Den Nobelpreisen auf der Spur

Der Lindauer Wissenspfad macht ab sofort die Lindauer Nobelpreisträgertagungen, deren Geschichte und vor allem das „Nobelwissen“ für Groß und Klein sicht- und (be-)greifbar. Auf den Spuren von Nobelpreisträgern und ihrer Forschung können alle Lindauerinnen und Lindauer, aber auch Gäste aus der ganzen Welt, auf Entdeckungstour durch Lindau gehen. An insgesamt 21 Wissenspylonen lernen sie dabei mehr über wissenschaftliche Alltagsphänomene. Vielleicht kommt dabei auch der eine oder andere Nobelpreisträger um die Ecke – in Lindau immerhin durchaus denkbar…

Die Leuchtturmstele am Lindauer Hafen. Picture/Credit: Lindau Nobel Laureate Meetings

Die Leuchtturmstele am Lindauer Hafen. Picture/Credit: Lindau Nobel Laureate Meetings

 

Der Lindau Spirit für Alle

Wissen sollte immer und überall frei zur Verfügung stehen. Das gehört zum Kernanliegen von Stiftung und Kuratorium der Lindauer Nobelpreisträgertagungen, zu ihrer Mission Education. Die Idee zum Bau des Lindauer Wissenspfades ist daraus entstanden. Die Stadt Lindau hat sie bei der Umsetzung unterstützt.
Schon seit über 65 Jahren kommen in Lindau einmal im Jahr Nobelpreisträger und junge Nachwuchswissenschaftler aus der ganzen Welt zusammen, um sich auszutauschen und voneinander zu lernen. Der Lindau Spirit, von dem die Teilnehmer dabei inspiriert werden, soll jetzt auf dem Lindauer Wissenspfad für jeden und vor allem das ganze Jahr über erlebbar sein.
Der Wissenspfad besteht aus insgesamt 21 Wissenspylonen, 15 davon können auf der Lindauer Insel entdeckt werden. Auf dem Lindauer Festland und auf der Insel Mainau stehen jeweils drei Stelen zur Erkundung bereit. Auf der Karte sind die einzelnen Standorte auf der Lindauer Insel zu sehen.

Die Karte zeigt die verschiedenen Standorte der Wissenspylone, die ab sofort in Lindau entdeckt werden können. Picture/Credit: Archimedes Exhibitions GmbH

Die Karte zeigt die verschiedenen Standorte der Wissenspylonen, die ab sofort in Lindau entdeckt werden können. Picture/Credit: Lindau Nobel Laureate Meetings

 

Für jeden etwas dabei – die Wissenspylonen

Auf den unterschiedlichen Pylonen lernen kleine und große Entdecker wissenschaftliche Begebenheiten aus den Bereichen der Nobelpreisdisziplinen kennen und verstehen: es gibt Physik-, Chemie-, und Medizinpylonen, aber auch eine Friedens- und eine Literaturstele. Zwei Wissenspylonen erklären Theorien aus den Wirtschaftswissenschaften, zwei weitere Stelen erläutern, wie die Lindauer Nobelpreisträgertagungen entstanden sind und was sich hinter dem Nobelpreis verbirgt. Man muss kein Naturwissenschafts-Experte sein, um die Erklärungen auf den Pylonen zu verstehen. Der Wissenspfad richtet sich an viele unterschiedliche Menschen; die Kinderspuren auf jedem Pylon bringen das ‚Nobelwissen‘ auch den jüngsten Forschern näher.

Natürlich bekommen die Nobelpreisträger auf dem Wissenspfad einen besonderen Platz: auf den Stelen wird nicht nur ihre Forschung sicht- und erlernbar gemacht, zukünftig werden sie an der zentralen Station auch besonders geehrt: Auf dem kleinen See wird es in Lindau bald einen Steg geben, der die Namen der Nobelpreisträger verzeichnet, die schon einmal in Lindau zu Gast waren. Und das sind schon mehr als 450 Laureaten!

Virtueller Wissenspfad: Mit der App auf Entdeckungstour

In Zukunft kann man den Nobelpreisträgern auf dem Wissenspfad auch virtuell begegnen. Die App macht das möglich: an sechs verschiedenen Standorten erklären virtuelle Nobelpreisträger, wofür sie den Nobelpreis bekommen haben. Sogar ein Selfie mit Preisträgern ist möglich!
Entlang des Wissenspfads können alle ‚Wissenspfadler‘ das Erlernte in der Rallye testen und über Quizfragen knobeln. Dafür muss man allerdings vor Ort sein. Damit möglichst viele Leute den Weg nach Lindau aufnehmen und den Wissenspfad auch in echt kennen lernen, werden die virtuellen Nobelpreisträger und die Quizfragen nämlich nur am Pylonenstandort freigeschaltet.

Mit der Lindauer Wissenspfad-App kann man in der Rallye z.B. Quizfragen beantworten. Picture/Credit: preto_perola/istockphoto.com, illustrations: eatmefeedme; editing: rh

Mit der Lindauer Wissenspfad-App kann man in der Rallye z.B. Quizfragen beantworten. Picture/Credit: preto_perola/istockphoto.com, illustrations: eatmefeedme; editing: rh

 

Der Wissenspfad auf dem Sofa oder im Klassenraum

Aber auch diejenigen, die nicht nach Lindau kommen (können), haben die Möglichkeit, einen Blick auf Lindau, die Nobelpreisträger und ihre Forschung zu werfen: sie können den Wissenspfad zuhause virtuell ablaufen und die Pylonen in der App abrufen. Das können sich auch Lehrer im Unterricht zu Nutze machen.
Der Wissenspfad lädt Schulklassen aber auch explizit ein, nach Lindau zu kommen und sich auf die Spur der Nobelpreise zu machen. Vor Ort kann man deshalb auch gemeinsam einen Preis gewinnen! Interessierte Lehrer können sich gerne mit dem Kuratorium für die Tagungen der Nobelpreisträger in Lindau in Verbindung setzten und weitere Informationen und Materialien erhalten.

Schüler an einem Wissenspylon. Picture/Credit: Lindau Nobel Laureate Meetings

Schüler an einem Wissenspylon. Picture/Credit: Lindau Nobel Laureate Meetings

 

Ermöglicht wurde der Wissenspfad durch die Unterstützung der Stadt Lindau und der Prof. Otto Beisheim Stiftung.

Life in Super-Resolution: Light Microscopy Beyond the Diffraction Limit

In 1979, South African Allan M. Cormack won the Nobel Prize in Physiology or Medicine for his development of X-ray computed assisted tomography (CT), which allows physicians to see internal bodily structures without cutting. A quarter of a century later, Sir Peter Mansfield of the United Kingdom was given the same award in 2003 for advances in magnetic resonance imaging (MRI) that led to scans taking seconds rather than hours.

Today, these two imaging techniques serve as essential diagnostic and investigative tools for both medicine and the life sciences. But one unique fact about Cormack and Mansfield stands out: Despite winning the most prestigious award in medicine, neither Laureate went to medical school nor had a background in biology — rather, they were both true-blue physicists.

Cormack spent most of his research career focusing on nuclear and particle physics, while his CT efforts remained an intermittent side project for almost two decades. For Mansfield, his postdoctoral work on nuclear magnetic resonance spectroscopy in doped metals gradually transitioned into scanning his first live human subject with the newly invented MRI technique.

The tradition of physicists driving advances in biomedical imaging continues, as made evident by the lectures of Steven Chu and Stefan Hell at the 66th Lindau Nobel Laureate Meeting. Both showed visually stunning examples of their research using super-resolution microscopy, a method that transcends the diffraction limit of conventional light microscopes to probe on a nanoscopic scale.

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Stefan Hell in discussion with young scientists at #LiNo16. Photo: Ch. Flemming/Lindau Nobel Laureate Meetings

“We learn in school that the resolution of a light microscope is fundamentally limited by diffraction to about half the wavelength of light,” said Hell, who gave his lecture on Thursday morning. “And if you want to see smaller things, you have to resort of course to electron microscopy.”

Hell, a physicist who currently serves as a director of the Max Planck Institute for Biophysical Chemistry in Germany, accomplished what was long thought to be the impossible. Using light microscopy and fluorescent labeling of molecules, he invented a super-resolution technique called stimulated emission depletion (STED) microscopy — the work that won him the 2014 Nobel Prize in Chemistry.

“The development of STED microscopy showed that there is physics in this world that allows you to overcome this diffraction barrier,” he said. “If you play out that physics in a clever way, you can see features that are much finer and details that are beyond the diffraction barrier.”

A conventional microscope cannot distinguish objects — say, molecules — that are packed within a space of about 200 nanometers because they all become flooded with light at the same time. Subsequently, a detector will simply record the scattering as a blurry blob of light without being able to image any individual molecules.

Hell got the idea of highlighting one molecule at a time by using fluorescent labeling, while also keeping other molecules in a dark state through stimulated emission. With a phase modulator, he could then force molecules in a doughnut-shaped area to stay dark and in the ground state while those in the center would produce light.

With this discovery, biomedical researchers could now image objects as tiny as proteins on the outside of a virus. For instance, STED microscopy was used to observe a major difference in envelope protein distribution that can be used to distinguish mature HIV that can infect cells versus those immature viruses that cannot.

“The misconception was that people thought that microscopy resolution was just about waves, but it’s not — microscopy resolution is about waves and states,” Hell emphasized. “And if you see it through the eyes of the opportunities of the states, the light microscope becomes very, very powerful.”

Steven Chu referenced Hell’s groundbreaking research during his lecture on Wednesday morning, which focused on his recent efforts in optical microscopy — quite a departure from his previous work in energy during a decade-long sabbatical.

“I sat down fresh out of government with no lab, no students, no postdocs, no money,” said Chu, who served as U.S. Secretary of Energy from 2009 to 2013. “The only thing that I could do was think, and that turns out to be liberating.”

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Steven Chu during his lecture. Photo: Ch. Flemming/Lindau Nobel Laureate Meetings

A venerable jack-of-all-trades, Chu received the 1997 Nobel Prize in Physics in yet another field — atomic physics — for his development of laser cooling and trapping techniques. His latest interest in microscopy grew out of a fascination with cell signaling and how dysfunctions in the process can lead to cancer.

“If you’re a cell embedded in an organism’s tissue, you don’t willy-nilly divide — that’s considered very antisocial behavior. You divide when the surrounding tissue says it’s okay to divide,” he described. “But if you willy-nilly divide and say ‘me-me-me,’ that is called cancer.”

Using imaging techniques, the cell signaling pathway can be investigated in detail to target areas that could prevent cancer from developing. Taking Hell’s work in super-resolution microscopy a step further, Chu discussed his use of rare earths embedded in nanocrystals to replace fluorescent organic dyes. A nanocrystal can be doped with 5,000 to 10,000 impurities so it emits a certain color in the near-infrared with a very narrow spectral peak. If each class of nanoparticle is synthesized to produce a different ratio of colors, this creates a spectral barcoding of probes.

The next step is to use nanoparticle probes to image molecules through tissue in a living organism without cutting. Adaptive optics — a technique that originated in astronomy — has been employed in order to take light scattering into account, enabling high-resolution microscopy of mouse brain tissue through an intact skull.

“The question is if you go deeper into the infrared, can you look not through 500 microns but maybe 5 millimeters?” said Chu. “This is an open question we’re working on this. We’ve gotten down to a millimeter but we’ll see.”

One of his ideas involves inserting nanoparticles into cancer cells and watch them over time in order to track which cells metastasize, with the ultimate goal of developing future therapies.

When chemists meet they talk about drugs

“You can make crystal meth in your lab?” asked my housemate who was pursuing a PhD in computer science. “Yes, it’s a fairly simple molecule. I haven’t looked but I bet that I won’t have trouble finding the chemicals needed to make it,” I said. At the time I was a lowly graduate student pursuing my PhD in organic chemistry, who was not keen on breaking any laws. So while I did not make any illegal drugs, I did spend three years in the lab making a molecule that could one day be a drug to treat colorectal cancer.

And while synthesis of illegal drugs hasn’t come up at the Lindau meeting (yet), no one should be surprised that a lot of people are talking about drugs. Chemists are bound to talk about one of their biggest contribution to humanity. Today, Aaron Ciechanover (Chemistry Nobel 2004) gave an excellent overview drug development since the time Egyptians chewed on the bark of willow trees to alleviate pain.

Credit: Louise Docker (flickr)

As Ciechanover pointed out, most drugs till the early 20th century such as salicylic acid and penicillin were found because of serendipity. Their immediate need and widespread use automatically made them “blockbusters”, drugs which made the manufacturers a lot of money.

It was only in the latter half of the 20th century that drug discovery was pursued more systematically. The process involved screening thousands of molecules to find the handful few that could attack the desired targets

Thanks to modern drugs, four times as many human beings live to be 70 as did in 1860. But the current methods are not the way forward for drug development in the 21st century, argued Ciechanover. Using the example of Angelina Jolie, he said that genetic analysis is only going to become cheaper and more accessible. This is bound to usher in the era of personalised medicine.

Ciechanover’s master class yesterday, which involved four young researchers talking about their work, was also about “new frontiers” in drug development. Mahmoud El-Sabahy from Assiut University in Egypt gave an excellent overview of the use of “nanoparticles” in diagnosing and treating diseases. The idea there is to use tiny particles (only few billionths of a meter long) that can be built to possess some special properties.

An example is their use in treating heart-related diseases. When a person suffers a heart attack, some of her heart cells are injured. Stem cells can repair this damage, but current methods limit the treatment. Stem cells have the power to transform into new heart cells and replace the injured ones, but for that to happen effectively doctors need to track the whereabouts of these cells. Nanoparticles can make that happen.

These nanoparticles have the property to be observed by shining lasers on them, or by hitting them with ultrasonic sound waves, or detect the tiny changes in their magnetic fields. When the nanoparticles are injected in stem cells, one of these three ways can be used to keep an eye on them and improve therapy many times.

There are other promising routes for new drugs that are emerging. Brian Kobilka (Chemistry Nobel 2012) spoke yesterday about the role of GPCRs, which are molecules that sit on the walls of cells as doormen. They detect chemical signals and convey those messages inside the cells. Many functions of the human body from smell and sight to heart rate modification is dependent on GPCRs. Not surprisingly, according to Kobilka about 40% of drug targets are GPCRs.

A similar picture emerges when you look at aquaporins, another class of molecules part of the cell wall. Their job is to control the flow of water. Manipulating them with the help of drugs may be the way to treat heart disease, brain edema after a stroke and even dry eye syndrome. Peter Agre (Chemistry Nobel 2003) will be speaking about his work with aquaporins tomorrow.

There are three big challenges that chemistry can solve (and most chemists would agree with them): explaining the origin of life, acquiring sufficient energy for future use and working on the constant need to improve human health. In the first two days, Nobel Laureates at the Lindau meeting have mainly addressed one of the three big challenges. I look forward to their take on the remaining two.

The challenges and allure of protein design: A memo for this year’s young researchers

An inspiration from the birth of aviation

A few weeks ago I visited the small coastal town of Kitty Hawk in North Carolina. Kitty Hawk is where the Wright brothers made their epoch-making first powered flight. Big stones mark the start and end points of the flight. There is a huge monument on top of a hill where they took off and then there are three stones at varying distances at ground level. The three stones indicate the distances covered on every flight; the brothers clearly got better at flying on every attempt.
The Wright brothers’ story is inspiring not only because of the watershed in human history which they orchestrated but also because it shows the evolution of a technology at its best. The projects which the brothers undertook cost a few hundred dollars and should serve as a beacon of inspiration in this era of “big science” involving hundreds of millions of dollars. The brothers had a bicycle workshop in which they fashioned many of the components of their infant gliders. They drew inspiration from Otto Lillienthal who had been the first aviation pioneer to make successful glided flights; tragically, Lillienthal was killed on one of his flights, but not before saying “Kleine Opfer müssen gebracht werden!” (“Small sacrifices must be made!”). One of the most important lessons that the Wrights learn from Lillienthal’s adventures was the great value of building ‘toy’ models. Toy models start from the simplest possible systems which retain the essential features of a phenomenon and then work their way towards greater complexity. This philosophy has been used by many other pioneers of technology, including the scientists and engineers who made the moon landings possible.

Why am I relating the story of the Wright brothers? I relate it not only because it is extremely interesting in its own right but because it holds lessons and insights for a field that is likely to have a great impact on medicine. Perhaps some of the students attending this year’s Lindau meeting will make significant contributions to this field. This field is the science and art of protein design and its roots go back to the classical discipline of organic synthesis. In organic synthesis humans found an opportunity to extend their reach into their environment and thus control matter at whim. By synthesizing molecules of exceedingly greater complexity, chemists first emulated and then tried to supercede nature. There have been many notable successes in this endeavor, most significantly in the construction of synthetic drugs, polymers and petrochemicals which have structures and properties better than those of any molecules found in nature. Over the last one hundred years, molecular design through organic synthesis has become a robust, creative and economically all-encompassing activity that has kept scores of academic and industrial chemists engaged. Organic synthesis has not only been an art of the highest degree in itself, but it has been a transforming and enabling science for medicine and biotechnology; indeed, it has been the bedrock of much of the modern way of life. Protein design holds as many possibilities for the future of medicine in the twenty-first century as organic chemistry did in the twentieth. 
 
The protein design problem

So what is protein design? As the title indicates, it is the ability to change the sequence of known proteins to improve their function and generate novel structures. Ultimately protein design would involve the on-demand enumeration of the amino acid sequences corresponding to any arbitrary protein structure.

 
The basic question that the protein design problem entails can be thought of as the opposite question of the protein folding problem. The protein folding problem- one of the most challenging problems in all of science- asks us to determine the unique three dimensional structure corresponding to a given sequence of amino acids. The essential hurdle in this problem is captured by the so-called ‘Levinthal paradox’. A typical amino acid chain can potentially fold into literally an astronomical number of structures; just imagine a very long thread and the number of ways it can fold up. Levinthal calculated from a simple back of the envelope calculation that if a typical protein were to actually try out all these folds before it found the right one, it would take many orders of magnitude longer than the age of the universe. Clearly this does not happen, or else life would not exist. In reality, as proteins are synthesized in our bodies at every moment of our existence, it takes milliseconds or seconds at most for them to find their right 3D structure. Thus Levinthal saw a paradox in what was expected and what was observed. But four decades of intensive research from physics, chemistry, biology and computer science has revealed that the ‘paradox’ only presents itself if we don’t know the precise nature of the folding process. In reality, protein folding is like evolution by natural selection. As a protein starts to fold, local structures form quickly, leading to a dramatic reduction of the available ‘space’ to be searched. These local structures then try out a more limited number of structures, with successive steps nailing down more and more of the correct structure. What seemed like a miracle is now quite well-understood, although it’s still a challenge to actually predict the specific steps for a given protein.

The protein design problem asks the opposite question- given a 3D protein structure, what are the possible sequences that can fold up into this structure. Just like the folding problem, the essential difficulty in protein design is to trawl through the astronomical number of sequences that may be compatible with a given structure. Not surprisingly, computer algorithms have been very useful in doing this. In one way the design problem is simpler than the folding problem because in the folding problem there’s only one right answer (one 3D structure) while in the design problem there are many (several sequences). Yet the task is undoubtedly daunting. In fact computer scientists have classified the design problem as ‘NP-complete‘, which plainly speaking means that there is no simple, fast solution to any such problem (although a solution when found can be relatively easily verified).

To cut down on the complexity of the design problem, several solutions have been proposed. One common solution is to do what’s called ‘fixed-backbone design’. Recall that an amino acid chain consists of the backbone, which is the peptide bond, and the side-chains; it’s the side-chains that define the identity of a particular amino acid. In fixed-backbone design, it is assumed that the orientation of the backbone of the protein is fixed, and only the side-chains are varied to find a optimum fit to the structure. By optimum fit we mean a new sequence that does not change the structure and does not lead to high energies. Varying only the side-chains significantly cuts down on the number of solutions to be searched. However, fixed-backbone design does not always work since if the given backbone orientation does not make the right contacts with the rest of the protein structure to begin with, no amount of side-chain tinkering can help (this is the case especially when you are desigining a new protein from scratch). Another solution is to look in the existing database of thousands of known protein structures- called the protein data bank (PDB)- and find sequences that are known to fold into parts of the structure which you are interested in. You can then possibly mix and match these structure-specific sequences to build your known superstructure. Both these solutions are of great utility in a number of applications. And that brings us to the potential applications of protein design in medicine.

How could protein design contribute to medicine?

The possibilities are endless, and we can mention only a few here. From a basic scientific standpoint, the most important application of protein design is in understanding the intricate signaling pathways that underlie all of life’s important functions. Whether you are sensing a photon of light, using your immune system to fight off an infection or using a drug to ward off a disease, the workings of our marvelous bodies and of all living organisms depend on a precise and astonishingly complex communication network of small and large molecules. The communication network usually functions as a cascade; a small molecule can trigger a protein, which activates two proteins which dissociate from each other and activate three other proteins…and so on. The end product of such a process is often the activation or suppression of specific genes that can in turn bring about a myriad number of physiological responses. During these processes, it is very important that every protein binds to its specific partners and none else. Considering the highly crowded environment of the cell which consists of thousands of diverse chemical entities, that such a process of partner-finding happens at all is a marvel; think of trying to find your friend who is lost in the crowd during Oktoberfest.

Yet evolution has optimized every protein for this kind of specific interaction. In fact such precise interactions are very important in diseases like cancer. If they are disrupted, predicted chaos will occur. This is where protein design holds promise. Initially, it can be used simply to understand the intricacies of these signaling pathways. Specific proteins can be modified and introduced into the cell to perturb their interactions. The effects of these perturbations can shed light on the signaling networks of the cell. Once these networks are understood, one can modify a specific protein- say, a protein overproduced in cancer cells- and then introduce that protein into the cancer cell to essentially trick it. The modified protein can interfere with the function of the normal protein, thus hindering the cancer cell from dividing and possibly causing its death.

Perhaps the most fascinating conceptual use of protein design is in what’s called ‘metabolic engineering’. Metabolic engineering is a branch of the new science of synthetic biology and entails mixing and matching genes from various organisms to produce certain important biomolecules on demand. For instance metabolites from one organism can be shuttled into enzyme systems produced by another by connecting the relevant genes from the two organisms the way engineers connect different kinds of pipes. The enzymes will then act on the initial molecules and synthesize new products. Individually organism A might produce molecule A and organism B might produce molecule B. But metabolic engineering can enable us to create a novel genetic system producing both A and B which can then react to make C. The possibilities are endless and fascinating. Recently, scientists from the University of California, Berkeley have used such tinkering to produce the very important antimalarial drug artemisinin, a compound which is sorely needed around the world and whose extraction from natural sources is tedious, expensive and resource-depleting. Protein design can manifest itself in such metabolic engineering in the form of enzyme design. Enzyme design is one of the most challenging and cutting edge aspects of protein design since it involves understanding and modifying the functions of enzymes at atomic detail. Recently in a groundbreaking piece of work, enzyme design was used to produce an enzyme that carries out a reaction that is not catalyzed by any known natural protein. When perfected, enzyme design will make it possible to introduce enzymes catalyzing novel reactions in model organisms by way of genetic engineering. A pipeline of such designed enzymes will allow us to make bacteria do the hard work of making virtually any molecule that we want, including even jet fuel. The baton would pass from traditional synthetic organic chemists to protein designers.

Lastly, protein design is already used for producing one of the newest class of drugs against life-threatening diseases- antibodies. Experimental scientists have already been ‘designing’ antibodies by using the process of directed evolution, in which random mutations are introduced in proteins and those leading to desired functions are retained. Millions of mutated antibodies can be screened against a specific antigen to identify those that bind to it most tightly. Directed evolution can likewise find variants of other proteins and even RNA that perform a particular function efficiently. But protein design can make this process much more rational. Using computational algorithms that ‘dock’ antibody and antigen against each other and calculate their binding energy, protein design can suggest mutations or amino acid changes that will improve the energy of this binding. While the large size of antibodies makes this process challenging, in principle protein design will be able to design not just antibodies but any protein that can bind to a chosen molecule. Again, the possibilities of such a process are limitless, from designing antibodies against the latest strain of flu viruses to designing enzymes that bind to and destroy chemical warfare agents.

From building simple and complex organic molecules to designing proteins, we have come a long way. But the field of protein design is only a decade old and is roughly at the stage that organic synthesis was in 1950 and aviation was back in 1903. Just like the Wright brothers, we have had success with simple systems and have occasionally achieved remarkable feats. Just like organic synthesists in 1950, we are starting to understand the general principles of protein origami but have yet to get to a stage where we can design arbitrary proteins of varying diversity and complexity. Yet this future is full of possibilities and is exactly what makes the field so exciting.

When Robert Burns Woodward- arguably the preeminent organic chemist of the twentieth century and a molecular manipulator without peer- received the Nobel Prize for Chemistry in 1965, the Nobel committee chairman had the following to say in tribute to Woodward’s extraordinary abilities: ‘When it comes to organic synthesis, Nature is the uncontested master, but I dare say that the prize-winner of this year, Professor Woodward, is a good second”.

I think we can dare say and hope that among this year’s group of young talents at Lindau, there will be at least one or two who will prove themselves to be good seconds to Nature’s protein design abilities. The future beckons.

From messy to magical: Preparing for the future of medicine

In the early 1940s, as war raged over the continent, the British mathematician Freeman Dyson and the Indian physicist Harish Chandra were taking a walk in Cambridge. Harish Chandra was studying theoretical physics under the legendary Paul Dirac while Dyson was getting ready to spend a depressing time calculating bombing statistics at Bomber Command.

“I have decided to leave physics for mathematics”, quipped Harish Chandra. “I find physics messy, unrigorous, elusive”. “That’s interesting”, replied Dyson. “I am planning to leave mathematics for physics for exactly the same reason.” Leave their respective disciplines the two did, and both of them had highly distinguished careers in their new fields at the Institute for Advanced Study in Princeton.

I narrate this story because I can imagine almost exactly the same conversation taking place today between a biomedical researcher and any other kind of natural scientist. In fact it’s interesting to compare the status of medicine today with the status of physics when Dyson and Harish Chandra had their conversation. By 1940 physics had underwent a great revolution in the form of quantum mechanics and relativity. Yet there was much to be done and the “second revolution” was in the making. In retrospect it’s clear that very little was known about the strong and weak nuclear forces and nothing was known about the particle “zoo” that would be uncovered in the next few years. It took the efforts of many brilliant individuals to unify crucial concepts and make the whole structure look more consistent and complete.

Medicine in the year 2011 is like physics in the year 1940. Just like physics it has had a recent revolutionary past in the advent of molecular biology. Just like physics there is much of it that is “messy, unrigorous, elusive”. And it’s exactly these qualities that make it a field ripe for another revolution. The future beckons for medicine and biology today as it did for physics in 1940.

What will this future look like? In Niels Bohr’s memorable words, “Prediction is difficult…especially about the future”. Yet prediction is not so much about being able to chart the objective course of events as it is about discussing the promises, possibilities and pitfalls of the future. We do not predict in order to be right, we predict in order to be interesting. This year at Lindau we have the opportunity to witness the collision of ideas between 20 Nobel laureates and more than 500 students. The Nobel laureates have achieved great things, yet the future does not belong to them. It belongs to the young researchers attending the meeting. But the young researchers can only try their wings by perching on the edifice erected by their illustrious forefathers. The question we wish to contemplate is “How would these promising young scientists contribute to the future of medicine and how will their work be related to that done by their Nobel predecessors?”

As fraught with uncertainty as the answer to this question is, one thing seems to be clear; the study of life and disease at the molecular level will continue to play a foundational role in the future development of medicine. As we indicated above, medicine has been revolutionized in the last fifty years by the development of molecular biology. The discovery of the structure of DNA was a watershed that made it possible to ask questions about paradigms as grand as cancer, neuroscience, aging and evolution at the molecular level. Today no fundamental question about metabolism, growth, illness and even interactions between species and individuals goes unanswered without at least a cursory look at molecular level events. However, the great achievement of the 20th century was not just to understand life but to try to control and recreate it, most recently exemplified by Craig Venter’s creation of a “synthetic cell”. Now a high-school student can easily extract, purify, splice and insert DNA into other organisms using standard kits and cheap equipment. The “domestication of biotechnology” is on the horizon and we will have to deal with its inevitable wonders and worries. Molecular origami will continue to be an elemental force in medicine’s future development.

This year’s Nobel laureates have laid the foundation for the work that will be done by Lindau’s young guests. They have contributed tools, insights and unifying concepts ranging from man’s perpetual struggle with microorganisms to the elucidation of key biomolecular structures and pathways to the invention of new tools to illuminate the workings of living systems. It’s also worth noting that about half of this year’s laureates have been awarded the Nobel Prize in chemistry. This is not surprising since of all the basic sciences, chemistry is closest to medicine in being able to provide explanations at a molecular level.

How will specific discoveries by these prize winners inspire those to whom the baton is being passed? Let’s look at scientists who have deciphered the structures of key biological molecules; these include the laureates who have cracked open the workings of the ribosome (Yonath and Steitz), the photosynthetic reaction center (Michel, Huber) and aquaporin (Agre). Without structure there is no understanding of function, so the business of structure elucidation will keep the next generation as busy as it did the previous one. Last year I compared structure determination of biomolecules, especially through x-ray crystallography, to climbing mountains beyond mountains. The peaks that crystallographers and structural biologists have scaled will be footstools on which the young people can stand tall. Structure determination of complex molecules provide a fitting example of science as the “endless frontier”; as molecules which were thought to be impenetrable thirty years ago yielded to intellect and effort, new structures of great complexity beckon the intrepid explorers of the future.

The second class of laureates this year concerns those who have developed new tools to explore biological systems. In science, the value of craftsmen who build tools has sometimes been relegated to that of the deep thinkers, yet today’s biomedical science would be completely diminished if it were not for the discovery of green fluorescent protein (Tsien, Chalfie), recombinant DNA (Smith, Arber) and gene knockouts (Smithies, Evans). All these scientists have provided tools of inestimable value which will supply powerful basic utility to the young generation; they in turn will continue to refine and generalize. The development of the tools provides one of the best examples of how science builds on itself, of how today’s novel discovery turns into tomorrow’s common laboratory protocol.

Another kind of discovery made by some of this year’s prize winners relates to the study of basic physiological pathways mediated by key molecules. If others have shed light on structure, scientists like Fischer (phosphorylation), Blackburn (telomerase), Ciechanover and Hershko (ubiquitin) and Murad (nitric oxide) have illuminated function. Not only have these discoveries led to practical benefits (such as the development of drugs blocking these processes in cancer cells), but they also reinforce one of the perpetual wonders of chemistry and biology; the fact that molecules both maddeningly simple in structure like nitric oxide and more complex ones such as kinases can have such a profound effect on human physiology. Given the staggering multitude of small organic molecules and proteins involved in biological events, one can be sure that there are molecular gems hidden away in caves, waiting to be discovered, polished and held up as further marvels of chemical and biological organization.

While many of this year’s scientists have provided insight into the inner lives of our cells, others have also accomplished the crucial task of delving deep into the inner lives of our oldest companions and enemies: bacteria and viruses. The fortunes of human wars wax and wane, but we will possibly be fighting the microbe wars until the end of time. Several of this year’s Nobel laureates have discovered the identities and strategies of some of our most dreaded adversaries, including HIV (Montagnier) and HPV (zur Hausen). The practical utility of these discoveries is obvious, but they are also furthering our understanding of the fascinating tactics used by these simplest of organisms to hijack our bodies and turn them into their personal replication factories. The fact that something as simple as the HIV virus can today kill 2 million human beings a year is a testament both to the fragility of seemingly infallible human life as well as the terrifying beauty of evolution and nature’s enduring creations. In addition, the discovery that human papilloma virus causes cervical cancer- a disease which for decades was thought to have non-infectious causes- opens the door to what is one of the most fascinating ares of future medical research: the relationship between chronic diseases likes diabetes, heart disease, Alzheimer’s disease and cancer, and infection. Yet most who boldly first ventured into postulating infectious causes for disease like cancer and ulcers were harshly criticized and shunned. The young researchers at Lindau who wish to explore the relationship between infection and disease will, in addition to scientific imagination, need a healthy dose of tenacity, spirit and conviction. It seems that their scientific heroes have much more to offer them than just innovative ideas. If they are willing to pick up the gauntlet, they will certainly be in august company.

Finally we come to a class of scientists who are underrepresented in this year’s list. There is every possibility that their ilk might dominate in future lists. Edwin Neher and Bert Sakmann received the Nobel Prize for their studies of single ion channels using the patch clamp technique, work that revolutionized neuroscience. Neuroscientists are spread relatively thin among Nobel laureates in medicine. If physics dominated the first half of the twentieth century, many feel that neuroscience will dominate the twenty-first. Very few fields promise as much in terms of startling and revolutionary discoveries as neuroscience. Why? Because put simply, there is still a lot of low-hanging fruit in the field. While great advances were made in understanding the brain in the twentieth century, it is only now that we have begun to make real forays into unraveling this “thin bone vault”, the seat of our thoughts and emotions, at a functional level. New techniques including single-neuron studies and functional magnetic resonance imaging (fMRI) promise unprecedented insights into the working of the most complex biological structure that we know. These studies, for the first time, are allowing us to build bridges between the natural sciences and social sciences like psychology and economics. The ultimate goal is to get a feel of the neural basis of human behavior and consciousness itself, although many caveats exist in establishing such connections. Groundbreaking advances in genetics are also now allowing us to compare brains between different species and postulating what possibly makes us humans special. In addition, because much of the brain is newly accessible virgin territory, the simplest of experiments can still provide the deepest of understanding, something that used to be true of much of science in the nineteenth and twentieth centuries. Finally, just like molecular biology in the last fifty years, neuroscience provides unprecedented opportunity for interdisciplinary contributions, with biologists, psychologists, chemists, biomedical engineers and even computer scientists all being able to contribute. If this year’s young researchers want to pick a field which may well be the most exciting of the new century, they could do no better than to delve into the mysteries of neuroscience.

Let’s return to the conversation between Dyson and Harish Chandra. If medicine is “messy, unrigorous, elusive”, it only means that it is poised on the edge of a new era of understanding. But the other reason why the terms apply is because we have also started to realize some of the limitations of the optimistic pronouncements that have dotted the landscape of medical research in the last twenty years. One is the promise of genomics-based medicine. While the value of genomics in understanding disease is wholly undisputed, some of the starry-eyed expectations about the mapping of the human genome enabling a revolutionary new era in the understanding and treatment of disease seem to have been premature. As we have made leaps in unraveling biological systems, new complexities have emerged. For instance, determining the genome sequence is one thing, but understanding the complex interactions of the signaling networks mediated by proteins and small molecules in the body poses a challenge on a totally different level. As we have also learnt in other sciences over the last few decades, new types of phenomena arising at every level of understanding- dubbed emergent phenomena- challenge us. Knowing the genome is necessary but far from sufficient for knowing signaling cascades in cells. Similarly our understanding of disease has been enriched, but this has also made prospects for treatment more difficult than what they seemed. Cancer, for instance, is now rightly recognized as not just one disease but as a multifaceted series of events that cause a body to rebel against itself.

But as is always the case in science, challenges inherently promise opportunity. The complexities of cancer only mean that we will have to explore the promises of personalized medicine, where every patient gets treatment that is tailored to his or her specific brand of cancer with its specific mutations. The complexity of biological networks only means that we need new approaches from computer science, data analysis and systems biology to fully comprehend living systems. Science may be the only human endeavor where new difficulties and challenges are not only accepted but they are relished. In science, roadblocks almost guarantee new and possibly revolutionary levels of understanding.

This year’s young researchers at Lindau should thus welcome the future of medical science. Building on the work of their predecessors, they have every opportunity to change this future from messy, unrigorous and elusive to clear, rigorous and well-defined. This future beckons and our young scientists are taking the right step to prepare for it by being at Lindau; as Antoine Saint-Exupery would have told them, “As for the future, your task is not to foresee it, but to enable it”.

An Interview with Francoise Barré-Sinoussi

Francoise  Barré-Sinoussi won the Nobel Prize for Medicine in 2008 for her role in the discovery of HIV. As she detailed in her plenary lecture on Monday 28th June, she considers a combined approach of mainly Western-led lab-based research and locally based education and treatment centres in developing countries as crucial for the control of the disease.

Martin Fenner and I talked to Professor Barré-Sinoussi on Thursday afternoon, covering topics including how to make a marriage work when one of you has a demanding job, her work in Africa and how to judge the merit of scientists based on more wide-ranging criteria than publication history.

Francoise Barre-Sinoussi

LW: We wanted to start with the comment that you made [during Monday’s plenary lecture] about being in the lab on your wedding day – how have you found it being a woman in science? And how was it for your husband that you are obviously very passionate about you work and that that can involve working long hours? Do you find he had to sacrifice his own career to support you? 

FBS: No, I don’t think he sacrificed his own career. He had his own career. He was not working in science at all; he was working at the National Radio. And of course, I think we were fine together because he had his own work; he needs some autonomy. You have to find the right partner with your own personality. So it’s probably why it has worked very well together. He knew that I enjoyed my work since we met. He knew that my prioirty in my life is my scientific career; it’s my passion. And he knew that I would not be happy in life if I could not express myself and he would not have been happy if I had not been happy as well. There is a balance and I think he was happy as well. I must say though that he died the year of my Nobel nomination but during his disease of course at one point I wanted to be closer to him and to take care of him and I found out that he was not happy at all that I was staying at home so often. So one doctor, colleague and friend who was taking care of him told me one day “Please have your life, like before. He’s not happy.”

MF: Was it easier or more difficult that he was not doing work related to science?

FBS: I think it really depends on each personality. For me, it was easier. It was easier becuase when I was at home or with him, we could have discussions outside of science. I think it was good for me to think outside and to have friends also not only in the field of science but working on National Radio to see how other people  had other problems and a different life.

LW: Were your friends who weren’t in science interested in what you did? Did they understand what you did?

FBS: Yes, I would almost say, unfortunately, because they were asking me a lot of questions. They were very interested.

LW: Do you think being a woman has had any benefits in your area of research? You have a very integrated approach to HIV – it’s not just about the lab work, but about the social factors. Do you think being a woman has made this easier, or in any other way?

FBS: Difficult. It’s difficult to say. Again it depends on each personality, I think because I know even male colleagues who have exactly the same approach as me and I know women who do not have the same approach so for me it is not a question of gender, it’s a question of personality. 

MF: So should there be special programmes or support for women in science? Or should we just treat them the same?

FBS: That’s a good question. Of course in one way I think that we should facilitate the promotion of women in science because in the past it was quite difficult, not to stay in science, but to get to the higer levels. If I remember well, when I started at the Pasteur Institute, almost 40 years ago there was only 4 or 5 women maximum that were professors in charge of a department. Now I think it’s not far from 40%. I think it’s the right evolution, but I’m not a feminist. Of course I am for equality, but taking into account the competency and qualification. Otherwise, if women are just getting higher positions because we just need to rebalance, then I am against that.

LW: Coming back to the more integrated approach for treating, managing and finding a cure for HIV, do you have a feeling whether we will eradicate it by social facors alone?

FBS: No, I believe in a combined approach, I don’t believe in only one approach. I think it will be very difficult to eradicate the disease but we can reduce, as much as we can, the incidences of infection around the world. So the social approach is just one approach and should be combined with the biomedical approach. Today we have the treatment as prevention which is a very good approach and of course it depends on visibility, but we should include that approach everywhere. When we have a vaccine we will have to improve the vaccine, of course, and we will have to work very hard on issues of injustice and the respect of human rights.    

I think scientists have their own territory or place where they are competent.  They should stay in the position where they are competent, even if it is for political action.

LW: There’s obviously a big social and political impact of the work you are doing. Do you think scientists in general should be taking an interest in, science politics, either to do with things within their field, or maybe even beyond that?

FBS: I think scientists have their own territory or place where they are competent.  They should stay in the position where they are competent, even if it is for political action. Of course for myself, when I push for governments to take decisions about things, it is about HIV/AIDS because that is the thing I know best. I can provide the scientific evidence that I know and I’m sure I can convince better because I have the expertise in this field. In other fields where I don’t have expertise, how can I convince? 

LW: Do you find now that you have the Nobel Prize that people come and ask for your opinions on things that aren’t your speciality?

FBS: Yes! For sure they ask for my opinion on everything! [laughs]

LW: And do you tell them?

FBS: They think that with the Nobel Prize you know everything! I just don’t answer, of course. I say look, just because I have the Nobel Prize it doesn’t mean I know everything. It’s impossible. They ask me to open conferences on Mathematics [laughs] No way! That’s not my place.

MF: Do you think that the interaction between scientists and politically organisations works well, expecially coming into contact with developing countries, not just in France.

FBS: It’s really a diverse situation of course because it is a diverse situation in different countries so I cannot give a global answer and it can even change over time. I can give you the example of Cambodia. When we started in Cambodia, it was nothing. It was just after the genocide – there were no doctors. There were just starting to get somewhere again but without evalulation because they just needed someone in the medical field. So this country had to start from zero so me, and all the others – the NGOs and other international organiations were in realtionship with the authorites and the outcome was very fruitful. Of course, by providing scientific evidence we started to convince the authorities to take the decision to have a strong national programme on HIV/AIDS, they did, it’s working. It’s the first country in that region that this year, in 2010, they will reach the target for the number of patients that are treated that need to be treated. This is an example of a very positive example that is becoming negative because the local authorities, of course, they are very proud and they are starting to say “look, everything is going very well, we don’t need international support, we know how to apply a development fund, we have money to run the programme and I’m a little bit concerned. I’m a little bit concerned because everything is going well in quanity, but in quality of the treatment they have to very careful and they don’t listen any more really because they think they are the best.  

Another country, where I personally thought when we started with them, that it would be easier, because they already had competencies and infrastructure, still only today is it just starting to work – that’s Vietnam. And the problem there was political, it was hard to convince the political leaders of this originally communist country that they had to make policy for drug addicts and prostitutes. Since the epidemic started it took a long time to really convicne the authorities to have a strong tack. And they have started now as of a few years ago. When they saw that pregnant women were affected they realised that they had to do something, but it was a long delay. So there is progress now, but it has been very long compared to the very close country, Cambodia, which is a poorer country. I give you these two examples to show you the diversity of the problem.

MF: It’s almost as if you’ve learned a second job: you need almost as much patience as you do in research. 

FBS: Sure, but of course one of the qualities scientists should have is to be very patient [laughs]. And of course with politicians you have to be very peristent.

 Usually when I go for the first time to a country, I’m not implementing anything, I’m just listening and visiting a lot.

MF: The Bill and Melinda Gates Foundation did something rather dramatic to help with HIV/AIDS in developing countries. Is this something you welcomed very much becaise it has progessed things or has it complicated things because it is so much money?  

FBS: In principle I am very positive, but with a few modulations.  Very often their programme is too much directed by the Gates foundation and they don’t consider enough the local situation. So most of the programme they want to support is based on their own processes and procedures and it’s not working that well because you have to adapt yourself in those countries. You have to adapt to policy, to local regulation, to culture, local traditions; to listen. Usually when I go for the first time to a country, I’m not implementing anything, I’m just listening and visiting a lot. I like to go to visit the hospital, to discuss with the patients and to meet the communities, to go to the market. To try to progressively have my own view of the local situation. Of course I know it is impossible to penetrate them completely and it is very important to maintain contact with your partners who are present in the local area, and to keep contact with communities. I think we cannot implement any programme if it is not based on local priorities. Then when we make a programme it cannot be something that is written in Paris or London or Washington DC, it should be defined with the community, on site.

And then when the program is written, you have to adapt according to the organization they have locally. Of course you they must accept ethical regulations. If they don’t respect, in their country, the international ethical regulations, that we can’t accept. You have to tell them that. The rest you can adapt. And we should adapt. With some of the programs I maybe had a bad experience, because I felt that they wanted to establish a project under the umbrella of saying we are going to implement reference centers in developing countries, but after a while I was wondering whether they really wanted to implement reference centers and network with reference centers locally, or whether they only wanted to collect samples for American laboratories for research. To be very direct and very frank with you. Just to make you understand why I have some reservations, even though I am in principal very positive.

MF: Is basic HIV research done in developing countries?

Very little basic HIV research is done in developing countries, and I am not encouraging them. It is not their priority. Maybe one day it will be their priority, and I would be very pleased. However, today I think the priority is clinical and operational research to provide the scientific evidence to convince the leaders and also the communities in their country. Of course sometimes you can have more basic science associated with this, but not determining the structure of a protein in the middle of the Central African Republic. You have to associate local people so that they can be trained in more basic science, like immunology or genetic susceptibility of infectious diseases for example, an important topic. And it is important for them because we know that the disease progresses differently according to the genetics. So they need to have this information locally, so this kind of program we can do, we just have to train them and to transfer the technology on site, because for me they shall do this themselves, and not to take the samples from the clinical research, bring the samples back to France, England or the United States. We must implement a program locally, and of course also supervise them locally in order to teach them, educate them, so that they can be the future in that country.

Of course some people tell me that I am crazy, that I am doing this for free, meaning that I will not be associated with the publications from this project. And I say “Yes. So what?”

MF: How many days per year do you spend outside of France?

I was in Cambodia when the Nobel Prize was announced. I used to go to Cambodia and Vietnam twice a year, about 10 days on each trip. On my first trip I try to analyze the situation, to get a general idea. Alone I don’t have all the competencies, so I start to contact colleagues, either in France or in other countries, giving them a short report of my visit. I tell them that we need their competencies and whether they would be ready to get engaged. I first start with a small network of people and then we decide to go together into the country to meet the local people. We try to find two or three people on whom we can rely and we start to train local people. It is of course easier in countries like Cambodia or Vietnam, as we have a Pasteur Institute there. It’s easier because they are 100% on site, some, like in Vietnam, are national Pasteur Institutes with no French people at all. But quiet a significant number of researchers has already been trained in France or in other countries. So we can rely on them and start from the Pasteur Institute. It is similar with the Welcome Trust, and the Welcome Trust program is also in Vietnam. The idea is to have a team on which you can rely, so that you don’t need to go there too often.

Of course I will go myself if it is a program where my lab is involved. In some programs my lab is not involved. I will organize, I will find the right people, I might give advice, but nobody in my lab will be involved. Of course some people tell me that I am crazy, that I am doing this for free, meaning that I will not be associated with the publications from this project. And I say “Yes. So what?” I don’t ask to be on publications of work that I have not been involved with.

MF: Do you think that women behave differently in this regard compared to men?

There are all kinds of different people, because I know women that will not do what I am doing, and I am working with men that are doing exactly the same.

It’s not what many people think is important, like publications, but receiving friendship, and close human relationships, that is what is important in life.

LW: There is an argument as discussed earlier in the week, that you are trained by public money so you should give what you can when it is appropriate.

FBS: When I say I’m doing this for free, this means free in terms of publications. But for me, what I receive in exchange is a lot of friendship. Take for example the reaction when I was awarded the Nobel Prize, I was in Cambodia at the time to meet this group of Cambodian people, not only doctors and biologists working at the Pasteur Institute, but also a group of patients that came to me with flowers, some of them were crying. I said “Look, you don’t have to cry, you should be happy.” I took them into my arms, and this is of course something that I will remember forever. It’s not what many people think is important, like publications, but receiving friendship, and close human relationships, that is what is important in life.

LW: Do you think that science will evolve to encompass more of that?

FBS: We had the discussion two days ago at the breakfast with young researchers, the topic was “How science can serve society?”. And one young researcher said, and she was right: “To tell you the truth, I’m not even thinking about this question yet. Maybe I will think about it one day. I am at the end of my PhD, my only objective is to publish, and even after my PhD I will do a postdoc in a laboratory where I can publish as much as possible, good publications in the best journals.” At one point I stopped her and said that of course she was right, that she was right at this level of her career. But we have a problem with our system of evaluations. So it’s not your fault, of course, you are a victim of this system. Of course I also think about publications, because it is one indicator. But it should be one indicator, not the only one.

Of course it will take time, probably several generations, to change this system of evaluations. It can work only if we change this at an international level, and I was explaining to the young researchers exactly what you said. Take this example. You have two young scientists, same age, one is in a very good laboratory with a very good advisor in a very nice scientific environment, in the UK, in Germany or in France, and he has wonderful publications in Science, Nature, whatever, high impact factor journals. And on the other side you have a young researcher with the same age, also at the postdoc level. He decides, instead of going to the UK or United States, to go to Africa. And of course he is not going to publish in Nature or Science. Of course he will not have the same supervision as you have in a laboratory in the UK. However, what he is doing on site is implementing, outside of his own research, a program in collaboration with local people, he is training local people to improve the competency and human resources, he is associated with implementations of health interventions, all something that you can’t publish. After five years he will have publications, even the same amount of publications, but not with high impact factors. Both apply for a permanent position, the one from the UK will get the position, and the one who worked in Africa will not get the position. This is not acceptable for me. Because if you take the one in the UK and you move him to Africa, you will see what the one in the UK will be able to do in Africa. Nothing. Not all of them, I know some situations where they were doing well, it is again depending on the personality.

I’m not against taking into consideration publications as one criterium, but it seems to me that the number of indicators is too limited.

LW: But how far can we go with non-publication credits? Should it for example also include science communication?

FBS: Of course, because I think that communication is also one criterium that should be considered for evaluation of a scientific career. I’m not against taking into consideration publications as one criterium, but it seems to me that the number of indicators is too limited. If we had a list of indicators that is larger than the one we have today, and if we can succeed – it is complicated to change the mindset of the reviewers, because it is not only indicators, it is also that the reviewers are using the conventional approach. They should be more open, they should have an open mind for the future.

MF: Do you think you a minority in this thinking among your colleagues?

FBS: Yes, I feel we are a minority, because when I say conventional that means the majority. Unfortunately. But even a minority can sometimes succeed. I once belonged to a scientific review committee, and the situation that I just mentioned happened. And I said almost what I just said, and finally the guy who had spent five years in Africa was recruited, actually both of them were.

LW: But that was because you had the experience and you valued it?

FBS: Probably. But maybe also because I was trained at the Pasteur Institute, and the situation I just described was in a scientific committee of the Pasteur Institute. It was of course an international committee and not all the members were from Pasteur. But I was telling the Pasteur members that they are forgetting their mission. They were recruited to this Institute, and the mission of the Pasteur Institute is not only research, but it’s also to be active for public health, everywhere in the world. 

 


More Interviews with Nobel Laureates at Lindau 2010:

Interview with Edmond Fischer: pianist, microbe hunter, pilot and Napoleon expert

A Conversation with Gross on the Edge of Knowledge

Lindau through the eyes of a Nobel laureate

On artificial and synthetic cells

Monday morning Jack Szostak talked about his ongoing work on creating artificial cells, where he is trying to create simple protocells from chemically synthesized material that in their simplest form only contain a membrane and genetic material.

Later in the afternoon Hamilton Smith gave a detailed account of the work by the J. Craig Venter Institute cumulating in the synthetic cell paper published in Science on May 20 (doi:10.1126/science.1190719, fulltext freely available).

Jack Szostak is interested to understand more about the origins of life, and for this is studying the simplest possible forms of living organisms, only containing a membrane and genetic material. A main motivation for his work has been the discovery in the 1980s that RNA is not only encoding genetic information, but can also catalyze chemical reactions inside cells – indicating that RNA might have existed before DNA and proteins. For this work, Jack Szostak and his laboratory have spent a large amount of work studying primitive membranes (e.g. Nature 2008, doi:10.1038/nature07018). Efforts to replicate genetic material using nucleic acids without the help of biologic material so far have not been successful. The work on artificial cells by Jack Szostak and others is fascinating, but extremely complicated (his lab has been working on this since the early 1990s). But we will probably learn a lot about basic biologic processes along the way.
Artificial cells are started from scratch and are completely human-made. In contrast, a synthetic cell is a cell controlled by a chemically synthesized genome and the human-made part is that genome. Hamilton Smith used the analogy from computers to explain the concept of synthetic cells: the genome is the operating system and the cytoplasm is the hardware.
The second genome ever sequenced (in 1995) is from Mycoplasma genitalium, the smallest genome (580 kB) of an organism capable of independent growth in a laboratory. In addition to 485 known coding sequences, M. genitalium contains 100 genes without known function. The synthetic biology group at the J. Craig Venter Institute started synthesizing oligos (later outsourced to several companies) that were then assembled into larger pieces by homologous recombination. It was easy to get to the quarter genome (144 kB), but assembling those last four pieces together proved difficult. The group moved to yeast in which they could assemble the full genome. The next step of transferring the synthetic genome into a receptive bacterial cytoplasm turned out to be very difficult.
After unsuccessfully working on this problem for a few months, Hamilton Smith and his group decided to use faster growing bacteria (M. genitalium has a fairly long doubling time of 16 hours). They switched to the Mycoplasma mycoides genome (1.1 MB) for the donor genome and Mycoplasma capricolum as a recipient. The process used to assemble the genome was the same (oligo synthesis, combination of fragments using homologous recombination, and final synthesis of the full genome in yeast). Hamilton Smith and colleagues then finally succeeded to transfer the synthetic genome into recipient M. capricolum. Along the way they lost three months during the assembly phase because of a single base pair deletion in an essential gene (the chromosomal replication initiator DnaA).
 
The resulting M. genitalium cells were almost indistinguishable from wild-type M. genitalium. Almost indistinguishable because the synthetic cells not only contain a tetracycline resistance to allow for selection, but also have undergone a few genetic changes in the process: 8 single nucleotide changes due to mutations, a 85 bp insertion, and a 777 bp insertion of an E. coli IS1 sequence (E. coli was used during the cloning process). 
 
TO LIVE, TO ERR, TO FALL, TO TRIUMPH, TO RECREATE LIFE OUT OF LIFE – James Joyce
In order to distinguish the artificial genome (and to have some fun), the synthetic M. mycoides also contains watermarks, human-readable information using a new DNA code that is biologically neutral. The scientists at the J. Craig Venter Institute encoded 46 names of people involved in the project, an email address (to contact when you cracked the code) and quotes from James Joyce, Richard Feynman and the R. Oppenheimer biography into the genome. As expected, it took less than three weeks for the code to be cracked and the names of researchers and quotes to be revealed (Using Arc to decode Venter’s secret DNA watermark).