Ten Astonishing Facts About Longevity

Constant rise in life expectancy after 1840: in early years, the most gains were achieved by reducing child mortality. In the mid-19th century, infectious diseases  were fought with vaccines, in the 20th century with antibiotics. Source: US National Institute on Aging, data from the Human Mortality Database

Constant rise in life expectancy after 1840: In early years, the most gains were achieved by reducing child mortality. In the mid-19th century, infectious diseases were fought with vaccines, and in the 20th century with the help of antibiotics. Source: US National Institute on Aging, data from the Human Mortality Database

In developed countries, life expectancy is still increasing linearly at a rate of about three months per year for women, and at a slightly lower rate for men. And also developing countries have witnessed considerable increases since the mid-20th century, albeit with setbacks like the HIV epidemic in Africa.
This trend has been evident since the mid-19th century – and it has sparked a longstanding scientific debate: Will this trend continue indefinitely into the future? Or is there a biological limit to human life? The latest contribution to this debate is a statistical study from the Albert Einstein College of Medicine in New York.

 

1. Most increases not in oldest age group

In this study, Jan Vijg, a Dutch-American geneticist, and his team analysed data from the Human Mortality Database that spans 38 countries and is run by American and German researchers. Since life expectancy increase is still strong, the researchers needed other theories and data if they are searching for indicators of a future slowdown. Their theory was: If there is no upper lifespan limit, the age group with the biggest increase in survival should get older continually. But contrary to this assumption, the largest increase in survival rates has plateaued around the age of 99 in 1980, and has only increased very slightly since. They interpred this plateau effect as an early sign of slowdown.

 

2. Supercentenarians rarely older than 115

To further test their theories, Dr. Vijg’s team also used data from the International Database on Longevity from the Max Planck Institute for Demographic Research in Rostock, Germany. Watch out! Now the ages of lucky individuals are analysed, whereas before, increases in age groups were studied. Jan Vijg’s team found that the maximum age reached by individuals plateaued at 115 years in the mid-1990s, with very few, yet famous, exceptions. The researchers see this as another sign of slowdown. “It seems highly likely we have reached our ceiling,” says Jan Vijg. “From now on, this is it. Humans will never get older than 115.”

 

3. Japan is different

Interestingly enough, the longevity database used by the Vijg team was assembled at the Max Planck Institute for Demographic Research, that is also one of the main contributers to the Human Mortality Database. But James Vaupel, founding director of this institute, doesn’t share Dr. Vijg’s interpretation. One of his objections is that in Japan, the age group enjoying the fastest growth is still getting older; this holds true for a few other developed countries as well. As James Vaupel wrote in an earlier paper, together with Jim Oeppen: Experts asserting that “life expectancy is approaching a ceiling … have repeatedly been proven wrong.”

 

Every third baby born in Britain today has a good chance of celebrating its 100th birthday, according to the Office for National Statistics ONS. Photo: iStock.com/David Freund

Every third baby born in Britain today has a good chance of celebrating its 100th birthday, according to the Office for National Statistics ONS. Photo: iStock.com/David Freund

4. Highest life expectancy, lowest birthrate

Japan has the highest life expectancy in the world and thus is of special interest to demographers: currently 86.8 years for women and 80.5 years for men. Japan also has one of the lowest birthrates. A web population clock from Tokyo University predicts that the last Japanese child will be born in the year 3,776 if this latter trend is not reversed – meaning that the Japanese will die out about one hundred years later. Some estimates suggest that by the year 2050, up to one million centenarians will live in Japan.

 

5. Can ageing be reversed?

In all other species, lifespans can be increased by genetic interventions, certain proteins or dietary changes. Several teams at James Vaupel’s institute in Rostock conduct research on these topics with different model animals, as well as many other research teams worldwide. So why should humans be an exception? “There is no time bomb that explodes at a certain age,” says Linda Partridge, director at the Max Planck Intitute for Biology of Ageing in Cologne, Germany, who is also specialising in strategies to influence ageing processes. In recent years, ageing in mice could be reversed with telomerase, and similar experiments were conducted successfully with human cells.

 

6. Animals that never age

There are some animals that don’t age. The biologist and mathematician Prof. Annette Baudisch for instance studied species like this, for instance robins and the freshwater polyp Hydra vulgaris, i.e. their mortality rate doesn’t increase with age, and they retain similar levels of health throughout their lives. Unfortunately, humans don’t belong in this group, the same holds true for most lab animals. But these surprising species may have some traits that could point to strategies against ageing as we know it in humans; human ageing comprises many factors: the slowdown of biological processes, the shrinking of organs, the deposit of lipofuscin, the accumulation of genetic mutations, etc.

 

Rita Levi Montalcini was an Italian neurobiologist who was awarded the 1986 Nobel Prize in Physiology or Medicine for her discovery of nerve growth factor, together with Stanley Cohen. She celebrated her 103rd birthday in 2012 and died the same year. Photo: Peter Badge

Rita Levi Montalcini was an Italian neurobiologist who received the 1986 Nobel Prize in Physiology or Medicine for her discovery of nerve growth factor, together with Stanley Cohen. She celebrated her 103rd birthday in April 2012. Photo: Peter Badge

7. Game changer: advances in medicine

Several researchers argue that Jan Vijg’s team didn’t take the medical advances of the future into account, that might target the afore mentioned ageing processes, as well many deadly diseases. “The result in this paper is absolutely correct, but it says nothing about the potential of future medicine, only the performance of today’s and yesterday’s medicine,” says biomedical gerontologist Aubrey de Grey of the SENS Research Foundation in Mountain View, California. Conversely, potentially negative trends like the global obesity epidemic, with the side effects of soaring type 2 diabetes and nonalcoholic fatty liver disease numbers, are also not taken into account.

 

8. New trends lower life expectancy

Even today, the increase in life expectancy is being reversed in developed countries for certain groups. As Nobel Laureate Angus Deaton and Prof. Anne Case showed, white middle-aged Americans without college degrees are dying younger than in the past. For all other ethnic groups, life expectancy is still rising in the US, but for this group it’s falling. The researchers could also explain how prescription drug abuse, alcohol and suicide shortens the lives of too many middle-aged Americans.

 

9. Centenarians are exceptions, not examples

Centenarians seem to be quite an exceptional group, as a recent German study showed, again: One third of the patients over 100 years of age didn’t show any signs of dementia, three quarters were not depressed, almost a quarter didn’t take any drugs on a regular basis, and an astounding 65 percent hadn’t been admitted to hospital in the last twelve months. If this group is so healthy, gerontological research might learn a lot from them – but because they’re so special, maybe they’re not the best group to predict everyone’s ageing process.

 

10. Longer life due to Nobel prize

Winning the Nobel prize adds one or two years of life expectancy. The British economists Matthew Rablen and Andrew Oswald wrote: “It has been known for centuries that the rich and famous have longer lives than the poor and ordinary,” but the causality behind that remained unclear. That’s why they looked for cases where a sudden rise in status occured, and biographical data were also available: they found Nobel Laureates. And really: the positive status shock of winning a Nobel prize adds one or two years compared to researchers of the same age and from the same country who were merely nominated for this prestigious prize.

 

Only time and future studies will tell if humanity has already reached an ‘age ceiling’ – or not. But if we consider quality of life together with the quantity of years, it becomes evident that adding years doesn’t automatically mean more healthy years. On the contrary, additional years often mean more years of disease. This is why Jan Vijg wrote in his study that we should pay more attention to our  ‘health span’ instead of concentrating solely on our lifespan.

 

Exercise is a vital ingredient both to longevity and to healthy ageing. Others are: normal weight, a diet rich in fibres and low in sugar and red meat - and meeting people, having fun and playing games to ward off dementia. Photo: iStock.com/Horsche

Exercise is a vital ingredient both to longevity and to healthy ageing. Others are: normal weight, a diet rich in fibres and low in sugar and red meat – and meeting people, having fun and playing games to ward off dementia. Photo: iStock.com/Horsche

Nobel Prize for Yoshinori Ohsumi

Autophagy is a fundamental process for degrading and recycling cellular components. Autophagy has been known for over fifty years, but its fundamental importance was only recognized after Yoshinori Ohsumi’s paradigm-shifting research in the 1990’s. For his discoveries, he is awarded this year’s Nobel Prize in physiology or medicine. Continue reading

Oliver Smithies: How potatoes revolutionised electrophoresis

Talking about his long life, Oliver Smithies often starts by conjuring up his happy childhood in pre-war Yorkshire. Banned from sports for health reasons, young Oliver spent much time with his best friend in the friend’s workshop; this friend’s father was a precision time clocks manufacturer and provided an attic workshop for his son. Before the age of 11, Oliver Smithies knew for sure that he wanted to be a scientist – but he didn’t know the word for his vocation. “The best I could come up with was: I want to be an inventor – as a result of reading comic strips about inventors,” he tells the rapt audience in his 2015 lecture at the 65th Lindau Nobel Laureate Meeting.

Oliver Smithies with a sketch of his work that won him the Nobel Prize in 2007. Here Smithies illustrates the method of gene targeting. When he started sketching, he asked the photographer, “is this red?”, for Smithies is colour blind. But he was able to earn a pilot licence and still enjoys flying his glider. Photo: Volker Steger, Sketches of Science

Oliver Smithies with a sketch of his work that won him the Nobel Prize in 2007. Here Smithies illustrates the method of gene targeting. When he started sketching, he asked the photographer: “Is this red?”, for Smithies is colour blind. Photo: Volker Steger, Sketches of Science, Lindau Nobel Laureate Meetings

Oliver Smithies was awarded the 2007 Nobel Prize in Physiology or Medicine, together with Mario Capecchi and Martin Evans, “for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells.” But when he tells his life story, he seems to prefer telling earlier stories, for instance about his invention of gel electrophoresis while working in Toronto in the 1950s. Before that, he had done postdoc work at the University of Wisconsin-Madison on a Commonwealth Fund fellowship, but this fellowship precluded his staying in the US afterwards. Normally he would have returned to the UK, but he had just gotten engaged to Lois Kitze, a graduate student in Wisconsin, so he started looking for a postdoc position in Canada.

He found work with David A. Scott in Toronto, a renowned insulin expert. In Toronto the very first diabetes patient had been treated by Frederick Banting with animal insulin in 1922. Only one year later, Banting received the Nobel Prize in Physiology or Medicine. When Smithies arrived in Canada, Scott told him: “You can do anything you like, as long as it has to do with insulin.” So Smithies set out to find an insulin precursor: “Now we know there is a precursor, but I didn’t discover it”, he says with a smile. He proceeded by studying insulin with the help of electrophoresis, but he soon became very frustrated with the method. Back then it was mostly conducted with filter paper that had been soaked in a buffer, then the sample was applied and allowed to migrate, but the results looked like long smears that didn’t help his research.

Then Smithies came across the recent work of Henry Kunkel and Robert Slater. The researchers had started to use a box filled with starch grains surrounded by a buffer, “rather like a sand box”. The results from this box were nice, clear peaks for each protein. But the downside was: you had to cut the probe into 40 slices and conduct a protein determination on every slice for a single electrophoresis run. “I didn’t have a technician, I couldn’t do that,” says Smithies in retrospect. “Then I remembered helping my mother doing the laundry.  She took starch powder and cooked it up with hot water and made a slimy substance that she would apply to the collars of my fathers shirts.” His father had been selling insurances to Yorkshire farmers and needed to look respectable. And at the end of a laundry day, the starch had settled into a jelly.

In Toronto in early 1954, Smithies made a gel from potato starch and stained it with insulin, creating a very nice, distinct band in the gel. (Incidentally, this first batch of gel would be the best for a long time.) In order to obtain his samples, Smithies often used his own blood. But “I was tired of bleeding myself, so I got blood from my friends – that’s what friends are for, isn’t it?” Now he could start to compare blood samples from different individuals. He soon discovered some extra banding patterns that some people had and others hadn’t; later he found, with the help of the Canadian geneticist Norma Ford-Walker, that this was a complicated genetic difference: haptoglobin types. Smithie says himself that he considers himself lucky that “Scotty” allowed him to pursue his research on blood proteins even though it had nothing to do with insulin.

But the quality of the potato starch remained a problem. Smithies tried different potato brands from all over Canada and the US, but none could reproduce the good results from his first batch. Finally he discovered this batch had been imported from Denmark. When Smithies’ work load kept increasing, he agreed to employ a technician, Otto Hiller from Germany. In 1960, Hiller even accompanied him back to Wisconsin, not as a researcher but as a manufacturer of gel electrophoresis equipment, mainly the plastic parts and the power supply, plus Danish potato starch that he sold to labs around the world. Gel electrophoresis is still widely used in medicine, research and even forensics today, for identifying certain proteins, for diagnostics, and for genetic fingerprinting.

When Smithies presents his results from the 1950s today, he shows his old pencil sketches – he didn’t own a camera in 1954 – and handwritten lab books. He explains this and urges his listeners, mostly graduate or PhD students and postdocs, to always make hard copies of important data. “This is a data file that is almost sixty years old – you won’t be able to produce your data file 60 years from now if you don’t make a hard copy!” They shouldn’t rely on their computers, “because you cannot read a floppy disk now, and you won’t be able to read a CD in ten years from now”: very sound advice indeed from a ninety-year-old.

 

Hobby pilot Oliver Smithies in front of his airplane (Screenshot from his Nobel Lab 360°).

Hobby pilot Oliver Smithies in front of his airplane. Despite being colour blind, he was able to get his pilot license and even train student pilots – and he still enjoys flying his glider. (Screenshot from his Nobel Lab 360°)

In 1978, Smithie’s first marriage ended, “and several years later I followed my mother’s example by falling for my post-doctoral student, Nobuyo Maeda”. In the early 1920s, his mother had been teaching English at Halifax Technical College where she met Smithie’s father, one of her students. When the Japanese researcher Maeda found a position at the Department of Pathology at the University of North Carolina, the couple left Wisconsin together and settled in Chapel Hill where they still live – and work. Smithies admits that he feels most at home in the lab: “This is where I’m most comfortable, I’m most relaxed and enjoying myself when doing experiments.” More recently, he’s been working with gold nanoparticles to see if the kidney separates proteins by gel permeation.

Oliver Smithies has attended the Lindau Nobel Laureate Meetings four times, and the audiences of his lectures were always delighted by his humorous, modest and lively presentations. Two of these lectures can be viewed as videos, and two Nature videos with Smithies interviews are available here. There’s also a Nobel Lab 360°: with this collection of videos, interviews and pictures, you can ‘visit’ Smithies in his lab in Chapel Hill – his favourite place in the world!

 

Oliver Smithies: Mit Kartoffelstärke zu genetischen Fingerabdrücken

Wenn Oliver Smithies erzählt, lässt er seine glückliche Kindheit im ländlichen Yorkshire wieder aufleben. Während er als Kind die Wälder der Umgebung durchstreifte, verbrachte er seine Jugend in der Werkstatt seines besten Freundes. Dessen Vater, ein Uhrenfabrikant, hatte seinem Sohn eine eigene Werkstatt eingerichtet. Schon vor seinem elften Geburtstag wusste Smithies, dass er Forscher werden wollte, nur fehlte ihm eine Bezeichnung für seinen Wunsch. Also sagte er, er wolle “Erfinder” werden, denn er hatte kurz zuvor einen Comic über einen solchen gelesen; dies alles erzählt er seinen begeisterten Zuhörern auf der 65. Lindauer Nobelpreisträgertagung 2015.

Oliver Smithies mit einer Zeichnung, auf der er die Arbeiten illustriert, für die er den Medizinnobelpreis 2007 erhielt. Das Thema sind gezielte Genveränderungen bei Mäusen. Beim Zeichnen fragte Smithies den Fotografen als erstes:

Oliver Smithies mit einer Zeichnung, auf der er die Arbeiten illustriert, für die er den Medizinnobelpreis 2007 erhielt. Das Thema sind gezielte Genveränderungen. Beim Zeichnen fragte Smithies den Fotografen als erstes: “Ist dieser Stift rot?”, er ist nämlich farbenblind. Foto: Volker Steger, Sketches of Science, Lindau Nobel Laureate Meetings

Smithies erhielt den Medizinnobelpreis 2007 “für die Entdeckung der Prinzipien, mit denen bestimmte Genveränderungen in Mäusen mit Hilfe embryonaler Stammzellen vorgenommen werden können”, zusammen mit  Mario Capecchi und Martin Evans. Doch wenn er aufgefordert wird, aus seinem Leben zu berichten, spricht er meist über frühere Entdeckungen, beispielsweise über seine Entwicklung der Gelelektrophorese in den 1950er Jahren in Toronto. Zuvor hatte er mit einem Stipendium des Commonwealth Fund an der University of Wisconsin-Madison gearbeitet, aber dieses Stipendium verbot ihm, nach dessen Ende in den USA zu bleiben. Eigentlich hätte er nach Großbritannien zurückkehren sollen. Da er sich aber in Wisconsin mit der angehenden Virologin Lois Kitze verlobt hatte, suchte er sich eine Stelle in der Nähe, eben in Kanada.

Er wurde bei dem Insulinforscher David A. Scott in Toronto fündig. Dort war Insulin erstmals zur Behandlung eines Diabetes-Patienten eingesetzt worden, und zwar 1922 von Frederick Banting, der schon im Jahr darauf den Medizinnobelpreis erhielt. Als Smithies nun an die Connaught Medical Research Laboratories kam, meinte Scott: “Sie können hier forschen, was immer Sie wollen, es muss nur irgendwas mit Insulin zu tun haben.” Also machte sich Smithies auf die Suche nach einer Insulin-Vorstufe. “Heute wissen wir, dass es diese gibt”, erzählt er schmunzelnd, “aber ich habe sie nicht entdeckt.” Er studierte nun Insulin mit Hilfe von Elektrophorese, für die damals meist Filterpapier verwendet wurde, getränkt mit einer Pufferlösung. Das Insulin sah auf diesen Papierstreifen jedoch nur wie ein verschmierter Fleck aus – Smithies frustierte diese ungenaue Methode sehr.

Da lernte er die neuartige Elektrophorese-Methode von Henry Kunkel und Robert Slater kennen, die hierfür eine flache Kiste mit Kartoffelstärke und Puffer gefüllt hatten. Und siehe da: Die Probe produzierte in dieser Anordnung eine klare, eindeutige Kurve. Der Nachteil war jedoch, dass man das Stärkegemisch in vierzig dünne Scheibchen schneiden und für jedes einzelne Scheibchen eine Proteinbestimmung durchführen musste, erst so erhielt man ein klares Ergebnis. “Ich hatte damals aber keinen Assistenten”, erinnert sich Smithies, “ich konnte diese Methode unmöglich anwenden.” Da erinnerte er sich, wie er seiner Mutter dabei zugeschaut hatte, wie sie Wäsche stärkte: “Sie kochte aus Stärke und Wasser eine schleimige Masse und trug diese auf Vaters Hemden auf.” Am Ende eines solchen Waschtags hatte sich die Stärke in einer Art Gelee verwandelt. Sein Vater verkaufte damals Versicherungen an Bauern in Yorkshire und musste immer korrekt gekleidet sein.

Anfang 1954 kochte Oliver Smithies nun aus Kartoffelstärke ebenfalls ein solches Gel und trug Insulin auf seinen neuen Teststreifen auf: Das Ergebnis war ein schönes, eindeutiges Bandenmuster. (Allerdings erreichte die verwendete Stärke lange Zeit nicht mehr dieselbe Qualität wie bei seinem ersten Versuch, dazu später mehr.) Zur Probengewinnung nahm er sich anfangs selbst Blut ab. “Aber ich wurde es leid, mich ständig zur Ader zu lassen. Deshalb fing ich an, meine Freunde anzuzapfen – wofür hat man schließlich Freunde?” Jetzt begann er, die verschiedenen Blutproben miteinander zu vergleichen. Dabei entdeckte er Bandenmuster, die einige Freunde hatten, andere hingegen nicht, und die er sich nicht erklären konnte. Später stellte er zusammen mit der kanadischen Genetikerin Norma Ford-Walker fest, dass es sich hier um verschiedene Haptoglobin-Typen handelte. Smithies war froh, dass “Scotty”, wie er ihn mittlerweile nannte, es ihm erlaubte, diese Themen zu verfolgen, obwohl sie nichts mit Insulin zu tun hatten.

In dieser Phase verfolgten ihn ständig die Qualitätsprobleme der verwendeten Kartoffelstärke. Er experimentierte mit den unterschiedlichsten Kartoffelsorten aus Kanada und den USA, aber keine konnte die guten Resultate seines ersten Versuchs reproduzieren. Schließlich fand er heraus, dass die allererste Stärke aus Dänemark stammte! Durch seine Erfindung stieg Smithies’ Arbeitsbelastung, schließlich stimmte er der Einstellung eines Assistenten zu, obwohl er eigentlich keinen wollte. Der deutsche Einwanderer Otto Hiller erwies sich als Glücksgriff: Er war technisch sehr geschickt, außerdem freundeten sich die beiden Forscher an. Hiller folgte Smithies 1960 zurück nach Wisconsin, arbeitete aber nicht an der Universität, sondern machte sich selbstständig: als Hersteller von Elektrophorese-Zubehör. Hauptsächlich vertrieb er Plastik- und Elektroteile, aber er verkaufte auch dänische Kartoffelstärke an Labore in aller Welt. Die Gelelektrophorese ist nach wie vor ein Standardverfahren der Medizintechnik und wird in der Forschung, für Diagnosezwecke und auch für genetische Fingerabdrücke verwendet.

Wenn Oliver Smithies seine Ergebnisse aus den fünfziger Jahren präsentiert, zeigt er liebevoll erstellte kleine Buntstiftzeichnungen, denn er besaß 1954 keine Kamera, und teilweise verschmierte handschriftliche Laborprotokolle. Er hält in seinem Vortrag kurz inne und rät seinen Zuhörern eindringlich, sie sollten von allen wichtigen Daten stets eine ‘hard copy’ erstellen, also zum Beispiel einen Ausdruck auf Papier. “Diese Daten hier sind fast sechzig Jahre alt – Sie aber werden Ihre Daten in sechzig Jahren nicht präsentieren können, wenn sie keine Version auf Papier haben!” Die anwesenden Studenten und Doktoranden sollten sich auch nicht allzu sehr auf ihre Computer verlassen, denn “schon jetzt kann man eine Diskette kaum noch lesen, und in zehn Jahren wird man eine CD nicht mehr lesen können” – ein sehr weiser Rat eines Neunzigjährigen.

 

Hobbypilot Oliver Smithies vor seinem Flugzeug (Screenshot aus dem Nobel Lab 360°).

Hobbypilot Oliver Smithies vor seinem Flugzeug. Trotz seiner Farbenblindheit machte Smithies mit 50 den Pilotenschein und unterrichtete sogar Flugschüler. Nach eigenen Angaben erhebt er sich immer noch gerne mit seinem Segelflugzeug in die Lüfte. (Screenshot aus dem Nobel Lab 360°)

Im Jahr 1978 wurde Smithies erste Ehe geschieden, “und mehrere Jahre später folgte ich dem Beispiel meiner Mutter und verliebte mich in eine Postdoc-Studentin, Nobuyo Maeda”. In den 1920er Jahren unterrichtete seine Mutter Englisch am Halifax Technical College, als sie Smithies Vater kennenlernte, einen ihrer Studenten. Als die japanische Forscherin Maeda ihre nächste Stelle an der University of North Carolina fand, zog das Paar gemeinsam nach Chapel Hill, wo sie heute noch leben – und beide noch arbeiten. Smithies gibt unumwunden zu, dass ein Labor sein natürliches Zuhause ist: “Hier fühle ich mich am wohlsten, am entspanntesten, hier habe ich Freude an meinen Experimenten.” Kürzlich beschäftigte er sich unter anderem mit Gold-Nanopartikeln, sie sollen helfen, bestimmte Prozesse in den Nieren besser zu verstehen.

Oliver Smithies hat bislang an vier Lindauer Nobelpreisträgertagungen teilgenommen, und seine Vorträge waren stets ein Highlight jeder Tagung. Zwei Vorträge liegen als Videos vor, außerdem gibt es zwei Nature-Videos mit ihm, sowie ein Nobel Lab 360°, mit dessen Interviews, Videos und Fotos man Smithies quasi in seinem Labor in Chapel Hill ‘besuchen’ kann – also an seinem erklärten Lieblingsplatz.

The Modest Nobel Laureate: Youyou Tu

Malaria is often dubbed ‘the killer of children’, and even today about 2,000 young children die of malaria every single day, mostly in Africa. But in the last 15 years, the mortality rate has dropped by astounding 60 percent, due to improved prevention and treatment: about half of this reduction can be attributed modern medication like the WHO-recommended ‘artemisinin-based combination therapy’, or ACT. In 2013, almost 400 million doses were delivered. But how this therapy was discovered is a story in itself: the active ingredient artemisinin is a spin-off of the Vietnam War.

Tu Youyou working with Prof Lou Zhicen in the lab. She has been working in the China Academy of Chinese Medical Sciences in Beijing for decades. Photo: Xinhua

Youyou Tu with Prof Lou Zhicen in the 1950s. She has been working in the China Academy of Chinese Medical Sciences in Beijing for decades, and is now Chief Scientist. Photo: Xinhua

In the mid-1960s, North Vietnam asked its powerful ally China to help with the malaria problem: malaria was killing more soldiers on both sides than active combat. Mao Zedong introduced the secret military ‘project 523’ that was a contradiction in itself: During the so-called Cultural Revolution in the 1960s, intellectuals were often displaced, imprisoned and even tortured. (When the pharmacologist Youyou Tu joined this project in 1969, her own husband was a detainee in a labour camp.) On the other hand, Mao desperately needed competent researchers to fight the greatest adversary in the Vietnam War: malaria. And the prevalent strain of the parasite Plasmodium was increasingly immune to chloroquine. The project’s name refers to the day it started: May 23, 1967. More than 500 scientists were recruited in about 60 participating institutes to search for effective antimalarials.

Photo of Youyou Tu from the official Nobel Prize press release. Tu is her family name, Youyou her given name. In China, as in other Asian countries, the family name comes first. In Western countries, she is sometimes calles 'Youyou Tu', sometimes 'Tu Youyou', both is correct. Photo: Nobelprize.org

Photo of Youyou Tu from the official Nobel Prize press release. Tu is her family name, Youyou her given name. In China, as in some other Asian countries, the family name comes first. In Western countries, she is sometimes called ‘Youyou Tu’, sometimes ‘Tu Youyou’, both is correct. Photo: Nobelprize.org

Youyou Tu had studied pharmaceutical science in Beijing, graduating in 1955, and she had trained in traditional Chinese medicine as well. When she began studying malaria in the southern Chinese province of Hainan, she had to put her small daughter into a nursery, because her husband was still imprisoned. When she returned several months later, her daughter didn’t recognise her. On the other hand, in Hainan she had seen many young children in the last stages of malaria that died very quickly – an experience she could never forget. “The work was the top priority, so I was certainly willing to sacrifice my personal life,” she said later.

Not only the Chinese researchers were baffled by the parasite Plasmodium and its resistances, South Vietnamese and American forces faced the same problem. Western researchers had allegedly tested about 240,000 different compounds against malaria over the years, initially without success. (In the 1970s, they found mefloquine, sold today under the name Lariam.) Because of her training in traditional Chinese herbal medicine, Youyou Tu’s team scoured ancient manuscripts for information on potential antimalarials. In the ‘Handbook of Prescriptions for Emergencies’ by the Chinese writer Ge Hong from 340 CE, she found a recipe to prepare malaria medication from Artemisia annua, also called sweet wormwood.

Tu and other researchers experimented with Artemisia extracts, but the results were inconclusive: some extracts worked against Plasmodium in a mouse model, some didn’t. So Tu went back to the old manuscripts and studied the extraction method that is described in detail: She found that modern extraction methods that use boiling water destroy the active ingredient artemisinin. Next she experimented with colder extraction methods, using ether as a solvent. With this novel active agent, she was able to eradicate Plasmodium parasites in mice and monkeys. After trying the potion on herself to see whether it was safe for humans, more than twenty malaria patients were treated – and the parasite could be eradicated! This was the breakthrough everyone had been waiting for.

In the West, these findings would have made Youyou Tu instantly famous. But in Mao’s China, her team wasn’t allowed to publish their results: After all, it was a secret military project. Mao died in 1976, and with him the Cultural Revolution. In 1979, the ‘Qinghaosu Antimalaria Coordinating Research Group’ published an article in English in the Chinese Medical Journal, no authors’ names were used; qinghaosu is the Chinese name for artemisinin. The first international publication followed in The Lancet in 1982, without Tu’s name. But she had been chosen to present the findings to a visiting study group from the World Health Organization in 1981 (reference in Louis Miller’s article in Cell).

Artemisia annua, or sweet wormwood. Photo: Jorge Ferreira, Public Domain

Artemisia annua, or sweet wormwood, the source of artemisinin. Today Artemisin is produced by Novartis and Sanofi-Aventis at cost price. Since 2014, Sanofi is also producing semisynthetic artemisinin. All antimalarials are usually combined with other active ingredients to lower the risk of resistances. Photo: Jorge Ferreira, Public Domain

In 2007, more than 25 years later, Louis Miller and Xinzhuan Su, both researchers from the National Institute of Allergy and Infectious Diseases in Rockville, Maryland, asked their Chinese colleagues at a scientific meeting in Shanghai about the scientist who actually discovered artemisinin. At first, now one was able to tell them. Extensive research in official papers – most had been stamped ‘secret’ for many years – finally lead them to Youyou Tu, who was then known as “the professor of the three Nos“: no post-graduate degree, no membership in the Chinese Academy of Sciences, and no research experience outside China. The two American researchers published their findings in the journal Cell in 2011.

When I asked Miller, now Chief of the Malaria Cell Biology Section at the NIH Institute, why he started searching for the discoverer of artemisinin in the first place, he had a surprising explanation: “I was always curious about the discovery of quinine by the Peruvian Indians (…) that led to the Jesuits trying quinine for malaria. This discovery was one of the major life saving discoveries in medicinal medicine. I am afraid that is lost and didn’t want this second important discovery of Artemisinin to be lost.” With his inquiry, he has not only documented Tu’s achievement, he has also brought the ancient story to our attention.

Being credited with the identification and isolation of artemisinin won Youyou Tu the Lasker Award in 2011, the most important American award in medical science, and this year’s Nobel Prize. But if a discovery is credited decades later, and even more if the original finding happened in a top-secret project, there will always be people who claim that others contributed as well – undoubtedly so if more than 500 researchers had been involved. Youyou Tu is very modest about this, in a video statement commenting on her Nobel Prize she says that finding artemisinin was “the effort of an entire team”, and that this award is also “for Chinese science and for traditional Chinese medicine”.


Chinese authors and papers don’t deny Tu’s decisive role in finding artemisinin, but they emphasise the contributions of many other researchers, for instance Li Guoqiao, the leader of the clinical trials at the Guangzhou University of Chinese Traditional Medicine, or Luo Zeyuan from the Yunnan Institute of Pharmacology where the purest crystals of artemisinin were first extracted in large quantities for clinical trials, among many others. But as Xinzhuan Su, the NIH scientist searching for the discoverer of artemisin together with Louis Miller, sums up his findings: “You can see a line, very clear, of her work from the beginning to the end.” Most of all, she persevered when the obstacles seemed insurmountable. And her perseverance paid off: since the 1970s, artemisinin has saved millions of lives.

Youyou Tu was the first Chinese researcher to receive a scientific Nobel Prize for research done in China, and the first Chinese woman ever. She gave her Nobel lecture with the title, “Discovery of Artemisinin – A gift from Traditional Chinese Medicine to the World“ in Stockholm last Monday and will receive the Nobel Prize in Physiology or Medicine today.

Nobelpreis 2015: Der Kampf gegen tropische Parasiten

Der diesjährige Medizinnobelpreis ehrt wissenschaftliche Entdeckungen, deren Anwendungen die Tropenmedizin revolutioniert haben. „Diese Entdeckungen haben der Menschheit wirksame Mittel zur Bekämpfung dieser schrecklichen Krankheiten zur Verfügung gestellt, die jährlich hunderte Millionen Menschen heimsuchen“, teilte das Nobelkomitee in Stockholm heute mit. Und meist seien die Verletzlichsten betroffen, nämlich Kinder in Entwicklungsländern.

 

 

Youyou Tu, die chinesische Preisträgerin, die für die Entdeckung eines Malariamedikaments geehrt wurde, kam 1930 in China zur Welt. Ihren Abschluss in Pharmazie machte sie 1955 in Peking, darüber hinaus bildete sie sich später in Traditioneller Chinesischer Medizin weiter. Während der sogenannten Kulturrevolution unter Mao ab Mitte der 1960er Jahre war es fast unmöglich, als Forscher zu arbeiten: Intellektuelle wurden willkürlich deportiert, inhaftiert und gefoltert. Gleichzeitig tobte der Vietnamkrieg, und Malaria stellte für die Kämpfer eine ernsthafte Bedrohung dar, außerdem gab es regelmäßig große Malariaausbrüche in Chinas Südprovinzen. Deshalb rief Mao Zedong das geheime Militärprojekt „Projekt 523“ ins Leben, um wirksame Medikamente gegen Malaria zu finden, denn Medikamente auf der Basis von Chloroquin hatten ihre Wirksamkeit weitgehend verloren.

Youyou Tu wurde zu einer wichtigen Forscherin in diesem Geheimprojekt. Da sie mit allen bekannten Malariamitteln unzufrieden war, suchte sie in über 2000 alten Manuskripten der chinesischen Medizin nach möglichen Wirkstoffen. Tu und ihr Team testeten 380 Substanzen an Mäusen, eines davon, aus der Pflanze Artemisia annua, konnte tatsächlich die Zahl der Parasiten im Blut senken. Die Pharmazeutin isolierte nun den Wirkstoff “Artemisinin” und testete ihn an sich selbst. Heute ist die Behandlung mit einer Artemisinin-Kombinationstherapie laut WHO der Goldstandard für die Malariabehandlung; die Kombination mit anderen Wirkstoffen ist nötig, um frühzeitige Artemisinin-Resistenzen zu verhindern.

Während Youyou Tu an diesem Medikament forschte, war ihr Mann in einem maoistischen Arbeitslager. Weil sie Malaria-Erkrankungen in der Provinz Hainan erforschte, war sie gezwungen, ihr bis dahin einziges Kind in dieser Zeit in ein Kinderheim zu bringen. Als sie von dem langen Forschungsaufenthalt zurück kam und ihr Kind abholen wollte, erkannte ihre Tochter sie nicht und weinte, als sie mit dieser „Fremden“ nach Hause gehen sollte. „Meine Forschung hatte damals Priorität“, erinnerte sie sich später. „Mein Privatleben musste ich dafür opfern.“ Tu ist die zwölfte Frau, die den Medizinnobelpreis erhält, und sie wird das halbe Preisgeld von acht Millionen schwedischer Kronen (850.000 Euro) erhalten.

 

 

Satoshi Ōmura ist ein japanischer Biochemiker, der sich auf bioaktive Substanzen aus natürlich vorkommenden Mikroorganismen spezialisiert hat. In den 1970er Jahren suchte Ōmura in Bodenproben nach neuen Stämmen von Streptomyces-Bakterien. Er beschrieb Tausende dieser Bakterienkulturen und suchte fünfzig Kulturen aus, die er für besonders geeignet hielt, um schädliche Mikroorganismen zu bekämpfen. Eine davon war „Streptomyces avermitilis“, die Quelle des Wirkstoffs Avermectin, den er 1978 erstmals isolieren konnte. Während seiner langen Karriere entdeckte Ōmura mehr als 400 Wirkstoffe, unter anderem neuartige Antibiotika sowie Krebsmedikamente.

Helminthen sind wurmartige Parasiten, die ihren Wirtsorganismen großen Schaden zufügen. In ihrer Begründung für den diesjährige Nobelpreis konzentrierte sich das Nobelkomitee heute auf die beiden schweren Parasiten-Krankheiten Elefantiasis und Flussblindheit. Doch eine große Zahl solcher Parasiten können viele verschiedene Krankheiten auslösen. Allen gemeinsam ist, dass sie die Gesundheit und das Immunsystem ihres Wirts schwächen. Sie führen auch zu Lernproblemen und können den Verlauf von Krankheiten und Syndromen wie HIV, Malaria oder Tuberkulose verschlimmern. Die Weltgesundheitsorganisation WHO geht von mehr als einer Milliarde Betroffener aus, die mit einem Wurm-Parasiten infiziert sind.

 

 

Nun aber zurück ins Jahr 1978: William C. Campbell, ein aus Irland stammender Biochemiker, bekam Proben von Ōmura; er arbeitete zu dieser Zeit für ein Forschungsinstitut des Pharmaunternehmens Merck in New Jersey. In seiner Forschung konnte Campbell nun zeigen, dass Streptomyces avermitilis besonders effektiv gegen Fadenwurminfektionen bei Nutztieren wirkte. Später wurde aus dem Wirkstoff Avermectin das noch stärker wirksame Ivermectin gewonnen. Diese Substanz wurde nun an Patienten mit parasitären Infektionen getestet: Sie konnte die Larven im Körper sehr effektiv abtöten – und zwar so gründlich, dass sowohl Elefantiasis als auch Flussblindheit laut Nobelkomitee kurz vor der Ausrottung stehen. Campbell arbeitet immer noch als eremitierter Fellow an der Drew University in New Jersey, Ōmura ist Emeritus an der Kitasato Universität in Japan, Tu ist Professorin an der Akademie für traditionelle chinesische Medizin.

Abschließend sagte das Nobelkomitee: „Campbell, Ōmura und Tu haben die Behandlung parasitärer Erkrankungen von Grund auf verändert. Die globale Wirkung ihrer Entdeckungen und ihr Dienst zum Wohle der Menschheit sind unermesslich.“

 

 

Wir sagen: Herzlichen Glückwunsch, und wir freuen uns darauf, die Preisträger nach Lindau einladen zu dürfen.


Verwendete Fotos in der Slider-Grafik: Ⓒ Nobel Media AB 2015

Nobel Prize 2015: The Fight Against Tropical Parasites

This year’s Nobel Prize in Physiology or Medicine emphasises scientific breakthroughs that have been applied with great success in tropical medicine. “The two discoveries have provided humankind with powerful new means to combat these debilitating diseases that affect hundreds of millions of people annually,” the Nobel committee in Stockholm announced today. And these diseases mostly effect “the most vulnerable” – children in developing countries.

 

  Youyou Tu, who discovered a higly efficient malaria drug, was born in 1930 and studied pharmaceutical sciences in Beijing, graduating in 1955. She also trained in traditional Chinese medicine. During China’s so-called Cultural Revolution starting in the mid-1960s, working as an academic was almost impossible, with imprisonment, torture and displacement being ubiquitous. But at the same time, the Vietnam War was raging, and malaria was a huge problem for both sides. It was also a major cause of death in southern Chinese provinces. Thus Mao Zedong started the secret military ‘Project 523’ to find an effective malaria treatment, because the parasite Plasmodium was becoming increasingly immune to other substances. Youyou Tu became part of this secret project. After being dissatisfied with the substances she found, she studied more than 2000 ancient manuscripts of traditional Chinese remedies and found that many anti-malaria drugs included the plant Artemisia annua. Tu and her team made 380 herbal extracts and tested them on mice. One of the compounds did indeed reduce the number of malaria parasites in the blood. Next, Tu isolate the active agent ‘artemisinin’ and tested it first on herself. Today, artemisinin-based combination therapies are recommended by the WHO as the most effective malaria treatment; the combination with other agents is necessary to prevent artemisinin resistances. When Tu started her malaria research, her husband was in a labour camp and she had to give their only child to a nursery to study malaria in the southern Chinese province of Hainan. When she came back, her daughter did not recognise her and cried when she tried to take her home: “The work was the top priority, so I was certainly willing to sacrifice my personal life,” she commented later. Tu is the twelfth woman to win the Nobel Prize in Medicine, she will receive half of the eight million Swedish crowns (about 850,000 Euros).  

 

Satoshi Ōmura is a Japanese biochemist who studied bioactive chemicals derived from naturally-occurring microorganisms. In the 1970s, he was searching for new strains of Streptomyces bacteria in Japanese soil probes. Ōmura characterised thousands of Streptomyces cultures and selected a few that were most promising in the fight against harmful microorganisms. One of them was ‘Streptomyces avermitilis’, the source of Avermectin, isolated in 1978. During his career, Ōmura has discovered more than 400 active substances, among them novel antibiotics and anti-cancer drugs.

Helminths are worm-like parasites that seriously affect their host’s health. The Nobel Prize committee focused on Elephantiasis and river blindness as two severe diseases. But the various helminth species can cause many different diseases and conditions, always weakening the hosts’ health and immune system, making learning difficult and exacerbating syndromes like HIV, tuberculosis or malaria. More than one billion people are estimated to be infected with helminths, the vast majority live in developing countries.

 

  Back to the year 1978: William C. Campbell, an Irish-born US biochemist, was able to acquire the Streptomyces probes from Ōmura. Campbell was working for the Merck Institute of Therapeutic Research in New Jersey at the time. He was able to show that Streptomyces avermitilis was especially effective against roundworm infections in farm animals. Avermectin was later modified into the more effective compound Ivermectin. This substance was later tested on humans with parasitic infections, and it proved to kill the parasites larvae very effectively – so effectively that both river blindness and Elephantiasis could be eliminated in the near future. Campbell is now an Emeritus research fellow at Drew University in Madison, New Jersey, Ōmura is a Professor Emeritus at Kitasato University.  

 

The Nobel committee concluded: “Campbell, Ōmura and Tu have transformed the treatment of parasitic diseases. The global impact of their discoveries and the resulting benefit to mankind are immeasurable.”

 

 

Congratulations, and we are looking forward to inviting the new Nobel Laureates to Lindau!


Pictures used in slider graphic: Ⓒ Nobel Media AB 2015