes of genetic data. But yet we have no way to officially merge this data. Think it’s a technical problem that is very achievable – to pool data and share it from different sources, and its solution will really help the lives of many.” 

Aiming squarely at foundations and philanthropists, Yonath also called for more investment in research that was seen as a risk: “To fund the roots of the trees that will be fruitful later on. Tomorrow is another day but there is another day after tomorrow.” 

Bill gates agreed this was the role of the foundation in the current straightened financial times – to take a risk on less experienced investigators, rather than proven researchers. However, he admitted they hadn’t yet completely cracked the way to fund novel research.

An Interview with Ada Yonath

Ada Yonath won the Nobel Prize for Chemistry in 2009 for her work on the structure and function of the ribosome. Born in Jerusalem, she has spent the majority of her scientific career in Israel and is currently Director of the Helen and Milton A. Kimmelman Center for Biomolecular Structure and Assembly at the Weizmann Institute of Science. She is the first Israeli woman to win a Nobel Prize.

 

Lorena Guzman from the Chilean national newspaper, El Mercurio and I talked to Ada Yonath on Tuesday afternoon about being a woman in science, why scientific data should always be shared and the challenges and inspirations she finds in life. 

LG: Do you think it’s tough to be a woman doing science?

AY: Do you think it’s tough to be a woman?

LG: In science?

AY: Do you think it’s tough to be a woman?

LG: Sometimes, yes. 

AY: This is my answer.  I don’t think doing science is difficult because you are a woman. What it is difficult to be a woman about, is the same for a scientist, for a business woman, for a reporter

Society does not encourage women to go into science. If they go and they do well, they will be honoured and inspire others. 

LG: But the science world in the past was really a man’s club, no?

AY: I’m not sure, you know. The first Nobel Prize was given to a man and the second to Marie Curie [laughs] And she won it twice! When people say that only now women are winning Nobel Prizes, it is not correct. If you look at faculties, yes, there are not many women, but that is not because of men, it is because society does not encourage women to go into science. If they go and they do well, they will be honoured and inspire others.

LW: But there’s a conflict with, for example, being a mother, and the point at which your scientific career takes off as a women. Isn’t there?

AY: Society thinks there’s a problem. 

LW: But there’s a perception at least that when you’re in your thirties and chasing your first PI position, you should be working really long hours in the lab and putting all your energy into that.

AY: There’s a perception, yes. But this is not always the truth. How about doctors? Women that want to be an MP? There are many of those. It’s long hours, sometimes the whole night. What about this? Society is not against women in medicine. There are occupations where women are paid less or that put them on tracks where they cannot be promoted. This is not just a problem for science – this is for the cashiers in the supermarket. It’s very easy to say women cannot do science because there are long hours, but this is not correct. Nurses are working long hours and nurses are women. Society is, or was, against intellect in women and the idea that women could compete in an intellectual or scientific way. It’s not that it is difficult for a woman to do science. Science is very demanding from both men and women. I didn’t feel any gender problem and I think that everyone I know from my girl friends, no one complains directly about a gender problem. Science just is demanding – you cannot enjoy science unless you are curious and usually you do well because you educate yourself and you work hard, because you like it, not because you are a woman or a man.

And one more point: for many years people laughed at me; they were very sceptical about my ideas. It was not easy to get into science for almost 15 years. People called me all sorts of names, “dreamer” etc. I didn’t care. I just didn’t care.  But when the results started to come, they said “If you were a man, they wouldn’t be so nasty.” I think men are nasty to other men in everything that they have to progress in – whether that is science or business – as much as they are nasty to women. There are more awful stories about men trying to kick out another competitor than just a woman. 

I am not a competitive character. Maybe if I was, I would have got to the structure of the ribosome earlier! 

LW: Do you have female colleagues or collaborators and do you find it less competitive when you are working with them?

AY: You see I am not a competitive character. Maybe if I was, I would have got to the structure of the ribosome earlier! [laughs] And I do science by enjoying science, not by thinking whether I will be first. Of course, there is pressure, for your institute, from the funding agencies, from students, so somehow I have to give up some of my life philosophy. But in our department, until recently there were 13 faculty people, 7 of them were female -professors! The head of department was female and the head of faculty, female. And maybe I have seen more women cry because they are upset, but when men get upset they are impossible! [laughs] I think I take my department as an example that things can be different.

People ask me why there aren’t many women with Nobel Prizes in Chemistry? What can I do? We have to remember that Marie Curie got it, Dorothy Hodgkin got it. And there is this story of Rosalind Franklin, that she got missed out, but I’m not sure it was because she was female – this is the way Watson tries to describe it but I looked into it and it turns out she was stronger than a lot of the men around in her in many ways. Her admiration of them was lower than their admiration of her. And she had tough luck – they jumped into things and had better intuition but I’m sure this was because she was a woman.

LG: How many children do you have?

AY: One. I wanted many – I really wanted many –  but after the first one, I had a miscarriage and it was such that I couldn’t become pregnant anymore. I didn’t think about adopting and there was no fertility treatment at that time so I’m stuck with one although I wanted many. I wanted five even, but it’s not because of my work [that I didn’t have more] – she was such an easy child.

LG: And how old were you when you had her?

AY: 28 and in the middle of my PhD and she didn’t disturb it.

LG: But being a mother and a scientist must be hard, no?

AY: No, no. It just depends how you plan your life.  You think that to be a mother you need to be at home all day to clean the floor, to do the washing, to cook and wait for the child? And then when the child grows up, you tell the child “I gave everything up for you. I could have done this or that and now you just want to go drinking with your friends?” No. I think if you love your child and you love your work, you find ways to get by. It is the quality of relationship that you have, rather than the number of hours. 

LG: But I guess you had some difficult times?

AY: Yes, and before I had a family I had more difficult times. 

LW: And do you think those difficult times served as a good motivator for you?

AY: No. Difficult times make you stronger. They educate you to be stronger. We were very poor, my father died, we had a mother that didn’t cook. This was much more difficult [than having a child]. They couldn’t even support me when I was 11, 12 years old when I already went to work. 

LW: And did that make you more determined to do the things you wanted to do?

AY: Not more. I cannot compare because I didn’t want anything else. I think it is the love of science and love of family that makes the difference.

LG: You said before that you had a period of about 15 years of trying to convince everyone to take you seriously…

AY: I didn’t try to convince anyone! I tried to work [laughs]. I tried to get funding and to work. 

LG: And what happened in that period?

AY: We published! 

LG: But did you have doubts?

AY: Yes, I had lots of doubts. I had to solve things doubt by doubt.

I had lots of times climbing one Everest to find that there is a bigger Everest, but don’t you find your life like this too? 

LG: And how did you deal with getting stuck with something?

AY: I look for how to get out of it. I try to use here [points to her head]. I tried to read, I tried to talk to others. I tried my best to get out of it. I had lots of times climbing one Everest to find that there is a bigger Everest, but don’t you find your life like this too?

LW: And do you ever go somewhere else for your inspiration, like another hobby – going for a walk, listening to a piece of music?

AY: Yes, this I can understand a lot. I like reading, I like swimming.I go snorkeling if I can. But not because I’m stuck, but because I enjoy them. And when I am swimming or whatever, I find I have more time to think. 

LG: When you received the phone call telling you that you had won the Nobel Prize, what was your first thought?

AY: Well my granddaughter received the phone call! First it was one of the scientists in my group, and they transferred it to my cell phone and she picked it up. 

LW: That’s why you’re the best grandma in the world! [All laugh]

AY: Ah, but I became the best grandma before that. Four years before that. And I still am – so it means I didn’t mess up my reputation!

LG: So what happened with the phone call?

AY: She gave it to me and there was this guy from Sweden and I was sure he was making fun of me. And then he asked “Do you agree to accept it?” and so I said “Yes, of course.” Even if he makes fun of me, I can agree! [laughs]. My real hot point in science, that was the result. That was internal, deep inside me. The Prize, it was nice, it acknowledges me, especially as I was the village fool for so many years. 

LW: So have you ever felt like that since, that same feeling of discovery?

AY: Oh yes. I’ve had 3 or 4 moments like that but I’m already over 70 so maybe it’s not that many. 

LW: So you’re still looking? You’re not just doing things for fun now?

AY: Oh no, no. I still have some problems that I want to solve. 

I’m looking for the minute that I can start writing novels. There are so many stories [to write about] and stories with take-home lessons and thoughts about my experiences

LG: So do you think you’ll retire? Or just keep doing experiments?

AY: I already wanted to retire 20 years ago [laughs]. So somebody asked me earlier today “If you didn’t work, what would you do?” and I replied that I wanted to write a novel, so I’m looking for the minute that I can start writing novels. There are so many stories [to write about] and stories with take-home lessons and thoughts about my experiences – sort of part autobiography…

LW: So who are your favourite authors?

AY: That’s a difficult question. When I was a child and interested in discoveries, the first book that made an impression on me was called “Discoveries of the World” but it wasn’t about geography, it was about Marie Curie! [laughs] And then there is a beautiful Italian story – from the mountains in Italy to the Pyrenees, a kid goes to look for a flower with a golden heart inside for his ill mother. This made a big impression on me.  I also read lots of Isreali authors that you probably haven’t heard of. And Victor Hugo and Tolstoy, I just swallowed it. 

LW: Some of these seem to have the theme of discovery and persistence?

AY: Many, but not all. Recently, I have gone back to my roots and I read a lot of Israeli. Stories across life, across all human life. 

Some people view education as a tool for making money or at least for making a good life, rather than understanding and digging down into something, which was my motivation. 

LG: Do you think being a scientist now is very different to how it was when you started?

AY: Yes, because the level of basic knowledge is much higher but also the way to extract the basic knowledge is much easier. The distinction between what is important or not is many times dictated by the number of references, not always quality. Many students today think that their achievements are dictated by their knowledge, not by their wish to understand the processes of how things work. And I think tht is why I became a scientist, because I really wanted to understand, I had a lot of curiosity. Today, in my opinion, people are more interested in the number of papers and the way of judging people has become much more statistical. Pupils are already doing this right from the beginning. Also, very few people go into basic science, there’s a big thing about making money e.g. biotech. Some people view education as a tool for making money or at least for making a good life, rather than understanding and digging down into something, which was my motivation.

LG: And if you could have one wish before you die, what would you do or discover?

AY: Oh I don’t know. I’ll call you! [laughs] I don’t know what I will do before I die. I’m driven by my curiosity, but not by one wish. Of course, I want my family to be happy and so on, but this is too much of a slogan! [laughs]

LG: And so what direction is your curiosity taking you?

AY: I still don’t understand everything about the ribosome. I must say that the more lectures I give and the more questions that I get, the more thoughts they trigger. And also, we are now interested in the proto-ribosome, how life started. So we are trying to understand this and this really excites me, not just from the point of view of philosophy, we are trying to show it. 

LG: I think the importance of interviewing a Nobel Prize winner is to try to understand that they are just human beings.

AY: But you know that there are so many people that are equal to us or better that didn’t get the prize. You cannot go round the whole world and ask “are you better than me?”

LG: And for me, to spend a week with 59 Nobel Laureates, it’s a big thing, you can’t avoid that.

LW: I think a lot of the students here have appreciated the mentoring that occurs at this meeting. Science can be tough and it is good to get some advice and to reassure yourself that you’re still on the right path.

AY: As long as it is just suggesting and not forcing. Forcing can be direct and indirect: “You do this otherwise I won’t talk to you anymore.” This is direct. Or there is: “If I was you I would do this…” This may be dangerous because what works for one project and one person, doesn’t necessarily work for another. And besides, it takes the initiative out of a person, the imagination, the possibility to search for your own ways of surviving, ingenuity, imagination, dedication. It’s like, “he/she said so, therefore I have to follow”. This doesn’t always work and when it doesn’t work, it can be dangerous and very depressing for the person.

LW: Since you’ve won a Nobel Prize, do you think people now want your opinion on everything?

AY: Yes! Yes. Unfortunately. I am asked questions on things that I have an opinion, as much as the next  person, but all of a sudden it has much more influence and reporters, without being against you personally, either don’t really understand or they want to understand differently and all of a sudden I’m given a different opinion or they put together two different things and I sound stupid. As long as you want to talk about science, being a woman, my life then I am more or less in control. But if you ask me about global warming, I don’t know anything more about it than you do.

LW: And do you think scientists have a responsibility to be interested in science policy and politics?

AY: I don’t like the word responsibility because then it becomes too…administrative, too compulsory. Scientists should, in my opinion, strive to do their best science and to encourage the best science elsewhere, everywhere and this means they have to be involved somehow in science policy – if there is policy! The driving force should be excellent science and if that depends on some intervention here and then, then yes, you should.

I believe that the results of science should be fully given to the community. Fully. Absolutely. 

LW: And what about communicating science both to other scientists and to the lay person?

AY: First of all, I believe that the results of science should be fully given to the community. Fully. Absolutely. And all types of competition such as who did it first and “I cannot tell him because he will copy me” and so on – these are not arguments. Society financed this science, if not directly, then the education and the way I got there, so society should get back what I found. It is not my finding. In this, I am not very popular, I must say. I released the exact procedures we used even before we had results and people came to me and said “How come you give such accurate, correct descriptions?” and I asked whether they wouldn’t do the same and they said “No. If I had data like this I would hide it”. Society put so much into me that of course they should get it back.

And as for making contact with the layperson, I think young people, teenagers and those in their early twenties, don’t have enough exposure to science, they don’t know what it is. I myself have been working on this for many years – I give lectures at many different events and to different groups.   

Personalities, puns and pictures in the plenaries

We’ve all had bad experiences of sitting in lectures, trying to focus on the slides while feeling like we’re really missing out on the key points of the subject. You want to stay motivated and learn something new, but somehow the speaker doesn’t make it easy for you. How to encourage good science communication was something that came up in the panel discussion at Monday night’s social event. So how do Nobel Laureates make their talks entertaining and memorable? I’ll mention some highlights from Monday and Tuesday mornings’ plenaries, showing that scientists can be captivating, witty and even brave enough not to take themselves too seriously.

Last year’s winner Ada Yonath opened this year’s series of lectures with a talk entitled “The Amazing Ribosome”. Recognising that her audience were not all structural biologists or even biochemists she started off with the basics of the Central Dogma (DNA makes RNA makes protein) illustrating this with pictures from a children’s book, quipping that the only inaccuracies were in the pictures of the ribosomes.

Whizzing enthusiastically onto the nub of her research into ribosomal structure and function, Yonath showed the two subunits of the bacterial ribosome –  the smaller of which she referred to as “the duck” and the larger as “the clown”, instantly making them more memorable.

You can be a scientist and a loved family member. Please ladies, go into science, it’s a lot of fun

After talking about the catalytic activities of rRNA as well as the mechanisms of antibiotic action, Yonath finished with some more personal thoughts; the first was a photograph of a painting her grand-daughter had given her, proclaiming her as “the best grandma in the world” an accolade she has to re-earn every year.This prompted her declaration that “You can be a scientist and a loved family member. Please ladies, go into science, it’s a lot of fun”. This she reinforced with a cartoon of herself where her trademark frizzy hair had been converted into a structural diagram of the ribosome, fixing her in all our minds. 

Highlights: unafraid to go back to basics to explain her subject to the audience, enthusiastic, very human, memorable anecdotes.

 

 What I cannot create, I do not understand

Tuesday morning opened with Roger Tsien presenting on “Designing molecules and nanoparticles to help see and treat disease”. His entire talk was punctuated by references as to how and why he’d made certain decisions in his scientific career while successfully narrating the science of GFP and other fluorescent compounds that it has been comprised of. From admitting to “liking pretty colours” since he was a child, as well as being from a family of engineers, to describing an affinity with Feynman’s famous quote “What I cannot create, I do not understand”, his explanations were lucid, often personal and derived from basic principles. Even his decision to move into more clinical applications of flurorescent imaging techniques has been prompted by the deaths of his father, nephew and PhD supervisor due to cancer.  This human angle was reasserted in his expressed dislike of being asked for a photograph or autograph “as if people thought he was a good luck charm and that some of his luck might rub off on them”. He confessed to preferring to have a conversation with any interested students than being viewed as an idol.

However, it wasn’t all seriousness – he showed a humour in his awareness of the pressures and politics in science with statements such as “that was all well and good and it got me tenure, but I needed to do something that was more acceptable…”. He also jested about naming the rainbow of fluorescent markers that his lab developed by using the colour scheme on the Crayola website.   

Tsien ended the talk with a helpful slide of key pieces of advice for the young scientists which included:

  • try to find important projects that give maximum payoff for minimum pain
  • learn to make lemonade from lemons i.e. persist
  • accept that your batting average (i.e. number of papers/key breakthroughs) will be low, but hopefully not zero.
  • Exercise is the best way to keep your brain healthy
  • Prizes are ultimately a matter of luck so avoid being motivated or impressed by them
  • Find the right collaborators and explioit them kindly for mutual benefit.

 

Highlights: clear explanations as to why he’d made certain career decisions, specific advice, humour in the face of challenges   

identify the victim, kill it, get rid of the body, destroy the evidence

Robert Horvitz‘s talk on “Programmed cell death and disease” was similarly lucid with the highlights for me being his creation of memorable ways to recall key facts, such as his summary of the key stages in apoptosis as comparable to a murder: “identify the victim, kill it, get rid of the body, destroy the evidence”. He also brought the process of doing research alive by showing a fax of one of the “eureka!” moments when on February 12 1992 they realised that bcl-2 was the human homolgue of C.elegans ced-9,  an anti-cell death gene.

Highlights: witty ways of remembering processes, insight into what it’s like to do science

Tuesday morning’s plenary’s ended with a lively talk by Martin Chalfie on “Adventures in Nontranslational research”. Chalfie’s sense of the adventure and enjoyment of scientific research clearly came through: he joked about having done all of his original key GFP experiments using microscopes that he’d borrowed from the manufacturers to “test them for a couple of months” and confessed to having done something similar recently, without admitting to what! He also illustrated some of the politics of publishing data, both in iterations of the title of his key Science paper where he was told to omit the word “new” because “everything in Science is new”. He then showed a copy of a letter that his wife had sent to him, consenting to the use of unpublished data, but only on the condition that he make Saturday morning coffee, prepare a special French dinner and take the garbage out. Finally, Chalfie appealed for audience participation, enquiring as to how many biologists had used GFP during their studies (a majority) before finishing with a few bullet points of advice:

  • success may come via many routes
  • scientific progress is cumulative
  • students and post-docs are the lab innovators
  • basic research is essential
  • all life should be studied, not just model organisms 

 

Highlights: conveyed that doing science can be fun, specific advice, audience participation

All of these lectures (and others that I’ve not included here) were entertaining at the same time as being informative. Do share your thoughts about them in the comments if you were there or listened online.

 

*You might also be interested in Martin Fenner’s interview with Roger Tsien and Akshat Rathi’s view on the plenary lectures.