Science in Mexico: Long Tradition, Bright Future

Two stelae from Monte Alban, an archaeological site in Oaxaca in south Mexico. These stelae contain what is thought to be one of the oldest calendar signs from Mesoamerica. Image: Siyajkak, CC BY-SA 3.0

Two stelae from Monte Alban, an archaeological site in Oaxaca in south Mexico. These stelae contain what is thought to be one of the oldest depiction of calendar signs from Mesoamerica. Image: Siyajkak, CC BY-SA 3.0

Did you know that Mexico’s first university was founded already in 1551? Or that today’s Mexico is the largest flat-screen TV manufacturer in the world? Mexico has a long and varied tradition of science and technology. The Olmec civilization invented the number zero. Mayan mathematicians and astronomers have perfected its use, for instance in the famous Mayan calendar: this calendar was crucial for determining seedtimes, rainy seasons, festivities, and much more.

On the one hand, there are particularly Mexican topics, like the research of Mayan, Olmec and Aztec civilizations, or the exploration of the Chicxulub crater. The American Nobel Laureate Luis Alverez first suggested in 1980 that an asteroid or comet impact was a major cause for the dinosaurs’ extinction 66 million years ago, together with his son Walter Alvarez. A giant crash would result in an impact winter, making photosynthesis impossible for plants or plankton, thus effectively cutting off major food chains. The discovery in the 1990s of Chicxulub crater near Yucatan peninsula bolstered the Alvarez hypothesis.

On the other hand, Mexican scientists have made several significant contributions to international research. An early example from the field of chemistry is the 1801 discovery of the element Vanadium in Mexico by Andrés Manuel del Río, chair of chemistry and mineralogy at the Seminario de Minería (College of Mines) that had been established in 1792 in what was then called ‘New Spain’. One hundred years later, vanadium was used in steel alloys for the first time: Henry Ford applied these alloys to build the chassis of his famous Model T. Vanadium allowed for reduced weight while simultaneously increasing the tensile strength of steel. Today it’s still mainly used to reinforce steel, and vanadium pentoxide is a common catalyst to produce sulfuric acid.

The Model T is an early example of the long-term and vital economic and scientific connections to the United States. Today, Mexico is the world largest exporter of flat-screen televisions, as well as the second largest electronics supplier to the US, notably smartphones and tablets. The North American Free Trade Agreement NAFTA, established in 1994, has boosted close trade relations in the last twenty years. And although the incumbent American president had rallied against NAFAT, he now declared he won’t terminate it after all.

 

The rectorate building (left) and the CETEC towers at the Monterrey Institute of Technology and Higher Education, Monterrey Campus, in Monterrey, Nuevo León, México. Credit: Creative Commons Monterrey, CC BY-SA 3.0

The rectorate building (left) and the CETEC towers at the Monterrey Institute of Technology and Higher Education, Monterrey Campus, in Monterrey, Nuevo León, México. Photo: Creative Commons Monterrey, CC BY-SA 3.0

 

For the current electronics boom, Mexican managers can resort to a skilled workforce with experience in automotive and pharmaceutical production. As Aristóteles Sandoval, govenor of Jalisco, a federal Mexican state, points out: “All the products made in Jalisco can be delivered anywhere in the U.S. in less than 24 hours, (…) and the time zone is almost the same.” Besides geographical, there’s cultural proximity: Mexicans speak American English, not British English like many Asians, and American culture and products are well known and understood.

Of course, education contributes considerably to Mexico’s hightech boom. The prestigious Monterrey Intitute of Technology alone has 31 campuses in all regions of the country, teaching more than 90,000 students. And even in remote areas like Oaxaca in the south, the founder of the Oaxaca State Universities System, Modesto Seara-Vázquez, found that the local indigenous languages, which are tonal like Mandarin, give his students a special aptitude to learn mathematics and coding. All students here are at least trilingual: they speak Mixtec or Zapotec, Spanish and English.

 

Computer engineering students at UNAM building a mobile robot. UNAM, the National Autonomous University of Mexico, is one of the oldest and most prestigious universities of the country. Photo: PumitasUNAM, CC BY-SA 4.0

Computer engineering students at UNAM building a mobile robot. UNAM, the National Autonomous University of Mexico, is one of the oldest and most prestigious universities of the country. Photo: PumitasUNAM, CC BY-SA 4.0

But as Octavio Paz wrote, the Mexican Nobel Laureate in Literature: there are always two Mexicos, one developed, one underdeveloped, existing side by side. And although the topics and players have changed since 1950, this sadly still holds true. The news we hear about Mexico is too often about drug wars and murders of politicians and journalists.

There are places where the two Mexicos meet, for instance at the military-style checkpoint for Intel’s ‘Guadalajara Design Center’, Intel’s only research lab in Latin America. The jobs here are not about manufacturing, they’re about creating chips and apps for next generation smartphones. Guadalajara, Jalisco’s capital, is often dubbed the ‘Mexico’s Silicon Valley’, a term it shares with Monterrey further north. More than 120 million dollars have been invested in 300 start-ups since 2014, with at least 25,000 engineers working here.

Even if the distances seem huge between Intel’s lab on the hilltop and the shanty town below, and not just in terms of kilometers, education can help to bridge this gap. As the city’s mayor Enrique Alfaro confides to the Washington Post: “Graduates being courted by Google don’t pick up a gun,” meaning that poverty and unemployment can make the recruitment by drug cartels too easy. Ultimately, only education and employment will brake the vicious cycle of poverty, drugs and violence. This is why the new mayor is implementing school programmes to encourage STEM training, and why he’s installing a tech zone and wants to improve municipal infrastructure for companies. And on the national level, the 57th Mexican president Enrique Peña Nieto announced a new research agenda with increased spending for science and education in 2013.

Mario J. Molina is the first Mexican to be awarded a scientific Nobel prize. In the 1970s, he described, together with his boss F. Sherwood Rowland, how chlorofluorocarbons (CFCs) destroy the ozone layer in the stratosphere, thus weakening the Earth’s protective shield against UV radiation. The two chemists found that CFCs released into the atmosphere do not decay until they reach the stratosphere, where they are destroyed by solar radiation. In this process, chlorine atoms are released that finally destroy ozone. They not only published their findings, but also announced them outside of the scientific community to stop the further emission of CFCs.

Finally, their warnings were taken seriously and the harmful substances were banned in the Montreal Protocol in the mid-1980s. This protocol, together with the Vienna Convention two years earlier, can be considered as “perhaps the most successful international treaties the world has seen”, as the prestigious Michigan Journal for International Law wrote. For their findings, Molina, Rowland and Paul Josef Crutzen were awarded the 1995 Nobel Prize in Chemistry. In recent years, Molina has been informing the public about the data and dangers of global warning with the same fervour as his fight against CFCs. He is one of the 76 Nobel Laureates to sign the Mainau Declaration 2015 on Climate Change that urges international governments to take decisive steps against global warming. This appeal is now more urgend than ever, as US President Donals Trums plans to reverse his predecessor’s climate policy.

Molina has attended six Lindau Nobel Laureate Meetings, and has given four lectures and joined panel discussions on climate change. We’re looking forward to this year’s lecture on June 27th, 2017: ‘Climate Change: Science, Policy and Risks’.

This year, Mexico hosts the International Day at the Lindau Nobel Laureate Meeting on Monday, June 26th. This day will start bright and early with a Science Breakfast at 07:00 a.m., with Mario Molina attending and Christian González Laporte as moderator, Brussels representative of CONACYT. In the evening, CONACYT Director General Enrique Cabrero Mendoza will give a speech on ‘Science in Mexico: Research and Policies’. The band Mariachi El Dorado will provide a genuine Mexican ambience.

 

Mario Molina delivering his lecture 'The Science and Policy of Climate Change' at the 62th Lindau Nobel Laureate Meeting in 2012. Photo:

Mario J. Molina delivering his lecture ‘The Science and Policy of Climate Change’ at the 62th Lindau Nobel Laureate Meeting in 2012. Molina had received his first academic degree at UNAM and later became an assistant professor there. In 2004, he started teaching at the University of California in San Diego. Before that, he has worked at the UC in Irvine, for the Jet Propulsion Laboratory and for MIT. In Mexico City, he set up a center for the studies in energy and environment. Photo: Christian Flemming/LNLM

Tomas Lindahl and the Surprising Instability of DNA

Today we know that each and every day, our DNA is damaged by UV light, free radicals or carcinogenic substances. And even without such external attacks, DNA can undergo many changes, for instance during replication. But in the 1960s, with the discovery of DNA’s double helix structure only one decade earlier, DNA was viewed as something inherently stable.

 

Tomas Lindahl during the Nobel Prize press conference in Stockholm in December 2015. Photo: Holger Motzkau, CC BY-SA 3.0

Tomas Lindahl during the Nobel Prize press conference in Stockholm in December 2015. Lindahl has worked in the UK for several decades and is emeritus director of Cancer Research UK at Clare Hall Laboratory in Hertfordshire. Photo: Holger Motzkau, CC BY-SA 3.0

In 1969, Tomas Lindahl set out to tackle a question that seemed so far-fetched at the time that he didn’t even apply for a grant. Instead, to study the stability or instability of DNA exerimentally, he used money he had been awarded beforehand.

Already as a postdoctoral researcher in Princeton, Tomas Lindahl had found that tranfer RNA, or tRNA, could be quite unstable under certain conditions. This finding ran against the current belief that DNA should be extremely stable. Since RNA is usually single-stranded, some reduced stability would be expected. But still Tomas Lindahl couldn’t get the question of the inherent stability or instability of DNA out of his mind.

In the US, he had been the first to describe the previously unknown enzymes DNA ligase and DNA exonuclease, both important for repairing DNA breaks. But at the time, “we did not have the techniques available to attempt to prove their roles in intracellular recombination events,” Tomas Lindahl writes in his autobiography for Nobelprize.org.

Back in Stockholm and with his own small lab, he now began to look for signs of DNA decomposition in a neutral aqueous solution. He decided to start out with some pilot experiments, “and if the results did not seem promising – quietly bury the project,” Lindahl describes these early steps in his Nobel Lecture. But the results were indeed promising, and so he carried on with “a series of time-consuming experiments to attempt to quantify and characterise the very slow degradation of DNA solutions under physiological conditions”.

With the help of chromatography, he found that some base residues were lost from DNA. Also, the remaining DNA bases had changed, “the most important of these is the deamination of cytosine residues to uracil”. This change is described in the graph below, deamination meaning ‘loss of an aminogroup’.

When Lindahl started to quantify these observed changes, he found the startling number of thousands of DNA changes per day in any mammalian cell: a number that should have made the development of life on earth as we know it impossible. The compelling conclusion was that there were powerful DNA repair mechanisms at work round the clock.

 

Base excision repair

 

Step by step, Lindahl was able to describe the pathway of a repair mechanism that became kown as ‘base excision repair’. Several enzymes need to work together to find, to excise, and finally to replace a damaged nucleotide. Cytosine, one of the four building blocks of DNA, easily loses one aminogroup, as mentioned above, the result is a base called uracil. But uracil cannot bind with guanine, the other half of the GC base pair. Now, an enzyme called glycosylase detects this problem and excises uracil. Next, the enzyme DNA polymerase fills the gap with cytosine, and finally the strand is sealed by DNA ligase. By finding this pathway, Lindahl’s research came full circle: he could now prove the role of the enzyme he had first described as a postdoc years earlier.

In 2015, the Nobel Prize in Chemistry was awarded to Tomas Lindahl, Paul Modrich and Aziz Sancar ‘for mechanistic studies of DNA repair’. Aziz Sancar has described ‘nucleotide excision repair’, the mechanism that cells use to repair UV damage to DNA, and Paul Modrich has demonstrated how cells correct errors that occur when DNA is replicated during cell division. This repair mechanism is called ‘mismatch repair’.

This means that base excision repair is only one repair pathway among many, albeit an important one. And not all pathways have been discovered yet. Correspondingly, there are many different enzymes involved in the various repair pathways. And each and every enzyme is an interesting starting point for cancer drug research, because inhibiting one of these enzymes also means suppressing DNA repair. As Lindahl himself likes to point out: these repair pathways can be seen as a ‘double-edged sword’, because normal cells use them all the time to remain healthy, but cancer cells use them as well to stay alive and cancerous.

 

Angelina Jolie at the launch of the UK initiative on preventing sexual violence in conflict, May 2012. One year later, she made public that she is the carrier of a BRCA mutation and that she underwent a double mastectomy and later an ovariectomy to reduce her cancer risk. BRCA genes are responsible for DNA repair, their mutations can lead to a very high cancer risk. Photo: Foreign and Commonwealth Office, Open Government Licence v1.0 (OGL)

Angelina Jolie at the launch of the UK initiative on preventing sexual violence in conflict, in May 2012. One year later, she made public that she is the carrier of a BRCA mutation: BRCA genes are responsible for DNA repair, and their mutations can lead to a sharply increased cancer risk. Photo: Foreign and Commonwealth Office, Open Government Licence v1.0 (OGL)

As a result of this research, novel ‘targeted therapies’ now aim to affect the repair pathways that some cancer cells rely on, hopefully leaving healthy cells unaffected. One drug that is mentioned in the scientific material of the Royal Swedish Academy of Sciences is the cancer drug Olaparib: it’s a PARP inhibitor, inhibiting a polymerase named PARP (poly ADP ribose polymerase), one of the many enzymes of DNA repair. It is approved for use against cancers in patients with BRCA1 or BRCA2 mutations.

Female carriers of these mutations are five times more likely to develop breast cancer and up to thirty times more likely to develop ovarian cancer. These mutations, which are more frequent in certain popluation groups like for instance Ashkenazi jews, became widely known when Hollywood actress Angelina Jolie explained publicly that she was a BRCA1 carrier and that she had a double mastectomy and ovariectomy to hopefully prevent her getting cancer. After she made this step public, there has been a marked increase in women seeking tests for their BRCA status – an important step for making an informed decision about medical procedures.

In his 2015 Nobel Lecture, Tomas Lindahl concluded that many more small molecules than are currently known can probably damage DNA, meaning “that there are more DNA repair enzymes waiting to be discovered”. And each and every one can be viewed as a new hope for cancer patients. Lindahl’s vision for the future is that cancer will become a disease of old age, like type 2 diabetes: you need to take some medication against it, but you can live with it and enjoy a good quality of life.

This summer, Tomas Lindahl will visit the Lindau Nobel Laureate Meetings for the first time. We’re looking forward to welcoming him in Lindau and to hearing his lecture on DNA repair.

 

The Helix Bridge  is a pedestrian bridge linking Marina Centre with Marina South in Singapore. Its design is based on the double helix model of DNA. This can be seen best at night, when pairs of the coloured letters G and C, as well as A and T, are lit up in red and green. They represent cytosine, guanine, adenine and thymine, the four bases of DNA. Photo: joyt/iStock.com

The Helix Bridge is a pedestrian bridge in Singapore linking Marina Centre with Marina South. Its design is based on the double helix model of DNA. This can be best seen at night, when pairs of the coloured letters G and C, as well as A and T, are lit up in red and green. They represent cytosine, guanine, adenine and thymine, the four bases of DNA. Photo: joyt/iStock.com

 

When Science Is Under Attack…

 

Written by Ulrike Boehm (Washington, DC) and Hermann Broder Schmidt (San Francisco)

 

Thousands of scientists protested in Washington, DC, and over 600 other cities on six continents on Saturday, 22 April 2017, to voice support for science, with calls for evidence-based public policy and increased funding for scientific research.

 

The March for Science in Washington, DC

The rally of the March for Science in DC, which was supported by more than 100 scientific organizations and advocates, started at 10 am with a four-hour rally of speeches and musical performances on the grounds of the Washington Monument, with its main stage facing the White House.

 

Participants of the March For Science in Washington DC on 22 April 2017. Photo: Ulrike Boehm

Participants of the March For Science in Washington DC on 22 April 2017. Photo: Ulrike Boehm

 

During the rally an overwhelming large number of speakers like Bill Nye (American science educator and television presenter), Megan Smith (Former U.S. Chief Technology Officer), Rush Holt (CEO, American Association for the Advancement of Science (AAAS)), Rachel Kyte, (CEO and Special Representative to the UN Secretary-General for Sustainable Energy for All), Leland Melvin (astronaut and S.T.E.A.M. explorer) and many more stressed the importance of science and evidence-based public policy.

“Without scientifically literate citizens, the United States – any country, in fact – cannot compete on the world stage,” said Bill Nye in his speech. “Yet today we have a great many lawmakers – not just here, but around the world – deliberately ignoring and actively suppressing science. Their inclination is misguided, and in no one’s best interest.” Nye furthermore touted the ways scientific discoveries have improved global quality of life, arguing that science is not merely “purview of a different, or special, type of citizen.” “Our numbers here today show the world that science is for all,” he said, and government must come to recognise that “science serves every one of us.” (Video of Bill Nye’s speech)

After the rally, the crowd – organisers received a permit for up to 75,000 people – marched down Constitution Avenue to the foot of Capitol Hill at 2 pm. Some people wore lab coats; others pink, knitted “brain” hats, but almost everyone was carrying a self-made sign with statements like “In peer review we trust”, “The oceans are rising, and so are we” or “There is no planet B”.

Besides being one of the largest protests for science in US history in Washington, DC, the March for Science was also a huge celebration of science and the difference it makes for all of us.

 

Impressions from the March for Science in Washington, DC, 22 April 2017 (to proceed to the next one, simply click on the image):

 

 

Photos: Ulrike Boehm

 

The March for Science in San Francisco

More mitosis, less division!’ was one of the key messages put forward by the more than 15,000 science enthusiasts that gathered in San Francisco. This nerdy reference to the molecular process in which the genetic material of a cell is duplicated and orderly passed on to its daughter cells beautifully highlighted that the crowd did not intend to further divide the public in already tumultuous times. In fact, their main demand simply was that politics and policies must be based on proven facts, rather than mere belief. The very same message was echoed by marches throughout the Bay Area, including San Jose and Santa Cruz, where another estimated 15,000 people spoke up for science, immigration and protection of the environment.

In addition to the rallies and fairs that were part of the marches and featured a diverse mix of Nobel Laureates, aspiring young investigators and prominent science advocates from TV, many local scientific institutions such as the renowned University of California San Francisco (UCSF) opened their doors for additional public events. Hundreds of scientists of all ages and career stages from nearby Stanford University already started their march on the CalTrain, and engaged with the public en route to San Francisco or San Jose. All in all, the Bay Area enthusiastically celebrated science on its streets, peacefully bringing together scientists and their families, friends and pets – even some alternative cats were spotted!

 

Impressions from the March for Science in San Francisco 22 April 2017:

 

 

Photos: Hermann Broder Schmidt

 

The beginning of a new activism for science

The March for Science in DC was organised shortly after US President Donald Trump’s inauguration in January, largely in response to widespread alarm about his administration’s attitude towards science. Trump has repeatedly called global warming a “hoax” and promised to roll back numerous environmental protection laws, whose importance was only recently stressed by several Nobel Laureates in a common statement, the Mainau Declaration 2015 on Climate Change. Furthermore, in March, the White House released a budget proposal that included double-digit cuts to agencies such as the Environmental Protection Agency (EPA) and the National Institutes of Health (NIH). According to this proposal the NIH funding would be cut by 18 percent, to $25.9 billion, making it one of the hardest-hit research agencies. This cut would undermine the fiscal stability of US universities and medical schools, many of which depend on NIH funding, and it would therefore diminish opportunities to discover new ways to prevent and treat diseases.

Faced with such attacks on science, Harold Varmus, Nobel Laureate and former director of the NIH from 1993 to 1999 and of the National Cancer Institute from 2010 to 2015, said that we should “…speak up, even when other important issues crowd the political horizon, and frame the issue properly: As I have learned from my own time at the NIH, this is not about Republicans versus Democrats. It is about a more fundamental divide, between those who believe in evidence as a basis for life-altering and nation-defining decisions and those who adhere unflinchingly to dogma.” (New York Times article)

On Saturday, 22 April 2017, scientists and science enthusiasts worldwide raised their voices and spoke up for science.

 

Although the March for Science is over, it may be only the beginning of a new worldwide movement for sciences.

“Every [scientist] should go public to talk about science and its impact for society, because science is too important to be downgraded and dismissed,” said Rush Holt (CEO, American Association for the Advancement of Science (AAAS)) during his pre-rally speech at the AAAS headquarters in Washington, DC. “We have to defend the conditions under which science can thrive.”

Julie Pullen (professor in Ocean Engineering and member of The Oceanography Society) also encouraged scientists in her speech to “share [their] stories with the world,” and she stressed that “the energy and excitement should not end today.”

Nobel Laureate William Daniel Phillips furthermore said that scientists “need to tell [their] stories to remind people of how essential science is for our society, in particular now that science is under attack.”

 

The author and Nobel Laureate William Daniel Phillips, who spoke during the pre-rally of the march for science at the AAAS headquarters in Washington, April 22, 2017. Photo: Ulrike Boehm

The author and Nobel Laureate William Daniel Phillips, who spoke during the pre-rally of the march for science at the AAAS headquarters in Washington, 22 April 2017. Photo: Ulrike Boehm

 

To help scientists to tell their stories and to engage and educate, AAAS put in place a very helpful Advocacy Toolkit.

Also, the organisers of the march for science extend their activism for science beyond the march. Currently, they are planning to build an organisation centered on informed advocacy, community building, and accessible education and aim to create new programmes and scale existing programmes to improve the relationship between science and society.

Extend your activism as well and become an active advocate for science in your community and beyond. Let’s stand up for science!

Michael Levitt: Pionier der Computerbiologie

Chemische Reaktionen laufen mit unvorstellbarer Geschwindigkeit ab, beispielsweise springen Elektronen in Bruchteilen von Millisekunden von einem Atom zum anderen. Die experimentelle Chemie stößt hier an ihre Grenzen, sie kann nicht jeden einzelnen Reaktionsschritt nachzeichnen. Und selbst die klassische Physik kommt an ihre Grenzen, wenn mit ihrer Hilfe versucht wird, diese komplizierten Reaktionen Schritt für Schritt zu simulieren. Dank der Pionierarbeit von Michael Levitt, zusammen mit Arieh Warshel und ihrem Harvard-Kollegen Martin Karplus, kann seit den 1970er Jahren die klassische Physik gemeinsam mit quantenphysikalischen Modellen benutzt werden, um die Reaktionen an großen Molekülen im Detail zu modellieren.

Davor waren Chemiker gezwungen, sich bei Simulationen zwischen der klassischen und der Quantenphysik zu entscheiden. Die Vorteile der ersteren liegen auf der Hand: Die Modelle sind einfach und es können große Moleküle dargestellt werden. Der Nachteil: Chemische Reaktionen dieser Moleküle konnten nicht simuliert werden, auch nicht mit den leistungsstärksten Rechnern vor über vierzig Jahren. Hierfür braucht man die Quantenphysik, mit deren Hilfe jedes Elektron, jeder Atomkern usw. modelliert werden kann. Die vergleichsweise geringe Rechnerleistung ließ damals jedoch nur Kalkulationen mit kleinen Molekülen zu.

Die Arbeiten von Levitt und anderen ermöglichen es Forschern, diese quantenphysikalischen Modelle nur dort anzuwenden, wo sie gebraucht werden, nämlich im Herzen der chemischen Reaktion, im sogenannten Reaktionszentrum. Alle übrigen Moleküle werden mit den Modellen der klassischen Newtonschen Physik berechnet. Aus Rücksicht auf die damaligen Rechnerkapazitäten vereinfachten Levitt und Warshel ihr Modell noch weiter, indem sie mehrere Atome in ihrem Modell zusammenfassten. „Woher wir allerdings den Mut nahmen, neunzig Prozent der Atome schlicht wegzulassen, ist schon eine interessante Geschichte“, erinnert sich Michael Levitt in seinen autobiografischen Ausführungen auf Nobelprize.org. Offensichtlich haben die beiden jungen Forscher „das richtige Maß an Vereinfachung“ getroffen: Ihr Modell war nicht so kompliziert, dass sie damit nicht mehr arbeiten konnten, aber auch nicht so stark vereinfacht, dass es nutzlos geworden wäre.

Doch wie entwickelte sich ein kleiner, schüchterner Jungen aus Südafrika zu einem Weltklasse-Forscher? An allererster Stelle muss hier natürlich sein außergewöhnliches intellektuelles Talent genannt werden, doch seine eiserne Beharrlichkeit half ebenfalls, sowie etliche glückliche Zufälle, von denen ich drei hier beschreiben möchte.

 

Michael Levitt hält eine Rede in dem Park um das 'Museum of Natural History' in New York City. Dort steht eine Marmorsäule, in die alle Namen der amerikanischen Nobelpreisträger eingraviert werden. Dieses Foto entstand während der Eingravierungs-Zeremonie für Levitt im Jahr 2014. Foto:  Consulate General of Sweden in New York City, 2014, CC BY-SA 2.0

Michael Levitt hält eine Rede in dem Park um das ‘Museum of Natural History’ in New York City. Dort steht eine Marmorsäule, in welche die Namen aller amerikanischen Nobelpreisträger eingraviert werden. Dieses Bild entstand während der Eingravierungs-Zeremonie für Levitt im Jahr 2014. Foto: Consulate General of Sweden in New York City, 2014, CC BY-SA 2.0

 

Zunächst einmal hatte er eine Tante und einen Onkel in London, Tikvah Alper und Max Sterne, die beide angesehene Forscher waren. Die Ärztin Alper entdeckte, dass die Erreger von Scrapie, einer Schaf- und Ziegenseuche, keine Nukleinsäure enthielt. Dies war ein wichtiger Schritt, um die Übertragungswege von spongiformen Enzephalopathien („schwammförmigen Hirnleiden“) zu verstehen, zu denen auch die Creutzfeldt-Jakob-Krankheit beim Menschen gehört. Ihr Mann Max Sterne entwickelte in Südafrika einen sicheren und zuverlässigen Impfstoff gegen Milzbrand, der heute noch verwendet wird. Als der junge Michael Levitt beide Ende 1963 in London besuchte, war es also kaum zu vermeiden, dass sein Interesse an Lebenswissenschaften geweckt wurde. Heute gilt er als Pionier der Computerbiologie – das Programmieren in Fortran lernte er während eines Praktikums in Berkeley, das ihm seine Tante Jahre später vermittelt hatte.

Obwohl Levitt 1963 gerade einmal 16 Jahre alt war, hatte er schon mehrere Monate an der Pretoria University studiert. Die ersten Monate in England verbrachte er jedoch „wie gebannt vor dem Fernseher [seines] Onkels und [seiner] Tante sitzend“: Ihn faszinierte die Winterolympiade Anfang 1964, weil er noch nie Schnee gesehen hatte. Und weil es damals in Südafrika kein Fernsehen gab, konnte er gar nicht genug von diesem neuen Medium bekommen. Am liebsten schaute er die BBC-Serie „The Thread of Life“, in der Nobelpreisträger John Kendrew die neuesten Entwicklungen der Lebenswissenschaften erklärte; Kendrew hatte den Chemienobelpreis erst ein Jahr zuvor erhalten. Diese Serie war „eine hervorragende Einführung in die Molekularbiologie“, weil erst kurze Zeit klar war, dass „das Leben zeitlich und räumlich exakt strukturiert ist, wie ein Uhrwerk, aber milliardenfach kleiner und unendlich komplizierter“. Schon damals faszinierte Levitt die Vorstellung, welchen Beitrag die Physik leisten könnte, um diese winzigen und super schnellen Prozesse zu entschlüsseln.

Um an einer guten britischen Universität studieren zu können, musste er das englische Abitur nachholen, denn sein Immatrikulations-Examen aus Pretoria reichte hierfür nicht. Gute Noten waren kein Problem für ihn, und nach dieser Extrarunde begann er am King’s College in London Biophysik zu studieren. Nach seinem Abschluss wollte er gerne eine Doktorarbeit am Laboratory of Molecular Biology (LMB) in Cambridge schreiben, am liebsten bei John Kendrew. Dieser lehnte sein Bewerbungsschreiben an – doch Levitt gab sich nicht geschlagen. Er schrieb erneut und bat, ein Jahr später als Doktorand anfangen zu dürfen. Hierauf erhielt er nur eine vage Antwort. Schließlich lieh er sich das Auto seiner Mutter, zog seinen Bar-Mitzvah-Anzug an und fuhr nach Cambridge, um Kendrew oder Max Perutz, dem zweiten Direktor, aufzulauern. Als erster ließ sich Perutz blicken. Er bat Levitt in sein Büro und versprach ihm, sein Anliegen zu prüfen. Schließlich bekam Levitt die Zusage, im darauffolgenden Jahr am LMB seine Doktorarbeit beginnen zu dürfen. Doch statt der erhofften Weltreise bekam er den Auftrag, ein Jahr nach Israel zu Shneior Lifson an das renommierte Weizmann-Institut zu gehen, um mehr über dessen Kraftfeld-Methode (Englisch „force field“) zu lernen. Diese Theorie wurde als Meilenstein zur Modellierung großer Moleküle gesehen, und ist nicht mit den Kraftfeldern der klassischen Physik zu verwechseln.

 

Die Verwandlung von

Die Verwandlung von “einem gewöhnlichen Sterblichen zu einem Nobelpreisträger” hat laut Michael Levitt viele Facetten, beispielsweise folgende: “Es ist nicht so einfach, wenn plötzlich jeder Unsinn, den man erzählt, von allen geglaubt wird.” Foto: Peter Badge/Lindau Nobel Laureate Meetings

 

Nach Israel geschickt zu werden, entpuppte sich als ein weiterer Glücksfall. Michael Levitt selbst beschreibt, dass sein erstes Jahr dort „einen echter Wendepunkt“ in seinem Leben bedeutete: In nur zehn Monaten legte er den Grundstein sowohl für eine erfolgreiche Wissenschaftskarriere als auch für ein glückliches Familienleben. In den ersten Wochen in Israel lernte er seine Frau Rina kennen, eine studierte Biologin, die später als Künstlerin Erfolge feierte. Das Paar heiratete noch vor der gemeinsamen Rückkehr nach England. Am Weizmann-Institut schrieb Levitt ein Computerprogramm zur Modellierung großer Moleküle unter Verwendung der Kraftfeld-Methode, zusammen mit Arieh Warshel; gemeinsam erhielten sie 2013 den Chemienobelpreis für diese bahnbrechende Entwicklung.

Der dritte glückliche Zufall ereignete sich Mitte der 1980er Jahre, also viele Jahre, zahlreiche Entdeckungen und viele Publikationen später. Die Familie Levitt war mehrfach von England nach Israel gezogen und zurück, es gab auch noch andere Zwischenstationen. Als sie nun in Cambridge, Massachusetts, an einer privaten Cocktailparty teilnahmen, rief zufällig an diesem Abend sein alter Freund Roger Kornberg an, Nobelpreisträger an der Stanford University. Als dieser hörte, dass die Levitts Israel verlassen wollten, schlug Kornberg sofort vor, sie sollten nach Stanford kommen: Seit 1987 forscht Michael Levitt dort, bis heute. „Mein erster Eindruck in Stanford war: Hier ist alles so einfach“, erinnert er sich. „Es war, als wären wir auf dem Jupiter aufgewachsen und würden nun zum ersten Mal die Erdanziehung spüren“, was so viel bedeutet wie: Alles fühlte sich total leicht an. Levitt gründete seine erste Forschungsgruppe und seine erste Firma, der älteste Sohn besuchte Berkeley. Nach ein paar Jahren zog seine Frau mit den Kindern zurück nach Israel, damit die Söhne dort ihren Militärdienst ableisten konnten. Danach kam sie nach Stanford zurück, zog dann aber wieder nach Israel, um dort mehr Zeit mit dem ersten Enkelkind verbringen zu können.

„Als ich dachte, mein Leben könne gar nicht mehr besser werden, erhielt ich am 9. Oktober 2013 um 02:16 Uhr einen Anruf aus Stockholm“, erinnert sich Levitt. In den Jahren zuvor hatte er sich häufig gesagt: „Kein Mensch darf damit rechnen, einen Nobelpreis zu bekommen.“ Deshalb war dieser Anruf mitten in der Nacht eine echte Überraschung. Wir haben uns damals mit ihm gefreut und hoffen, dass Michael Levitt in den kommenden Jahren an einer Nobelpreisträgertagung in Lindau teilnehmen wird.

 

Michael Levitt: a Pioneer of Computational Biology

Chemical reactions happen unbelievably fast. In fractions of a millisecond, electrons jump from one atom to another. Classical chemistry cannot keep up with this: neither can every step of a reaction be unveiled experimentally, nor can calculations based on classical physics simulate these fast and complex processes. Due to the pioneering research of Michael Levitt, together with Arieh Warshel and their Harvard colleague Martin Karplus, it’s now possible to have the classical Newtonian physics work side-by-side with simulations based on quantum physics.

Previously chemists had to choose. If they used classical physics, their calculations were simple and they could model large molecules. The downside was: chemical reactions couldn’t be simulated, especially not in the 1970s when this ground-breaking research was conducted. To simulate these reactions, chemists had to use models from quantum physics, meaning that every electron, every atomic nucleus etc. was accounted for. But these calculations require enormous computing power, meaning that their application was limited to really small molecules.

Nowadays, chemists apply the demanding quantum physics calculations only where they are needed: at the core of the reaction, also called the reaction centre. The rest of the molecule in question is modelled using classical physics. Taking into account that computers were infinitely slower in the early 1970s compared to computer speed today, Levitt and Warshel reduced the calculations even further: they merged several atoms in their model. In his autobiography on Nobelprize.org, Levitt comments: “How we dared to leave out 90 percent of the atoms is an interesting story.” Obviously, they reached “the right level of simplicity” with this approach: neither too complicated, nor so simple that the model would be meaningless.

But how did a shy young boy from South Africa become a world-class biophysicist? Of course, most of his success is due to his great intellectual talent. But his fierce perseverance also helped, as did many lucky coincidences. Let me give you three examples of the latter.

 

Michael Levitt during his talk at the Inscription Ceremony in the park surrounding the Museum of Natural History in New York City, when his name was added to the stone pillar where all names of American Nobel Laureates are inscribed. Photo: Consulate General of Sweden in New York City,2014, CC BY-SA 2.0

Michael Levitt during his talk at the Inscription Ceremony in the park surrounding the Museum of Natural History in New York City, when his name was added to the stone pillar where all the names of American Nobel Laureates are inscribed. Photo: Consulate General of Sweden in New York City, 2014, CC BY-SA 2.0

 

First of all, he had an aunt and uncle in London who were both established scientists: His aunt Tikvah Alper found that the infectious agent in Scrapie, a degenerative sheep and goat disease, did not contain nucleic acid. This finding was important in understanding the mechanisms of all forms of transmissible spongiform encephalopathy, like Creutzfeldt-Jakob disease in humans. Max Sterne, her husband and Levitt’s uncle, developed an effective and safe vaccine against anthrax in South Africa that is still used today. When young Michael Levitt visited them in London in late in 1963, he couldn’t help but become interested in life science. He later became one of the pioneers of computational biology; he first learned how to programme in Fortran during an internship in Berkeley that his aunt had organised for him a few years later.

In 1963, Michael Levitt was only sixteen and had already studied several months at Pretoria University. He spent the first few months in London “glued to [his] uncle and aunt’s TV set watching the Winter Olympics,” because he had never seen snow, and there had been no television in South Africa. But the BBC series “The Thread of Life” by Nobel Laureate John Kendrew, who had been awarded the Nobel Prize in Chemistry only one year earlier, made an even larger impression. For young Levitt, this was “a remarkable introduction to molecular biology”, because it had become clear just a few years earlier “that life was highly structured in space and time, just like a clock, but a billion times smaller and infinitely more complicated.” Already at this young age, he became fascinated by the role modern physics could play to elucidate biological processes.

In order to be admitted to a good British university, he had to pass A-level exams, his South African matriculation exam wasn’t sufficient. He chose to study at King’s College in London, where the tradition of biophysics was strong. After his first degree, he wanted to pursue a PhD at the Laboratory of Molecular Biology (LMB) in Cambridge. So he wrote to John Kendrew – only to get rejected. Michael Levitt persisted, asking to join LMB a year later, again without a clear result. But Levitt didn’t give up, put on his Bar Mitzvah suit and waited outside the offices of John Kendrew and Max Perutz, also a Nobel Laureate of 1962. The latter came out first, talked to Levitt and promised to consider his request. Finally, he was accepted as a doctoral student for one year later. But instead of the world trip that Levitt had imagined, he was sent to the Weizmann Institute in Israel to learn more about the force field method from Shneior Lifson, an important theory behind the computer modelling of large molecules, not to be confused with the force field in classical physics.

 

Michael Levitt photographed by Peter Badge. The transition from normal mortal to Nobel Laureate according to Levitt:

The transition from “being a mere mortal to a Nobel Prize winner” has many aspects, according to Levitt, including the following: “It is not easy when people start listening to all the nonsense you talk.” Photo: Peter Badge/Lindau Nobel Laureate Meetings

 

Being sent to Israel, after persevering in Cambridge, was the second lucky coincidence. As Levitt himself writes, his first year in Israel was “the real watershed” of his life: in only ten months, he laid the foundations both for a successful career in science and for a happy family life. Together with Arieh Warshel, another student and later co-recipient of the 2013 Nobel Prize, he wrote the computer programme that used the force field method to calculate properties of molecules. And Michael Levitt met his wife Rina only weeks after arriving in Israel, and they got married before he left again for Cambridge in August 1968 to finally pursue his PhD. A biologist by training, Rina Levitt later became an accomplished multimedia artist.

The third lucky coincidence happened in the mid-1980s, many years, numerous ground-breaking findings and publications later (and after moving back to Israel, then back to Cambridge, etc.): Rina and Michael Levitt where attending a private cocktail party in Cambridge, Massachusetts, when Nobel Laureate Roger Kornberg called and heard that they considered leaving Israel. Kornberg immediately suggested that Michael should come to Stanford – where he has been since 1987, and still is. “My dominant memory of coming to Stanford was how easy everything was. It seemed as if we had grown up on Jupiter and then moved to the Earth’s gravity.” Levitt founded his first research group and his first company, his eldest son attended Berkeley. A few years later, his wife and sons moved back to Israel so that all three boys could complete their military service. Levitt himself was “mainly in the air between Israel and Stanford” during this time. His wife moved back to Stanford, but a few years later left for Israel again to spend more time with their first grandchild.

“Just when I thought things could not get any better, I was woken at 2:16 AM on the morning of 9 October, 2013,” he remembers. Levitt had said to himself many times that “No one should expect the Nobel Prize,” so the call from Stockholm came as a great surprise.

We sincerely hope that Michael Levitt will be able to attend a Lindau Nobel Laureate Meeting in the coming years.

 

New Super Tool for Cell Biology

Researchers from Stefan Hell’s department at the Max Planck Institute for Biophysical Chemistry in Göttingen have achieved yet another breakthrough in light microscopy: With their new MINFLUX microscope they can separate molecules that are only a few nanometres apart, meaning its resolution is 100 times higher than conventional light microscopy, and about 20 times higher than super-resolution light microscopy.

The 2014 Nobel Prize in Chemistry was dedicated to the breaking of the optical diffraction limit. For more than a century, half the wavelength of light – about 200 nanometres – was considered the absolute limit for light microscopes. When Stefan Hell was studying physics in Heidelberg, this limit was still taught – but Hell couldn’t accept it. By developing stimulated emission depletion (STED) microscopy the following years, he was the first researcher to successfully venture beyond this limit in the 1990s, both theoretically and experimentally. Based on these breakthroughs he received the 2014 Nobel Prize in Chemistry, together with the American physicists Eric Betzig and William E. Moerner, “for the development of super-resolved fluorescence microscopy”.

But how does STED work, and how does it lay the foundations for MINFLUX? Hell explains STED in his own words: “If I cannot resolve two points because they are too close together and they are both emitting fluorescence, I need to darken one of them – and suddenly, you’re able to see the other point. If I make sure that all molecules are dark, except the one or the few that I’m interested in, then I can finally resolve this one, or these few.” The darkening is achieved by optical interference: Since a laser beam is used to excite fluorescence in molecules, it’s also possible to darken some molecules in the probe with a second laser beam whose wave properties cancel out the first beam. This second laser beam is doughnut-shaped, leaving only a small centre spot still emitting fluorescence. Thus STED functions by depleting a circular region of the sample, while leaving a small focal point (see graph below).

 

How a STED microscope works: with a laser excitation focus (left), a doughnut-shaped de-excitation focus (centre) and remaining fluorescence (right). Credit: Marcel Lauterbach, CC BY-SA 3.0

How a STED microscope works: with a laser excitation focus (left), a doughnut-shaped de-excitation focus (centre) and remaining fluorescence (right). Credit: Marcel Lauterbach, CC BY-SA 3.0

With the MINFLUX microscope, Hell’s research group combined the advantages of STED microscopy with the principles of PALM (photo-activated localization microscopy) developed by Eric Betzig. In PALM, also called PALM/STORM, single molecules are also excited by switching them on and off, but these molecules light up randomly, they’re not targeted. Betzig and his colleagues would use a very short laser pulse, thus exciting only a few molecules which could then be localised. As these molecules bleach out, the researchers turn the laser on again to see the next batch and so forth. Finally, the entire probe has been activated, seen and plotted. The result is a graphic resolution far beyond the diffraction limit.

With this approach, PALM already operates on the single-molecule level but the exact location of each molecules isn’t easily determined. With STED, the location of an excited molecule is well known, but the laser beam isn’t able to confine its emission to a single molecule. MINFLUX, on the other hand, switches individual molecules randomly on and off. Simultaneously, their exact positions are determined with a doughnut-shaped laser beam, something we know from STED. But in contrast to STED, this doughnut beam excites the fluorescence instead of darkening it. So if a molecule is located on the ring, it will glow; if it is exactly at the dark centre, it will not glow – but its exact position will be known.

Dr. Francisco Balzarotti, a researcher in Hell’s department, developed an algorithm to locate this centre position fast and with high precision. “With this algorithm, it was possible to exploit the potential of the doughnut excitation beam,” the first lead author of the Science paper explains. Klaus Gwosch, a PhD student in Hell’s group and third lead author, obtained the molecular-resolution images: “It was an incredible feeling as we, for the first time, were able to distinguish details with MINFLUX on the scale of a few nanometres”, the young physicist describes the team’s reaction to the potential of studying life at the molecular level.

 

Stefan Hell gemeinsam mit den Erstautoren der Studie Dr. Francisco Balzarotti, Yvan Eilers und Klaus Gwosch am Mikroskop (von links). Foto: Irene Böttcher-Gajewski, Max-Planck-Institut für biophysikalische Chemie

Stefan Hell and the three lead authors of the MINFLUX Science publication, Dr. Francisco Balzarotti, Yvan Eilers and Klaus Gwosch (from left) with their ground-breaking microscope. Photo: Irene Böttcher-Gajewski, Max Planck Institute for Biophysical Chemistry

In addition to the high optical resolution, this new microscope has another advantage over both STED and PALM: high temporal resolution. Stefan Hell: “MINFLUX is much faster in comparison. Since it works with a doughnut laser beam, it requires much lower light signal, i.e. fewer fluorescence photons, per molecule as compared to PALM/STORM for attaining the ultimate resolution.” MINFLUX stands for “MINimal emission FLUXes”, alluding to this reduced light requirement. Already with STED, researchers had been able to record real-time videos from the inside of living cells. But now it is possible to trace the movement of molecules in a cell with a 100 times better temporal resolution.

Yvan Eilers, another PhD student involved and the second lead author of the Science paper, was responsible for ‘filming’ protein actitivity within a living cell. He filmed the movements of ribosome subunits inside a living E. coli bacterium. “The past has shown that major resolution enhancements have led to new insights into the biology of cells, as STED and PALM have demonstrated,” Eilers elaborates. “Now everybody here is optimistic that this will hold true for MINFLUX as well.” The researchers in Hell’s group are convinced that in the future, even extremely fast changes in living cells will be investigated with the help of their new microscope, for instance the folding of proteins.

I asked Klaus Gwosch whether other research groups had already been in touch to acquire a MINFLUX microscope. “The Science publication has of course reached a large international audience,” he replied. “Currently, the department of NanoBiophotonics in Göttingen has the only MINFLUX microscope, but we expect other research groups to adopt and implement our approach.” His boss Stefan Hell agrees: “I am convinced that MINFLUX microscopes have the potential to become one of the most fundamental tools of cell biology. This could revolutionise our knowledge of the molecular processes occurring in living cells.”

Both Yvan Eilers and Klaus Gwosch will participate in the 67th Lindau Nobel Laureate Meeting this summer as young scientists, together with their doctoral adviser Stefan Hell. William Moerner, the third recipient of the 2014 Nobel Prize in Chemistry, will also attend and talk about super-resolution microscopy. We are looking forward to an interesting and inspiring week in Lindau!

 

 

MINFLUX microscopy separates molecules optically that are only a few nanometers apart. On the left, a schematic graph of the fluorescent molecules. PALM microscopy (right) only delivers a diffuse image of the molecules, whereas the position of each molecules can easily be discerned with MINFLUX (centre). Image: Klaus Gwosch, Max Planck Institute for Biophysical Chemistry

MINFLUX microscopy optically separates molecules that are only a few nanometers apart. A schematic graph of the target molecules is shown on the left. PALM microscopy (right) only delivers a diffuse image of these molecules, whereas the position of each molecule can easily be discerned with MINFLUX (centre). Image: Klaus Gwosch, Max Planck Institute for Biophysical Chemistry

Membranproteinen ihre Geheimnisse entlocken

Vor ungefähr 2,3 Milliarden Jahren kam es „zum wohl größten Massensterben der Erdgeschichte“, so Hartmut Michel zu Beginn seines Vortrags auf der Lindauer Nobelpreisträgertagung 2015. Er beschreibt die sogenannte Große Sauerstoffkatastrophe (englisch GOE, für Great Oxygenation Event), die sich ereignete, als erstmals große Mengen an freiem Sauerstoff in die Atmosphäre gelangten – für die Mehrzahl der damals existierenden Organismen ein tödliches Gift. Doch wie kam es dazu? Die Vorfahren der heutigen Cyanobakterien entwickelten die Photosynthese: Mit Hilfe von Licht, Wasser und Kohlendioxid stellten sie Sauerstoff und Kohlenhydrate in bislang nie dagewesenen Mengen her.

Hartmut Michel erhielt den Chemienobelpreis 1988 „für die Ermittlung der dreidimensionalen Struktur eines Photosynthesezentrums“, zusammen mit Johann Deisenhofer und Robert Huber. Das Nobelpreiskomitee nannte die Photosynthese „die wichigste chemische Reaktion auf Erden“, weil sie Atemluft und Nahrung für Mensch und Tier bereitstellt. Zudem ist sie für die Entstehung der meisten fossilen Energiequellen wie Kohle, Öl und Gas verantwortlich, allerdings mit ein paar Millionen Jahren Verzögerung.

Vor Milliarden Jahren standen die Kleinstlebewesen vor der Herausforderung, mit den großen Sauerstoffmengen zurechtzukommen. Außerdem mussten sie mit den Molekülen der sogenannten reaktive Sauerstoffspezies umgehen können (englisch ROS, für reactive oxygen species). Ein sehr effizienter Weg, freien Sauerstoff unschädlich zu machen, sind Sauerstoff-Reduktasen, also spezielle Enzyme, die Sauerstoff zu Wasser reduzieren. Sie werden auch Oxidoreduktasen genannt. Gleichzeitig helfen sie, die Energie zu speichern, die bei solchen Reaktionen freigesetzt wird. Seit über zehn Jahren analysiert Hartmut Michel nun solche Reduktasen am Max-Planck-Institut für Biophysik in Frankfurt am Main, wo er seit 1987 Direktor ist.

 

Schematische Darstellung des Elektronentransport der inneren Mitochondrienmembran. Die Cytochrom-c-Oxidase ist Teil des Komplex IV. Grafik: T-Fork, auf der basis der Grafik von LadyofHats, beide public domain

Schematische Darstellung des Elektronentransports in der inneren Mitochondrienmembran. Die Cytochrom-c-Oxidase ist Teil von Komplex IV. Grafik: T-Fork, auf der basis der Grafik von LadyofHats, beide public domain

 

In den vergangenen Jahren analysierte Hartmut Michel zusammen mit seiner Forschungsgruppe vor allem zwei Sorten von Oxidoreduktasen: Die Superfamilie der Häm-Kupfer-Oxidasen und die Cytochrom-bd-Oxidase. All diese Oxidasen befinden sich in Membranen. Ein bekanntes Beispiel der Superfamilie ist die Cytochrom-c-Oxidase, das letzte Enzym im Elektronentransport der inneren Mitochondrienmembran (siehe Grafik oben). Diese Oxidase erhält jeweils ein Elektron von vier Cytochrom-c-Molekülen und transportiert diese zu Sauerstoffmolekülen. Aus diesen Zutaten werden zwei Wassermoleküle gebildet. Sie ist außerdem behilflich, zwei Protonen, die für die Bildung von ATP nötig sind, durch die Membran hindurch zu pumpen. „ATP ist die allgemeine Energiewährung des Lebens“, erklärt Michel in seinem Lindau-Vortrag von 2015. Wussten Sie, dass Ihr Körper täglich bis zu 75 kg ATP produziert, damit wir zum Atmen, Verdauen und Bewegen ausreichend Energie zur Verfügung haben? Außerdem müssen wir unsere Körpertemperatur halten, und es gibt viele weitere Prozesse im Körper, die viel Energie benötigen.

 

Hartmut Michel während seines Vortrags in Lindau beim 64. Nobelpreisträgertreffen 2014. Foto: Christian Flemming/Lindau Nobel Laureate Meeting

Hartmut Michel während seines Vortrags in Lindau bei der 64. Nobelpreisträgertagung 2014. Foto: Christian Flemming/Lindau Nobel Laureate Meetings

Interessanterweise waren Oxidoreduktasen wohl bereits vorhanden, bevor sich freier Sauerstoff massenhaft in der Atmosphäre anreicherte. Aber welche Funktion hatten sie damals? Dieses ‘Paradox’ hat die Forschung bislang nicht aufklären können. Ein weiteres interessantes Ergebnis von Michel ist, dass sich die beiden Oxidase-Gruppen zwar strukturell deutlich unterscheiden, aber doch etliche Gemeinsamkeiten aufweisen: Beispielsweise transportieren beide Systeme häufig vier Elektronen gleichzeitig – so wird die Bildung von ROS effektiv verhindert. „Es scheint, als habe Mutter Natur dieselbe Erfindung gleich zweimal gemacht“, folgert Michel in seinem Vortrag.

Das photosynthetische Reaktionszentrum, für dessen Beschreibung Michel, Deisenhofer und Huber den Nobelpreis erhielten, ist ebenfalls ein Membranprotein – das allererste, dessen Struktur bestimmt werden konnte. Als Hartmut Michel noch Student in Tübingen und Würzburg war, galt die Lehrmeinung, dass Membranproteine grundsätzlich nicht kristallisiert werden können. Damals wie heute ist die Röntgenstrukturanalyse die beste Methode, um die molekulare Struktur, und damit die Funktion von Proteinen, zu ermitteln. Ohne Kristallisation kann sie jedoch nicht angewendet werden. Für die Entwicklung und Verbesserung der Röntgenstrukturanalyse wurden in den letzten hundert Jahren übrigens etliche Nobelpreise verliehen.

Doch Hartmut Michel wollte sich nicht mit der herrschenden Lehrmeinung abfinden. Also machte er sich daran, das erste Membranprotein zu kristallisieren. Ein großes Problem hierbei war die Tatsache, dass es sich bei diesen Proteinen eigentlich um eine Mischung aus Lipiden und Proteinen handelt, was dazu führt, dass sie teilweise hydrophob sind, also wasserabweisend, und sie deshalb nicht in wässrigen Flüssigkeiten gelöst werden können. Also braucht man Lösungsmittel, und Michel machte sich auf die Suche nach passenden sogenannten Detergenzien. Viele von ihnen bilden jedoch Mizellen. Das sind Zusammenballungen von Seifenmolekülen, die ihre hydrophilen Enden nach außen und die hydrophoben nach innen ausrichten. Der Nachteil hierbei ist, dass die gelösten Proteine in den dichten Mizellen ‘versteckt’ werden können.

 

Die Struktur eines Proteins mit Hilfe der Röntgenstrukturanalyse zu ermitteln ist ein aufwändiges Verfahren: Zunächst einmal muss das Protein kristallisiert werden, das ist bei Membranproteinen besonders schwierig. Dann wird mit Röntgenstrahlen ein Beugungsbild erstellt (diffraction pattern). Mit fortgeschrittener Analysis wird aus diesem Bild eine Elektronendichtekarte ermittelt, schließlich kann auch eine Struktur des Moleküls errechnet werden. Grafik: Thomas Splettstoesser, www.scistyle.com, CC BY-SA 3.0

Die Röntgenstrukturanalyse ist ein aufwändiges Verfahren: Zunächst einmal muss das Protein kristallisiert werden. Das ist bei Membranproteinen besonders schwierig. Dann wird mit Röntgenstrahlen ein Beugungsbild erstellt (diffraction pattern). Mit fortgeschrittener Analysis wird aus diesem Bild eine Elektronendichtekarte ermittelt. Schließlich kann auch die Struktur des Moleküls errechnet werden. Grafik: Thomas Splettstoesser, www.scistyle.com, CC BY-SA 3.0

Endlich fand Michel ein passendes Lösungsmittel, Heptan-1,2,3-triol, das kleinere Molekül-Verklumpungen bildet, sodass die Proteine herausgelöst, kristallisiert und analysiert werden können. Als nächstes musste er sich für ein bestimmtes Membranprotein entscheiden. Nach mehreren Fehlversuchen entschied er sich für das Purpurbakterium Rhodopseudomonas viridis, wörtlich „eine rote, falsche Zelle, die grün ist“. Diese Bakterien sind Photosynthese-fähig, genau wie Pflanzen, und ihr Reaktionszentrum hierfür kann isoliert werden. Auf diese Weise gelang Michel 1981 die Kristallisation des ersten Membranproteins.

Doch mit der Kristallisation war es nicht getan: Die Röntgenstrukturanalyse erfordert eine anspruchsvolle höhere Mathematik, um aus dem Beugungsbild der Röntgenstrahlen an den Elektronen des Kristalls eine dreidimensionale Struktur zu errechnen (siehe Schaubild rechts). Der Beitrag von Deisenhofer und Huber an diesem Projekt waren diese mathematischen Methoden. Die drei Forscher publizierten ihre Ergebnisse 1985. Nur drei Jahre später erhielten sie dafür den Chemienobelpreis. In den frühen 1980er Jahren brauchte Hartmut Michel noch ungefähr vier Monate, um einen kompletten Datensatz mit vielen Röntgenbildern zu erstellen. Heute entsteht ein solcher Datensatz automatisch innerhalb von Sekunden.

Seit dieser ersten Entdeckung entschlüsselten Forscher die Strukturen von über 600 Membranproteinen. Ungefähr fünfzig davon sind menschliche Membranproteine – doch es gibt insgesamt mehrere tausend! Hier ist also noch eine Menge zu tun.
Warum ist es überhaupt so wichtig, die Struktur und Funktion von diesen Proteinen zu kennen? 80 Prozent aller Arzneimittel wirken auf Membranproteine, und über 50 Prozent von ihnen haben diese Proteine als Zielstruktur. Das hat einen Grund: Sie spielen bei vielen Infektionen eine Schlüsselrolle, sowohl bei Viren als auch bei Bakterien, und sie sind an vielen Krebserkrankungen beteiligt. Diese Tatsache fasst Michel in seinem 2016er Lindau-Vortrag folgendermaßen zusammen: „Die meisten Krankheiten entstehen entweder durch eine Fehlfunktion, oder durch eine Über- oder Unterstimulierung eines bestimmten Membranproteins.“

Hartmut Michel ist ein langjähriger Unterstützer der Lindauer Nobelpreisträgertagungen. Er nahm bisher an zwanzig Tagungen teil, Videos seiner Vorträge finden Sie hier. Und er ist Mitglied im Kuratorium der Lindauer Nobelpreisträgertagungen. Wir freuen uns sehr, ihn im Juni 2017 bei der 67. Tagung, die dem Fach Chemie gewidmet ist, begrüßen zu dürfen.

 

 

 

Roger Tsien: “All Colours of the Rainbow”

Roger Tsien was one of the most productive and creative contemporary chemists. He’d been awarded the 2008 Nobel Prize in Chemistry “for the discovery and development of the green fluorescent protein, GFP”, together with Martin Chalfie and Osamu Shimomura. GFPs enable researchers to watch live cells at work: If they’re interested in a certain protein that can be expressed by an organism, they can fuse the GFP gene with the protein-encoding gene. From now on, each protein molecule can be traced through all its stages with the help of blue to ultraviolet light via fluorescence.

The advantage over many other markers is the fact that GFP is non-toxic, and also the light to see its fluorescence is non-toxic. GFPs have been widely used in many species, from yeast to insects, fish and mammals, as well as in human cells. The original GFP molecule was discovered in the jellyfish Aequorea victoria. This is why Roger Tsien thanked the jellyfish in his banquet speech at the official Nobel Prize Banquet Dinner on December 10th, 2008: “So my final thanks are to both the jellyfish and corals: long may they have intact habitats in which to shine!” Some of the fluorescent dyes developed by his research group were also derived from corals, others from bacteria.

 

With the help of genetic engineering, the GFP gene can be fused to target genes that will glow in ultraviolet light - also generations later! Slide from Roger Tsien's LNLM lecture in 2010. Photo: Bastian Greshake, CC BY-SA 2.0

With the help of genetic engineering, one of this mouse’s genes was fused with the GFP gene so that it glows under ultraviolet light. Also generations later, this mouse’s offspring will shine! Slide from Roger Tsien’s Lindau lecture in 2010. Photo: Bastian Greshake, CC BY-SA 2.0

 

Already as a PhD student of physiology in Cambridge, UK, Roger Tsien had developed his first tracking dyes for calcium activity in living cells. He hadn’t told his PhD supervisor about his new research adventure because he was sure that he would only explain how important it was to finish one project before starting a new one. Some of these dyes are still used today, like BAPTA and Fura-2; the latter was developed when Tsien had already become an assistant professor at the Department of Physiology-Anatomy at Berkeley.

After his move to UCSD in San Diego in 1989, mostly for better lab equipment, the Tsien group found fluorescent indicators that “glow in all colours of the rainbow”, as the Nobel Prize committee wrote. Over the years, his research group has also developed fluorescent indicators for ions like magnesium, copper, iron, lead, cadmium, and many more.

From an early age, Roger Tsien had been fascinated with the chemistry of colours. “I’ve always been attracted to colours,” he told the San Diego Union-Tribune when he learned that he had ben awarded the Nobel Prize. “If I had been born colour-blind, I probably never would have gone into this.” And in his autobiography for the website Nobelprize.org he wrote how his first chemical experiments in the basement of his parent’s house in Livingston, New Jersey, reflect “an early and long-lasting obsession with pretty colours”. He captions this essay with the following joke: “What do elementary school pupils and Nobel Laureates have in common? They both have to write autobiographical essays on command.”

 

 

Roger Tsien’s father was an aviation engineer with a degree from MIT, but couldn’t find a suitable job because as a Chinese, he didn’t get the necessary security clearance. After several different jobs, he found work in the vaccum tube division of RCA, Radio Corporation of America, in New Jersey. When his parents wanted to buy a house in New Jersey, the developer wouldn’t sell it to them because they were Chinese, fearing that other families wouldn’t buy property next to them. His parents wrote to the New Jersey governor to complain, and the governor in turn wrote to the developer that racial discrimination was illegal. Not only could the Tsien family then buy the house – years later, the same developer used Roger’s photo as the winner of the nationwide Westinghouse Science Talent Search to advertise how good the Livingston schools were.

Only sixteen years old, much younger than most other contestants, Roger Tsien had written up his results from an NSF-sponsored summer programme at Ohio University that he had attended in the summer of 1967, his “first exposure to a research environment”. He was assigned a project where he had to analyse how metals bind to thiocyanate. “For lack of any alternatives, I wrote up my Ohio University project, trying my best to draw some conclusions from a mess of dubious data.” To his own surprise, Roger Tsien won the first prize.

 

San Diego beach scene drawn with an eight colour palette of bacterial colonies expressing fluorescent proteins derived from GFP and the red-fluorescent coral protein. Artwork by Nathan Shaner, photography by Paul Steinbach, created in the lab of Roger Tsien in 2006. Credit: Nathan Shaner, CC BY-SA 3.0

San Diego beach scene drawn with an eight colour palette of bacterial colonies expressing fluorescent proteins derived from GFP and red-fluorescent coral protein. Artwork by Nathan Shaner, photo by Paul Steinbach, created in the lab of Roger Tsien in 2006. Credit: Nathan Shaner, CC BY-SA 3.0

The same year, he started college at Harvard University with a scholarship, where he earned a Bachelor of Science in chemistry and physics, followed by a PhD in physiology from the University of Cambridge – and a productive career in the lab discovering and applying fluorescent dyes. Roger Tsien came to five Lindau Meetings, and the five lectures he gave demonstrate his wide interest in many scientific topics. In his 2015 lecture for instance (see above video), he explains his recent interest in two seemingly very different research areas: cancer therapy and long-term memory storage. But interestingly, both topics touch upon the same enzymes called proteases: enzymes that can cut proteins. Tsien himself explains his motivation for cancer research with the fact that his father died of pancreatic cancer. Together with medical doctor Quyen T. Nguyen he developed ‘fluorescence-guided surgery’ that helps the surgeon not only to find most cancer cells around a tumour, but also to preserve as many nerves and other important structures as possible.

The second topic of his 2015 lecture concerns memory storage in the perineuronal net, or PNN, an extracellular matrix structure that stabilises the adult brain. After a lifetime of studying intracellular activities, “here I’m forced to learn about extracellular matrix!” Tsien said in 2015. ‘Holes’ in the PNN act as the storage medium, “like a 3D punch card”, he explains, only to realise that today’s young scientists have never handled a punch card. In a mouse model, he was able to delete many long-term memories with the help of a certain matrix metalloproteinase, or MMP. He expects an even larger deletion share if more enzymes involved are understood. Sounds like the ‘neuralyzer’ from the Men in Black movies that can delete memories, doesn’t it?

On August 24th, 2016 Roger Tsien died unexpectedly on a bike trail in Eugene, Oregon, aged only 64. On this day, the world lost a brilliant scientist as well as a wonderful person with a great sense of humour.

 

Roger Tsien with young scientists on the annual boat trip to Mainau island on the last day of the 2009 Lindau Nobel Laureate Meeting, dedicated to chemistry. Photo: Christian Flemming

Roger Tsien (1952 – 2016) with young scientists on the annual boat trip to Mainau island on the last day of the 2009 Lindau Nobel Laureate Meeting, dedicated to chemistry. Photo: Christian Flemming/Lindau Nobel Laureate Meetings

Roger Tsien über Leuchtfarben, Quallen und Korallen

Roger Tsien gehörte zweifellos zu den kreativsten und produktivsten Forschern der Gegenwart. Er erhielt den Chemienobelpreis 2008 „für die Entdeckung und Entwicklung des grün fluoreszierenden Proteins GFP“, gemeinsam mit Martin Chalfie und Osamu Shimomura. Mit der Hilfe von GFP können Forscher lebene Zellen in Echtzeit bei ihrer ganz normalen Zellaktivität beobachten. Haben sie an einem bestimmten Protein Interesse, das ein Organismus herstellen kann, können sie das GFP-Gen mit jenem Gen verbinden, das genau dieses Protein herstellt. Ab diesem Moment kann der ganze Weg dieses Proteins verfolgt werden, weil es unter blauem oder ultravioletten Licht leuchtet, also fluoresziert.

Die Vorteile gegenüber anderern Markierungsmethoden liegt auf der Hand: GFP ist für den Organismus ungifitig, und auch das Licht, das man braucht um es zu sehen, ist unschädlich, anders als beispielsweise radioaktive Strahlung. GFPs und ähnliche fluoreszierende Marker sind schon in zahlreiche Organismen eingefügt worden, von Hefepilzen über Fische und Insekten bis hin zu Säugetieren und menschlichen Zellkulturen. Ursprünglich stammt das GFP-Gen von der Qualle Aeguorea victoria, daher bedankte sich Tsien in seiner Festrede beim offiziellen Nobelpreisbankett am 10. Dezember 2008 in Stockholm bei diesem Tier: „Meine letzte Danksagung gilt sowohl den Quallen als auch den Korallen: Möget ihr für lange Zeit intakte Habitate haben, in denen ihr ungestört leuchten könnt!“ Weitere Fluoreszensmarker stammen nämlich von Korallen, andere wiederum von speziellen Bakterien.

 

Ein Gen dieser Maus ist dem GFP-Gen markiert worden. Nun leuchtet sie grün unter ultrabviolettem Licht - und alle ihre Nachkommen! Die Abbildung stammt aus dem 2010er Vortrag von Roger Tsien in Lindau. Foto: Bastian Greshake, CC BY-SA 2.0

Ein Gen dieser Maus ist dem GFP-Gen markiert worden. Nun leuchtet sie grün unter ultrabviolettem Licht – und alle ihre Nachkommen! Die Abbildung stammt aus dem 2010er Vortrag von Roger Tsien in Lindau. Foto: Bastian Greshake, CC BY-SA 2.0

 

Bereits als Physiologie-Doktorand in Cambridge in Großbritannien entwickelte Roger Tsien seine ersten Farbstoffe, zunächst für die Kennzeichnung der Kalziumaktivität in Zellen. Sicherheitshalber hatte er seinem Doktorvater nichts von seinem neuen Steckenpferd erzählt, weil er befürchten musste, dieser würde ihm einen langen Vortrag darüber halten, wie wichtig es sei, zuerst das eine Projekt abzuschließen bevor man das nächste beginnt. Manche dieser Farbstoffe werden heute noch verwendet, zum Beispiel BAPTA und Fura-2; letzteren entwickelte Tsien als Assistenzprofessor in Berkeley.

Im Jahr 1989 wechselte er dann an die University of California in San Diego, in erster Linie wegen der deutlich besseren Laborausstattung dort. In den folgenden Jahren entwickelte seine Arbeitsgruppe zahlreiche Fluoreszenzfarbstoffe die “in allen Farben des Regenbogens leuchten”, so das Nobelpreiskomitee in Stockholm. Seine Forschungsgruppe fand außerdem Fluoreszenzindikatoren für zahlreiche Ionen wie Kupfer, Magnesium, Eisen, Blei, Kadmium und viele weitere.

Anlässlich der Nobelpreisverleihung 2008 erzählte er der Zeitung San Diego Union-Tribune, dass er schon als Kind von Farben fasziniert war. „Wäre ich farbenblind auf die Welt gekommen, hätte ich mir bestimmt ein anderes Thema gesucht.“ Schon als Schulkind führte er im Keller seiner Eltern in Livingston, New Jersey zahlreiche chemische Experimente durch, so schreibt er in seinem autobiografischen Essay für die Website Nobelprize.org, und auch damals motivierte ihn „eine frühe und langanhaltende Begeisterung für schöne Farben“. Am Anfang dieses Essays steht ein Witz: „Was haben Grundschüler und Nobelpreisträger gemeinsam? Beide müssen auf Knopfdruck autobiografische Aufsätze schreiben.“

 

Roger Tsien giving his 2014 lecture at the 64. Lindau Nobel Laureate Meeting. Photo: Rolf Schultes/Lindau Nobel Laureate Meetings

Roger Tsien giving his 2014 lecture at the 64. Lindau Nobel Laureate Meeting. Photo: Rolf Schultes/Lindau Nobel Laureate Meetings

Roger Tsiens Vater war ein Luftfahrtingenieur, der in den USA keine passende Anstellung finden konnte, trotz eines Abschluss von der amerikanischen Eliteuniversität MIT, weil er als Chinese keine Sicherheitsfreigabe bekam. Nach verschiedenen Jobs fand er schließlich eine Anstellung in der Abteilung für Vakuumröhren der Firma RCA, kurz für Radio Corporation of America, in New Jersey. Nun wollten die Eltern ein Haus in der Nähe kaufen, Roger war zu dieser Zeit sieben Jahre alt. Doch der Bauunternehmer wollte ihnen das Haus ihrer Wahl nicht verkaufen mit dem Argument, dann würden die anderen Häuser unverkäuflich, weil niemand neben Chinesen wohnen wollte. Daraufhin schrieb das Ehepaar Tsien einen Brief an den Gouverneur von New Jersey, der wiederum dem Bauunternehmer schriftlich mitteilte, dass Diskriminierung aufgrund der Herkunft in den USA illegal sei. So kam die Familie Tsien schließlich zu ihrem Haus.

Und nur neun Jahre später machte derselbe Bauunternehmer mit einem Foto von Roger Tsien Werbung für seine Häuser! Anlass war der erste Preis eines landesweiten Forschungswettbewerbs, den der sechzehnjährige Roger gewonnen hatte. Der Bauunternehmer wollte mit seinem Foto für die guten öffentlichen Schulen werben, dabei hatte sich Roger die anorganische Chemie anhand von Lehrbüchern überwiegend selbst beigebracht. Für den Westinghouse-Talentwettbewerb hatte er die Ergebnisse eines kleinen Projekts zusammengefasst, das er im Rahmen eines NSF-Nachwuchsprogramms an der Ohio University durchführen durfte. Er hatte dort die Aufgabe zu erforschen, wie sich verschiedene Metalle an Thiocyanate binden. „Weil ich nichts anderes vorzuweisen hatte, versuchte ich, aus dem Chaos unklarer Daten irgendwelche Schlüsse zu ziehen,“ schrieb er bescheiden im Nachhinein. Zu seiner großen Überraschung gewann er damit den ersten Preis.

 

Kunst aus der Petrischale: Mit verschiedenen fluoreszierenden Bakterien hat Nathan Shaner im Jahr 2006 im Labor von Roger Tsien in San Diego eine Strandszene in eine Petrischale 'gemalt'. Verwendet werden Farbstoffe, die auf dem GFP-Gen basieren, sowie Korallenfarbstoffe. Photo: Paul Steinbach, Credit: Nathan Shaner, CC BY-SA 3.0

Kunst aus der Petrischale: Mit verschiedenen fluoreszierenden Bakterien hat Nathan Shaner im Jahr 2006 im Labor von Roger Tsien eine Strandszene in eine Petrischale ‘gemalt’; das Labor befindet sich in San Diego, daher das Motiv. Verwendet wurden Farbstoffe, die auf dem GFP-Gen basieren, sowie Korallenfarbstoffe. Photo: Paul Steinbach, Credit: Nathan Shaner, CC BY-SA 3.0

Im selben Jahr, mit gerade mal 16 Jahren, begann Roger Tsien mit Hilfe eines Stipendiums in Harvard zu studieren. Mit einem Bachelor of Science in Chemie und Physik schloss er dieses Studium ab und ging nach England, um dort im Fach Physiologie zu promovieren. Er interessierte sich für die Schnittstelle zwischen Chemie und Biologie und wollte sich nicht auf ein Fach festlegen. Danach entfaltete sich seine unglaublich produktive Forscherkarriere. Roger Tsien nahm an fünf Lindauer Nobelpreisträgertreffen teil, und seine fünf Vorträge dort spiegeln sein breites Interesse an verschiedenen Forschungsthemen wider. In seinem 2015er Vortrag beispielsweise sprach er über zwei ganz unterschiedliche Themen: Krebsforschung und Langzeitgedächtnis. Auch wenn beide Themen scheinbar nichts mit einander zu tun haben, so handeln doch beide auf molekularer Ebene von Proteasen, also von Enzymen, die andere Proteine spalten können. Tsien selbst erklärt, dass seine Motivation, sich mit Krebsforschung zu beschäftigen durch den Krebstod seines Vaters ausgelöst wurde. Gemeinsam mit dem Arzt Quyen T. Nguyen entwickelte er eine fluoreszensgestützten Operationstechnik, bei der nicht nur alle Tumorzellen eingefärbt werden, damit der Chirurg sie möglichst vollständig entfernen kann, sondern auch alle wichtigen Strukturen wie Nerven, die nicht verletzt werden dürfen, gefärbt werden.

Das zweite Thema seines Vortrags war die Speicherung von Langzeiterinnerungen im sogenannten Perineuronalen Netz, kurz PNN, das als Matrix zwischen den Zellen für die Stabilität des erwachsenen menschlichen Gehirns sorgt. Nachdem Tsien sich sein ganzes Forscherleben hindurch mit Vorgängen innerhalb von Zellen befasst hat, „musste ich mich jetzt plötzlich mit der extrazellulärer Matrix beschäftigen“, ergänzte er in seinem Vortrag. Löcher in der PNN sind die eigentlichen Speichermedien, „wie in einer 3D Lochkarte“ – erst da wurde ihm klar, dass die meisten Nachwuchsforscher im Raum noch nie eine Lochkarte benutzt hatten. Im Mausmodell gelang ihm, ungefähr die Hälfte aller Langzeiterinnerungen durch die Gabe einer bestimmten Matrix-Metalloprotease (MMP) zu löschen. Er geht davon aus, dass ein deutlich größerer Anteil gelöscht werden kann, wenn die weiteren beteiligten Proteasen bekannt sind. Klingt ein bisschen nach dem ‘Neuralyzer’ aus dem Film Men in Black, oder?

Am 24. August 2016 starb Roger Tsien völlig unerwartet auf einem Radwanderweg in Eugene, Oregon im Alter von nur 64 Jahren. An diesem Tag verlor die Welt einen genialen Forscher sowie eine faszinierende Persönlichkeit mit einem großartigen Sinn für Humor.

 

Roger Tsien (1952 - 2016) während der traditionellen Bootsfahrt zur Insel Mainau am letzten Tag des Lindauer Nobelpreisträgertreffens 2009. Foto: Christian Flemming/Lindau Nobel Laureate Meetings

Roger Tsien (1952 – 2016) mit Nachwuchsforschern während der traditionellen Bootsfahrt zur Insel Mainau am letzten Tag des Lindauer Nobelpreisträgertreffens 2009. Foto: Christian Flemming/Lindau Nobel Laureate Meetings

Marie Curie’s American Adventure

Thanks to a lucky twist of fate, Marie Meloney, a prominent American journalist, took it into her head to persuade Nobel Laureate Marie Curie to do an interview with her and refused to be put off by Curie’s stubborn refusal. Meloney had started her career in journalism at the Washington Post at the age of just 15, worked as a correspondent for the Denver Post at 18 and was later the editor of various major magazines. She also hosted glamorous receptions, had political ambitions and was a feminist. Meloney was a confidante of Eleanor Roosevelt, who admired her for her determination.

Marie Curie in her chemistry laboratory at the Radium Institute in France, April 1921.

Marie Curie in her chemistry laboratory at the Radium Institute in France, April 1921. Source: Nationaal Archief of the Netherlands / No known copyright restrictions

When the long-desired meeting with Curie finally took place in 1920, despite her 20 years experience as a journalist, Meloney’s courage initially failed her: “The door opened and I saw a pale, timid little woman … with the saddest face I had ever looked upon. (…) Suddenly I felt like an intruder.”

Meloney perceived Curie as ‘helpless’ and took refuge in a discussion about the admiration of American women for her work. Without beating about the bush, Marie Curie got straight to the topic closest to her heart: radium. She knew the precise locations in America where a great deal of it was available. Meloney was completely astonished by the spartan working conditions of the two-time Nobel Laureate. Pierre and Marie Curie had registered no patents and had decided that their research findings should be available to all of humanity and not individuals. This meant that they were reliant on other sources of income.

During the interview Marie Meloney asked a question that went on to have far-reaching consequences: What would Marie Curie wish for, if she could wish for anything? The answer came without hesitation: a gram of radium! The reason for this was that the entire radium stocks of her French institute were used for medical applications, and Marie Curie was literally empty-handed.

Meloney devised a cunning plan: a gram of radium had a market value of 100,000 dollars in the USA – and she would raise the money for it. When an initial attempt to raise the money privately failed, Meloney launched the fundraising campaign later known as the “Marie Curie Radium Fund”, which was aimed at all American women who wanted to support Marie Curie’s work. And one year after the visit, the necessary funds had been raised.

Meloney-with-Irene-Marie-and-Eve_Curie-1921

Meloney, left, with Irène, Marie and Ève Curie. Credits: Public Domain

Meloney wrote to Curie and asked her to come to the USA and receive the gift in person. Warren Harding, the President of the United States of America, would present her with the radium himself. Her daughters could accompany her, and every attempt would be made to shield them from too much publicity. What the publicity-shy scientist feared most was to be paraded in public as an individual. Curie had single-mindedly avoided public appearances up to then; life for her was all about science and her family. But this was an offer she could not refuse, so at the age of 54 she embarked on her first major official trip abroad in spring 1921. A jubilant crowd and a horde of photographers awaited her on her arrival in New York.

The generous donors to the Radium Fund were women of very different origins and class – Curie was feted as a cancer healer, a role model for female scientists and a working mom. Marie Curie was an ideal representative of the type of woman with whom women in America identified in the 1920s. Her veneration in the academic world, which was also strongly masculine in its orientation in America, did not detract from this: Marie Curie was showered with honorary doctorates and other awards. Although Harvard – unlike Yale – denied her this honour, the majority of American academics could not understand why Marie Curie was not similarly honoured and supported in France.

The schedule for the visit proved to be a heavy burden on the scientist, whose state of health was already very frail, and her host and the press were concerned about her. Her modest appearance and cerebral air seemed to fuel the enthusiasm for her even more, however. The most important commitments, which Curie was unable to fulfil herself, were assumed by her daughters Irène and Ève.

The tour started with visits to women’s colleges and the crowds of enthusiastic female students who feted Curie, and an overwhelming reception in Carnegie Hall. Marie Curie entered the event to the thunderous applause of over 3,500 members of the International Federation of University Women. The French and Polish ambassadors were also in attendance. This was followed by a party at the Waldorf Astoria with over 500 representatives of scientific organisations – all before the presentation of the gift on 20 May 1921 at the White House.

Marie Curie with President Warren Harding at the White House in Washington DC. Credits: World History Archive / Alamy Stock Photo

Marie Curie with President Warren Harding at the White House in Washington DC. Credits: World History Archive / Alamy Stock Photo

Every trick in the publicity book was used for the presentation ceremony: Marie Curie entered on the arm of President Warren Harding and was presented with a parchment scroll (the deed of donation) and silk scarf tied with a small key – the key to the casket containing the radium; the latter was fake, however, as the radium remained in the factory so that it did not pose a threat to anyone present. In his address, President Warren Harding referred to Marie Curie as a “…noble creature, the devoted wife and loving mother who, aside from her crushing toil, had fulfilled all the duties of womanhood”. Curie thanked him for his kind words saying she had been honoured “… as no woman has ever been honoured in America before”.

Marie Curie’s trip to the USA was a great personal success and undoubtedly made an important contribution to providing security for her further scientific work, her institute and all the young researchers working there. It also gave her greater latitude in her private life. In her biography of her mother, Ève Curie wrote: “I believe the journey to America taught my mother something. It had shown her that the voluntary isolation in which she confined herself was paradoxical. (…) Marie was responsible for a new science and a new system of therapeutics. The prestige of her name was such that by a simple gesture, by the mere act of being present, she could assure the success of some project of general interest that was dear to her.”

Thanks to Marie Meloney, Marie Curie enjoyed greater fortune in the following years and the two women remained friends for life. In May 1922 Marie Curie became a member of the International Committee for Intellectual Cooperation and was its Vice-President until 1934. During her 12 years of activity for this League of Nations’ committee she supported, among other things, the establishment of an international bibliography of scientific publications and a copyright system for scientists and their inventions.

A video presenting an overview of Marie Curie’s life and scientific achievements is available in the Mediatheque.


Madame Curie. A Biography, Ève Curie

A Devotion to their Science. Pioneer Women in Radioactivity, Marelene and Geoffrey Rayner-Canham

Marie Curie. A Life, Susan Quinn

The private lives of Science’s first family. Marie Curie and her daughters, Shelley Emling