The Joy of Discovery

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Bernard L. Feringa

Few events in the career of a scientist make such a lasting impression as the Lindau Nobel Laureate Meeting. In the beautiful setting of Lake Constance, Countess Bettina Bernadotte and the staff of the executive secretariat of the Lindau Meetings welcome hundreds of young talents from all over the world to discuss with several Nobel Laureates. Far beyond my daily joy of discovery in the molecular world, I experienced the excitement and stimulating atmosphere created by the discussions with so many bright young minds. The lectures of distinguished Nobel Laureates, covering various aspects of our discipline and far beyond, were equally stimulating, providing ample opportunities to open new windows to our common future. This memorable event, characterised by superb organisation and royal treatment, makes even the youngest participant feel proud to be a scientist. The numerous discussions with the students reminded me vividly of my own early days as a young scientist – the wonder and passion for chemistry but also the struggle with choices. Which are the most challenging topics or areas for the future, which directions to take, how to deal with the winding and unpaved roads to discovery, the balance in one’s personal life? How do you translate the advice of one of your heroes in the field and find the balance with your own knowledge and intuition? It was indeed a great joy to rediscover how the journey of a scientist starts as well as sharing my personal experiences with these daring and ambitious young men and women.

Few events in the career of a scientist make such a lasting impression as the Lindau Nobel Laureate Meeting.

The opportunity to advocate the values of science in general – our responsibilities for humanity and the important role of ‘quality of thought’ in academic training, through extensive discussions with participants from around the world – reflects to me one of the major assets of the Lindau Meetings. This extends to the many opportunities to engage with the press to emphasise the beauty and power of chemistry as the central science and the key role of all the young talents gathered in Lindau in making major contributions to invent our future. The considerable efforts of the Lindau organisation in reaching out to the community at large are to be applauded. The inspiring lectures and high-level social events, including an enchanting ’Mexican Evening’, provided the proper ‘wings’ to make us all feel as though we were flying during this magnificent week.

 

Ben Feringa with young scientists during the 67th Lindau Metting. Photo/Credit: Julia Nimke/Lindau Nobel Laureate Meetings

Ben Feringa with young scientists during the 67th Lindau Meeting. Photo/Credit: Julia Nimke/Lindau Nobel Laureate Meetings

 

For me, the absolute highlight of the event was the discussion forum, which lasted nearly two hours, with a large group of students. The topics ranged from personal highlights to decisive moments in my career, the challenging questions by the audience on the future of our discipline and the experiences shared by students from different continents, made this particular meeting a steep mutual learning curve for all of us. It was a fine example of the essence of science, asking questions and entering academic debate. It gave me much pleasure to share with the students my views on “how to discover your talent” being a scientist: “Be confident in following your dreams, as it allows you to discover what will give you lots of energy and to experience your limits in this adventure in the unknown beyond your current horizon.” 

The joy of discovery by the students, both scientifically and personally, experienced in all its facets during the Lindau week, will make a long-lasting contribution to the careers of these young chemists. The Lindau Nobel Laureate Meeting offers a magnificent ‘laboratory’ for young talents who are going to shape our future.

 

More reviews and highlights of the 67th Lindau Meeting can be found in the Annual Report 2017.

 

 

Go on a virtual tour through the Feringa lab at the University of Groningen in the Nobel Lab 360°.

An Opportunity Not to Waste

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I must admit to being incredibly intimidated about attending the 6th Lindau Meeting on Economic Sciences. About twenty of history’s greatest minds coupled with hundreds of the world’s most talented young scholars on one island – I felt like a stowaway on a celebrity cruise, and I wondered how on earth I’d participate in their conversations without being discovered for the imposter I was.

David Smerdon (right) with Countess Bettina Bernadotte and laureate Jean Tirole. Picture/Credit: Lisa Vincenz-Donnelly/Lindau Nobel Laureate Meetings

Countess Bettina Bernadotte, laureate Jean Tirole and David Smerdon. Photo: Lisa Vincenz-Donnelly/Lindau Nobel Laureate Meetings

 

But in hindsight, my fears were ill-founded. From the very first interaction at the airport arrivals, everyone I met was enthusiastic, approachable and, above all, friendly. I discussed how to best measure teacher quality and swapped job-market war stories with Chicago-based Nathan in the taxi ride from the airport and was amazed by the developments in climate finance after meeting Veronika, a Russian physicist, in the hotel lobby. Rushing off to dinner, I sat opposite Banji, who educated me about the consequences of Nigeria’s trade policy on its energy markets, and Eleni, who detailed the early results of a cash transfer pilot study in Ethiopia. On the bus, Roxana from Romania taught me a form of econometrics I didn’t even know existed. By the time I fell asleep that night, my notebook already had pages full of scribbles about the people I’d met and the conversations I’d had – and the official programme hadn’t even begun.

But it was the interactions with the laureates themselves that really surprised me. I had expected these esteemed statesmen to be cordial and pleasant – which they were – but I had not expected them to go so far beyond their official obligations (for lack of a better word). The laureates were not only tirelessly willing to acquiesce to our floundering flattery and sycophantic selfies, but were eager to interact with us on an intellectual level, engaging in stimulating conversation with different groups of scholars at every possible break in the programme. They actively encouraged us to ask the big questions, whether it was about their work, our own careers or the state of the science itself. They listened to our views, not dismissively or with well-crafted rebuttals but with real consideration. And while it was hard to ignore their obvious intellectual aura, on several occasions the laureates showed us their human sides and let their hair down (who knew they could dance like that?). One common thread of advice I picked up from the laureates was their earnest desire that young economists take up relevant, welfare-improving research topics, rather than just playing the classic publishing game. Coming from a policy background and thus a ‘late-starter’ to the world of academia, I very much appreciated hearing this admonishment – though one could imagine it is easier to dish out, let alone follow, with a Nobel Prize hanging in one’s office… Having said that, I found that this idealism was echoed by my fellow scholars, and it was a delight to listen to their presentations and the laureates’ comments in the parallel sessions – not to mention the many animated conversations we had over dinners, coffees and even swims in the lake. Judging by these short snapshots of research, it was even possible to imagine a few of them standing in front of the Swedish monarch at some point in the future.

I didn’t anticipate such positivism in a room full of economists, but on reflection I guess that’s what the Lindau Meetings are all about.

I particularly enjoyed chatting with people from vastly different streams of research to mine – including, mind you, other attendees such as the laureates’ and scholars’ partners, members of the Lindau Council and its executive secretariat and industry partners. In the cut-throat world of academia, it’s so easy to lose one’s self in the narrow silos into which we now specialise, so it was an unexpected pleasure to have such stimulating debates that combined all branches of economics and policy, joined by a common focus on real-world issues (I’d forgotten that macroeconomics can actually be fun). More importantly, there appeared to exist a collective motivation among the scholars that our careers should matter in some tangible way to the ‘outside world’ and that the investment made by ourselves and others in our education deserved to be returned with real contributions to improving welfare. To be honest, I didn’t anticipate such positivism in a room full of economists, but on reflection I guess that’s what the Lindau Meetings are all about.

It was surprisingly sad to leave Lindau after such a brief but hectic event. Sure, I’d been running on caffeine and naps for a week, visited the first-aid tent twice and had run out of clean socks, but attending the Lindau Meeting was, pardon the cliché, an unforgettable experience. I landed home with a folder overflowing with lecture notes, research ideas scribbled on napkins and crumpled business cards of the scholars and other attendees, all thanks to the wonderful opportunity that the Foundation and the Council for the Lindau Nobel Laureate Meetings provided. It’s an opportunity I’m not going to waste.

 

David Smerdon gave the farewell address of #LiNoEcon alongside Nobel Laureate Jean Tirole.

 

More reviews and highlights of the 6th Lindau Meeting on Economic Sciences can be found in the Annual Report 2017.

Molecules at Near-Atomic Resolution

The Nobel Prize Award Ceremony is traditionally held on 10 December, the day Alfred Nobel died in 1896, and the Nobel Week in Stockholm is arranged around this date. The three new Nobel Laureates in Chemistry are all expected to attend: Jacques Dubochet, Richard Henderson and Joachim Frank. They are honoured for their contributions to the development of cryo-electron microscopy, or cryo-EM. Besides their scientific achievements, it is also worth looking at their respective personalities – they are all real characters. And although all three are very different indeed, they have one thing in common: They were all asked countless times by their colleagues why they were pursuing a seemingly ‘hopeless topic’. As we can see this week, sometimes it pays off to work on subjects not many people are interested in.

The Francophone Swiss Jacques Dubochet describes himself on his website as the “first official dyslexic in the canton of Vaud – this permitted being bad at everything.” Apparently, his reading problems caused his school grades to slide so much that his parents sent him to a boarding school to pass his federal maturity exam. “I was a terrible student and now I’m a Nobel Laureate: any questions?” he says and smiles – Dubochet is always good for a joke.

Another funny incident: A few weeks after the Nobel Prize announcement in early October, Dubochet was at a conference at EMBL in Heidelberg, the very institute where he developed his famous method to produce vitrified water for cryo-electron microscopy. Now as he entered one of the labs, he saw a cryo-electron microscope standing there and commented: “Now, this is a wonderful machine, but, unfortunately, I forgot what it can do.” Everybody laughed, because he is one of the main pioneers in this field.

 

Jacques Dubochet (centre) with Gábor Lamm (left) and Gareth Griffiths at the 2015 Lennart Philipson Award Ceremony at EMBL in Heidelberg. Photo: EMBL Alumni Association, Lennart Philipson Award

The Swiss biophysicist Jacques Dubochet (centre) with Gábor Lamm (left) and Gareth Griffiths at the 2015 Lennart Philipson Award Ceremony at EMBL in Heidelberg. Photo: EMBL Alumni Association

 

A long-time challenge for cryo-EM had been the fact that the natural environment for most molecules is water, but water evaporates in the microscope’s vacuum. Freezing is one solution, but then the water crystallises, distorting both the sample and the picture. Now Dubochet came up with an innovative approach: He would cool the samples so rapidly that the water molecules had no time to crystallise. This left the molecules in a ‘glass pane’, freezing them in time, direction and in their natural shape. These cells weren’t alive anymore, but in a close-to-living state.

Though he’s an excellent scientist, Jacques Dubochet is also a man of many talents. “He has a unique power to pull his audience in,” says Marek Cyrklaff, Dubochet’s former EMBL colleague and long-term friend. “And he has a special structure of thinking, like being a dual person in one body,” Cyrklaff continues. “On the one hand, he’s a hardcore physicist, on the other, a top philosopher. The latter helps him to see far ahead, have visions, the former allows him to approach these goals in a structured way.”

He is also spontaneous, unconventional and “against all dogmas, in science and politics alike.” During his twenty years at the University of Lausanne, he has “devoted a lot of effort to the curriculum ‘biology and society’, and Lausanne at that time was unique in developing this curriculum for all our students,” as Dubochet himself explains on the telephone with Adam Smith from the Nobel Foundation. “It was not the kind of additional piece of education, it was a core programme in the study of biology. (…) The idea of this course is to make sure that our students are as good citizens as they are good biologists.” He still teaches in this programme, and he says that it’s very close to his heart. He’s also a member of the local council of Morges, where he lives with his wife. The day he learned that he was now a Nobel Laureate, he went to a council meeting in the evening.

 

Richard Henderson has worked at the MRC Laboratory of Molecular Biology for over 50 years. Photo: MRC-LMB

Richard Henderson is originally from Scotland and has worked at the MRC Laboratory of Molecular Biology now for over 50 years. Photo: MRC-LMB

Richard Henderson attended the same EMBL conference in November 2017 as Dubochet.  In a pre-dinner speech, Werner Kühlbrandt, Max Planck Director in Frankfurt, described his time in Cambridge where he received his PhD at the MRC Laboratory of Molecular Biology – and where Henderson had his own research group and later became director. “Richard never missed any of these occasions to meet and ‘have a chat’, as he would put it,” Kühlbrandt says, and “the discussions would continue at the lunch table, usually with Richard scribbling diagrams and quick calculations on the paper napkin.” Marek Cyrklaff also remembers Henderson never sitting in his office, but usually standing in the hallway and discussing projects with his colleagues.

If people now start to wonder when the LMB researchers ever finished their ground-breaking work, “the answer is very simple,” Kühlbrandt explains: “They talked to each other most of the day, but then worked doubly hard for long hours into the night.” He describes Henderson as “kind and helpful,” if strict and straight, as well as “a great optimist” – and to develop high-resolution cryo-EM, he needed to be an optimist.

Electron microscopes were believed to be suitable mostly for dead matter, because the powerful electron beam destroys biological material, and the specimens inevitably dry out in the microscope’s vacuum. Henderson started to tackle these problems in the early 1970s: He used a weaker electron beam and glucose solution to prevent the samples from drying out. In 1975, he was able to publish a low-resolution model of bacteriorhodopsin, a membrane protein. But that wasn’t good enough for him. Fifteen years later, in 1990, he succeeded in generating a three-dimensional atomic model of bacteriorhodopsin.

Richard Henderson describes himself as a ‘Scottish country lad’. When asked about “the biggest misconception” about his field of study, he replies: “That it is a boring technique rather than a minor art form.”

 

Joachim Frank is a German-American physicist. He was born in Germany during World War II, received his education in Germany, and moved to the US in the 1970s. Photo: Columbia University

Joachim Frank is a German-American biophysicist. He was born in Germany during World War II, received his education in Germany, and moved to the US in the 1970s. Photo: Columbia University

Talking about art forms: Joachim Frank is not only a world-class scientist, he is also a published author. He has written numerous poems, short stories and three (to date unpublished) novels. On his website ‘Franx Fiction’, there is a selection of his published works. Under ‘Nobel Prize‘, he writes how a stranger recognised him in the New York City subway and asked: “How come you still take the subway?“ According to this blogpost, the most important perk for Frank is the fact that he doesn’t need to write any more review articles: “Assignments like this make sense if you want to add an epsilon increment to the chance of winning the Nobel Prize. But, as I said, I’m already here.”

In an interview with the Austrian newspaper Der Standard, published three days before the Nobel Prize in Chemistry was announced, Frank explains his motivation to write fiction: “It’s all about balance. Without my writing, I would feel very isolated. The world is such a beautiful and complex place, and science only has limited access to its wonders. Science is dominated by strict rules which preclude emotions, and I would never allow my emotions to influence my research. So, to balance out my life, I write fiction and take photographs.”

In his research, Joachim Frank developed an innovative image processing method, between the mid-1970 to mid-1980s, in which an electron microscope’s fuzzy two-dimensional images of many molecules are analysed and merged to reveal a sharp three-dimensional structure. For this purpose, his team at Wadsworth Center in Albany, New York, devolped the image processing programme SPIDER. With this tool, the researchers were able to generate very detailed images of ribosomes, and Frank studied these, among other proteins, for three decades.

In 2014, Frank was awarded the Benjamin Franklin Medal in Life Science, and a video from the Frankling Institute explains how his science knowledge also adds to his artistic appreciation of the world. In the video, Frank explains how once, driving through the woods, “this idea occured to me, that in every cell of every leaf of every tree, there are ribosomes doing this thing,” and he shows with his hands the ratched-like motion of ribosomes that he discovered. “And it made me realise that I’m the only one who has this epiphany right now, because nobody drives around with this kind of appreciation.”

Frank, Henderson and Dubochet will meet in Stockholm on 8 December for their Nobel Lectures and two days later for the Nobel Prize Award Ceremony. They have known each other for years, and now they will share this memorable week in Stockholm.

 

Electron microscopes' resolution has radically improved in the last few years, from mostly showing shapeless 'blobs' to now being able to visualise proteins at near-atomic resolution. This is why the science magazine Nature chose cryo-EM as the Method of the Year 2015. Image: Martin Högbom.

The resolution of electron microscopes has radically improved in the last few years, from mostly showing shapeless ‘blobs’ to now being able to visualise proteins at near-atomic resolution. This is why the magazine Nature chose cryo-EM as the Method of the Year 2015. Illustration/Credit: Martin Högbom/The Royal Swedish Academy of Sciences

In Sync: Gut Bacteria and Our Inner Clock

Inner clock feature with credit

 

Already in the 18th century, the astronomer Jean Jaques d’Ortous de Mairan found that plants continue to follow a circadian rhythm even when placed into a dark room overnight, suggesting the existence of an inner clock that was independent of the perception of the environmental cues that differentiate day from night. Later, researchers found that not only plants but also other organisms including humans have a circadian rhythm. Nobel Laureates in Physiology or Medicine 2017 Jeffrey C. Hall, Michael Rosbash and Michael W. Young deciphered the cellular mechanisms that make the inner clock tick using the fruit fly as a model organism.

Although these findings were underappreciated at the time, we now know that our circadian rhythms exert a profound influence on many aspects of our physiology. Our inner clock regulates our sleep pattern, eating habits, hormone levels, blood pressure and body temperature at different times of the day, adapting to concurrent changes in the environment as the Earth rotates about its own axis. Circadian clock perturbations have been linked to higher risks of cancer and cardiovascular disease. Intriguingly, recent research has shown that the adaptation to a 24-hour cycle is not restricted to species that are exposed to the drastic light and temperature changes during the day, and extends to the microscopic organisms that live deep within us. 

We live in close symbiosis with trillions of microorganisms: Our microbiota plays an important role in many bodily functions including digestion, immune responses and even cognitive functions – processes that follow a circadian rhythm. The majority of our microbiota is found in the gastrointestinal tract. It turns out that these bacteria living in the depths of our gut themselves follow a circadian rhythm, and, further, that disruption of this rhythm also has negative consequences for our health. What’s more, perturbations of our inner clock affect the function of these bacteria and vice versa: the gut microbiome influences our circadian rhythm.

In 2013, French scientists demonstrated that gut microorganisms produce substances that stimulate the proper circadian expression of corticosterone by cells in the gut. Loss of bacteria from the intestine resulted in mice with several profound defects including insulin resistance. In a particularly eye-catching study from 2014, meanwhile, researchers based at the Weizmann Institute of Science in Rehovot, Israel, including Lindau Alumnus 2015 Christoph Thaiss, observed a diurnal oscillation of microbiota composition and function in mice as well as in humans and found that this oscillation was affected and disturbed by changes in feeding time as well as sleep patterns, i.e, perturbations of the host circadian rhythm. As a highly relevant example, they found that jet lag, for example, in people travelling from the USA to Israel, disturbed the rhythm of the microbiota and led to microbial imbalance, referred to as dysbiosis.

In sync: gut bacteria and our circadian clock. Picture/Credit: iLexx/iSTock.com

The bacteria in our gut also follow a circadian rhythm. Picture/Credit: iLexx/iStock.com

It is not only the timing of meals that affects the circadian clocks of our resident bacteria, but also what we eat. Thus, while a high-fat, Western diet naturally has direct effects on our bodies, a proportion of these effects is also mediated by the impact that such a diet has on our microbiota, which in turn acts to alter the expression of circadian genes in our bodies and disturb our metabolism. Further, a recent study showed that bacteria in the gut, through affecting our circadian rhythms, also influence the uptake and storage of fats from the food that we eat.

The circadian clock plays a critical role in immune and inflammatory responses, and it is thought that perturbations in the circadian rhythm make the gastrointestinal tract more vulnerable to infection. It has been shown in mice that a perturbed circadian rhythm indeed affects immune responses, suggesting that the time of the day as well as circadian disruption, such as jet lag or shift work, may play a role in the susceptibility to infections. In fact, the immune response of mice to bacterial infection with Salmonella is determined by the time of day, and disruption of the host circadian rhythm may be one approach that bacteria employ to increase colonisation.

These observations highlight once more the intimate relationship that we enjoy with our gut microbiota and the importance of circadian rhythms for both us, our bacteria and the relationships that bind us together. It is likely that the seminal findings of Hall, Rosbash and Young will continue to form the basis for further important insights for human health and for our relationships with other organisms. What we now know already has important and intriguing implications for human health. Indeed, it appears likely that a better understanding of the bidirectional relationship between the circadian clock and the gut microbiota may help to prevent intestinal infections. Further, they may allow us to determine optimal times of the day for the taking of probiotics or for vaccination against gut pathogens. It is also reasonable to assume that antibiotics have a markedly negative impact on the circadian clock of the gastrointestinal tract. Taken together, therefore, these findings offer a compelling scientific basis for the importance of regular sleep patterns and meal times in keeping us healthy.

 

 

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Amazing Gravitational Wave Astronomy

The very first gravitational waves measured directly came from two merging massive black holes – of all things!? Massive black holes were thought to be few and far between – and now when can ‘see’ them merge, in ‘real time’, just as the LIGO observatory becomes sensitive enough? The characteristic signal from 14 September 2015 was detected during a test run, even before Advanced LIGO started its formal observations four days later. Understandably, the researchers had to check and double-check to make sure that the signal wasn’t a secret test signal. The 2017 Nobel Prize in Physics honours this earth-shaking detection, which is the result of decades of intense research.

In a nutshell: The observatory had just been switched on moments ago, with only about one-third of its planned sensitivity – and finds an event that is expected to be extremely rare. And it is getting even better: A detailed analysis of the signal revealed that these two merging black holes each had masses higher than thirty times the sun’s mass, putting them squarely in the category of massive black holes, not to be confused with supermassive black holes.

 

The very first detection of gravitational waves on September 14, 2015. Signals received by the LIGO instruments at Hanford, Washington (left) and Livingston, Louisiana (right) and comparisons of these signals to the signals expected due to a black hole merger event. Credit: B.P. Abbott et al. (LIGO Scientific Collaboration and Virgo Collaboration) CC BY-SA 3.0

The very first detection of gravitational waves on 14 September 2015: Signals received by the LIGO instruments at Hanford, Washington (left) and Livingston, Louisiana (right) and comparisons of these signals to the signals expected due to a black hole merger event. Credit: B.P. Abbott et al. (LIGO Scientific Collaboration and Virgo Collaboration) CC BY-SA 3.0

 

The black holes that are believed to be most common in the universe are so-called stellar black holes. They are end-products of massive stars that exploded in supernovae after their lifespan and then collapsed to become stellar black holes. The resulting object is thought to have a mass of lower than twenty times the sun’s mass. Thus, the merging black holes from GW150914 were unusually large.

To complicate things more: They were also unusually close together, otherwise they couldn’t have merged. And in less than two years since this measurement, which shook the scientific community, already five black hole mergers have been recorded, and half of these black holes had been larger than twenty solar masses.

True, these findings are exciting, but they also pose some urgent questions: Do scientists need to change the theory of black holes to accommodate their large sizes, their large numbers as well as their proximity to each other? An interesting theory from early 2015, before the first black hole merger signal had been detected, drafts a compelling scenario, formulated by Madrid professor Juan Garcia-Bellido and postdoc Sebastien Clesse from RWTH Aachen University: maybe the universe is crowded with black holes of various sizes, remnants of large density fluctuations during the so-called inflation phase of the Big Bang.

 

Nobel laureate Brian Schmidt explaining Einstein's theory of general relativity #LiNo14. In this famous theory, Einstein predicted gravitational waves - but never expected that they could be measured. Photo: Lindau Nobel Laureate Meeting/Rolf Schultes

Nobel laureate Brian Schmidt explaining Einstein’s theory of general relativity at #LiNo14. In this famous theory, Einstein predicted gravitational waves – but never expected that they could be measured. One hundred years after this prediction, their signal was recorded by the two LIGO Observatories. Photo: Lindau Nobel Laureate Meeting/Rolf Schultes

As Nobel Laureate Brian Schmidt explains in his 2016 lecture at the 66th Lindau Nobel Laureate Meeting: According to the standard model of cosmology, the universe is thought to have expanded exponentially right after the Big Bang and “things at the quantum scales were magnified to the universal scales, quantum fluctuations were expanded to the scale of the universe.” He continues: “The magnification of the universe from the subatomic to the macro scales seems kind of crazy, but it keeps on predicting the things that we see in the universe.” This short period of rapid expansion is called inflation.

And already in 1971, the famous British physicist Stephen Hawking introduced the idea of ‘primordial black holes’. In the model of Garcia-Bellido and Clesse, these extremely old black holes would have formed in clusters – making it much more likely for surviving specimens to meet and merge. The authors even propose in their recent article for Spektrum der Wissenschaft, the German version of Scientific American, that these ubiquitous black holes might account for part of the mysterious Dark Matter.

The standard model assumes that the universe consists of roughly 69% Dark Energy, 26% Dark Matter, and less than 5% atoms – that ultimately provide for stars, galaxies, the earth, humans and everything we know. Without this hypothetical dark matter, the galaxies we can observe would be ripped apart: they’re simply too fast not to lose most of their stars. That this Dark Matter cannot be observed has been a dogma for several decades, but of course scientists are extremely unhappy with anything they can neither observe nor understand. (There have been many attempts to ‘see’ Dark Matter that I cannot describe here.)

What is so fascinating about the primordial black hole theory of Garcia-Bellido and Clesse is that it will be tested with current and future instruments. Finding many black hole mergers in the next few years will be a strong indicator that black holes are not few and far between but many and close together. Garcia-Bellido and Clesse conclude: “Already, the first observations show that black holes are binary more often than expected, and their masses are highly diverse.”

But there is still no proof that these black holes are primordial. The ‘smoking gun’ would be if a black hole in a merger was smaller than 1.45 solar masses: Below this so-called Chandrasekhar limit, no black holes can form after a stellar explosion – it would have to form in another process, making it more likely to be primordial. Unfortunately, many of the very small black holes are thought to have evaporated due to the so-called Hawking radiation.

 

Artist's impression of two merging and exploding neutron stars. Such a very rare event is expected to produce both gravitational waves and a short gamma-ray burst, both of which were observed on 17 August 2017 by LIGO–Virgo and Fermi/INTEGRAL. Subsequent observations with numerous telescopes confirmed that this object, seen in the galaxy NGC 4993 about 130 million light-years away, is indeed a kilonova. Such objects are the main source of very heavy chemical elements, such as gold and platinum. Credit: ESO/L. Calçada/M. Kornmesser CC BY-SA 4.0

Artist’s impression of two merging and exploding neutron stars. Such a rare event is expected to produce both gravitational waves and a short gamma-ray burst, both of which were observed on 17 August 2017 by LIGO–Virgo. Subsequent observations with numerous telescopes confirmed that this object, seen in the galaxy NGC 4993 about 130 million light-years away, is indeed a so-called kilonova. Such objects are the main source of very heavy chemical elements like gold and platinum. Credit: ESO/L. Calçada/M. Kornmesser CC BY-SA 4.0

 

Also, the Square Kilometre Array SKA, the largest-ever radio telescope being built in South Africa and Australia, will look for characteristic helium radiation from the very early universe that is expected to be found around primordial black holes. And the European LISA space mission will start searching for the characteristic gravitational wave background noise of merging black holes. And more missions are being planned to come to grips with the Dark Matter and Dark Energy problems, among others.

No matter whether the observed black holes are primordial or not: “If LIGO finds that large black holes are far more common than expected, they could help explain the elusive Dark Matter,” says Karsten Danzmann, Director of the German Albert Einstein Institute, which is part of the LIGO Scientific Collaboration. So even if the theory of Garcia-Bellido and Clesse is not confirmed in every detail, the Dark Matter mystery could be about to be solved.

Yes, gravitational wave astronomy is like opening a new window into the universe, enabling researchers to finally witness binary black hole mergers. But these instruments also open new windows in other fields of astronomy: For instance, on 17 August 2017, LIGO found gravitational waves from a rare neutron star merger. The researchers immediately alerted the astronomical community, resulting in one of the largest observation campaigns ever with 70 participating telescopes. With the help of these other instruments, the exact location of the merger could be determined – but, incidentally, another long-time astronomical mystery was solved: The recorded gamma rays reveal that at least some gamma-ray bursts are caused by merging neutron stars. This was expected theoretically, but now researchers can finally test their theories.

In the next few years, more gravitational wave events will be observed, and they will reveal astounding details about massive object. Moreover, other fields of astronomy will profit on a scale that we cannot foresee today.

The World at Home in Lindau

For nine years, host families from Lindau and the surrounding area have welcomed young scientists from all over the world who are participating in the Lindau Nobel Laureate Meetings. Through their engagement, the young scientists avail of the unique opportunity to get to know Lindau and its people in personal surroundings and learn more about their lives and culture first-hand. 

 

Reunited After Six Years – Elom Aglago and His Lindau Host Family

Brigitte Trojan and Hans Schweickert have been participating in the Lindau Nobel Laureate Meetings as a host family since 2011. They have already welcomed seven young scientists from all over the world (Egypt, Japan, Georgia, Chile, Iran, Lebanon and Togo). In 2011, young scientist Elom Aglago from Togo was their first guest. They have kept in touch during the past six years, and this year, Elom came back to Lindau to meet his host family again.

 

Elom Algago and his host family in Lindau. Credit: Christoph Schumacher/Lindau Nobel Laureate Meetings

Elom Aglago and his host family in Lindau. Credit: Christoph Schumacher/Lindau Nobel Laureate Meetings

 

How did you decide to become a host family?

Brigitte Trojan/Hans Schweickert: We had just moved here to Lindau, into a new house with garden, when we thought that we might welcome a young scientist from abroad. We love being at home, we love living here in Lindau, but we are also open to new cultures and perspectives. In addition, we are very enthusiastic about the Lindau Nobel Laureate Meetings. So, for us, it was a perfect opportunity to meet people from all over the world. It is also a great way for us to improve our English.

For us, it was a perfect opportunity to meet people from all over the world

How do you remember Elom’s first stay here in Lindau?

BT/HS: We felt happy and privileged to host Elom here in 2011. We had breakfast together every morning and talked about the daily programme. And every evening, he gave us a briefing about the day at the Lindau Meeting. We got lots of inspiration from him. He always liked to discuss things with us, and we truly appreciate that.

 

How did you stay in contact over the past six years?

BT/HS: We occasionally exchanged e-mails. For example, we wished each other a Merry Christmas each year. We sent him the news from Lindau, told him about the new young scientists, and in return received news from Togo, Morocco or France, depending on where he lived at the time. He shared the progress of his scientific career with us, the papers he published and his most important findings. Two years ago, we had the idea that he could visit us again. Last December, we have planned his visit for this summer – and now he is here again.

 

How was it to see each other again?

BT/HS: We met at the railway station and were happy to see each other again. Immediately, there was the familiar warmth and the same spark. We right away started again to discuss differences and in our philosophies, and to talk about the roles of family and parents in our different cultures and so on. We missed him, and our cat missed him as well (laughs).

 

Is he the same as you remember him?

BT/HS: Yes and No. He is as young and lively as he was then – but also a little bit more serious; it seems as if he has arrived where he wants to be.

 

Elom at the Bavarian Evening during the Lindau Meeting 2011. Photo/Credit: Courtesy of Elom Algago

Elom at the Bavarian Evening during the Lindau Meeting 2011. Photo/Credit: Courtesy of Elom Aglago

Elom Aglago: I have become wiser; I’m not as childlike as I was then. I think that my host family contributed in some way to that; they helped me to understand differences in cultures, to respect other cultures and learn from them. I think it all started with the Lindau Nobel Laureate Meeting. I experienced for the first time that we are all different but unique and special. We have to take that into account.

 

Are you closer to getting the Nobel Prize now than you were back in 2012?

EA: Personally, getting the Nobel Prize is not on my agenda at the moment (laughs). I would like to take on administrative position from which I can improve the transfer of knowledge, technology and responsibility to Africa. Many Africans get lost in their ambitions, not aware of the correct procedures. I plan to do this and continue with my research at the same time.

 

Did you have such good experiences with every young scientist you welcomed?

BT/HS: It is always a great opportunity to meet people who are able to bring the world forwards. All young scientists were very polite and got along well in our home. They were always very thankful; and were eager to engage in dialogue and to take in all information.

 

 

 The First Access to the World – Host Family Ober

The Ober family has been welcoming young scientists in Lindau since 2013. Thus far, all of them have been from Asia: Korea, Taiwan and Thailand. Often, two young scientists stay at their holiday apartment at the same time. Their son David enjoys the company of the foreign visitors and helps his parents as host.

 

Host family Ober with their two young scientists Nopphon Weeranoppanant (“Nop”, left) and Cholpisit Kiattisewee (“Ice”, second from right) and guest Pree-Cha Kiatkirakajorn (“Joe”, right). Photo/Credit: Courtesy of Catharina Ober

Host family Ober with their two young scientists Nopphon Weeranoppanant (“Nop”, left) and Cholpisit Kiattisewee (“Ice”, second from right) and guest Pree-Cha Kiatkirakajorn (“Joe”, right). Photo/Credit: Courtesy of Catharina Ober

 

Why did you become a host family for the Lindau Meetings?

Cathrin Ober: My niece Theresa came up with the idea of acting as a host family for young scientists. We wouldn’t have thought about if it wasn’t for her; she was the driving force behind our decision. She already knew five years ago, when she was 14, that she would become a physicist and had been at various events of the Lindau Nobel Laureate Meetings, for example, at the Grill & Chill or at the Matinee. She convinced us to volunteer as a host family and promised to care for the young scientists during their stay. When the first young scientists came to our home, our son, David, also became enthusiastic about the visitors. For example, he prepared the breakfasts for them. He was only five years old! If he wouldn’t have been that committed, we may have stopped after my niece had left Lindau. […] The Lindau Meetings are wonderful for our city. Everything is always working out that well, because everyone plays their part to the full. We are happy to contribute our bit.

Our son also became enthusiastic about the visitors

How is it to be a host family during the Lindau Meetings, especially with a young child?

CO: It is always a lot of fun! We benefit from the tightly packed programme of the young scientists. I mean, my husband and I are both fully employed; we’re doing this alongside our day jobs. Although we don’t have much time, the young scientists were always very grateful. We do have the mornings together, and on the only free evening, we are always cooking a German meal for our guests. This year, we made Kässpätzle, sautéed onions and Sauerkraut. Up to now, the two Thai boys we had here this year have been the most fun, it was amazing with them. They played tabletop soccer with David. They always tried to chat with him. In previous years, it was only sign language, but now he knows a few words in English. I think that it is a good thing for him and the other children in host families. It is his first access to the world. He has always joined when we spent time with them, and it is always him who first finds the young scientists at the train station. He looks at their photos before we pick them up at the station, and he always spots them right away!

During the interview, their son David enters the room, wearing a jumper with the inscription ’Time to go and change the world’. When asked how it is to have young scientists at their home every year, he simply replied: “Quite cool!”

 

Have you stayed in contact with the young scientists you have welcomed here in Lindau?

CO: We have never stayed in contact with any of our guests. I really do think that it is hard if you only get to know each other for one week. But if we’d like to get in touch again, it would surely be possible with all of them. Our young scientists this year were quite direct and said that all hell would break loose if we were to set foot into Thailand without getting in touch with them (laughs). We show them the beauty of Lindau and that’s all. We’re not well versed in natural sciences. That’s why we never really talked about their disciplines. We talked about their countries and customs, about their focuses in life.

The two young scientists were also enthusiastic about their stay at the Ober’s house. They told us about the “incredible experience” (Ice) with “an amazing host family” (Nop). They were particularly pleased with the exchange of their cultures. The conversations during the meals were “very important parts of my memory of Lindau. And Spätzle was my favourite! :)” (Nop)

 

 

Lindau Family for Life – Host Family Heller

Mrs. and Mr. Heller are a host family since 2012. Every year, they welcome at least one young scientist at their home.

 

Host family Heller and Alumna Dissaya in Lindau. Credit: Courtesy of Dissaya Pornpattananangkul

Host family Heller and Alumna Dissaya in Lindau. Credit: Courtesy of Dissaya Pornpattananangkul

 

Why did you decide to host young scientists?

Mr. Heller: I have spent ten years of my life abroad. I know what it’s like to be a foreigner in another country and how nice it is to get access to the local people and to get their support. Everybody wishes to enjoy hospitality: this means that you have to offer it yourself. In that way, you can get to know the world without stepping onto an airplane.
In addition, I do have a special interest in science in general and in astrophysics, medicine and economic sciences in particular.

In that way, you can get to know the world without stepping onto an airplane.

What is it like to be a host family?

H: Being a host family means to be tolerant and open. It implies to be considerate of others and to give someone you don’t know the benefit of the doubt. It is always exciting when a completely unknown person becomes part of your family from one minute to the next. In general, it is always an enrichment to spend time with those guests. The young scientists that come to Lindau are global elite. It is thus not surprising that they are pleasant, interesting, capable and astonishingly mature personalities. Unfortunately, we have not yet succeeded in persuading one of our guests to move to Germany and work here, although each of the scientists would mean an enormous gain for our country.

 

Were there huge differences between the different young scientists you have welcomed in Lindau up to now?

H: In our experience, the young and mobile generation in a global world is coming closer together. Their dreams and wishes are – despite all cultural differences – the same: they want to start a family, to develop professionally, to travel as well as to live in wealth, peace and security. Although there might be a loss of cultural diversity, I believe that the positive impact of this is predominant due to the fact that homogeneity has a connecting effect.

 

Is there a key moment you remember with one of the young scientists?

H: In 2013, we welcomed a young scientist from Thailand: Dissaya. With her, we immediately had a special connection. She really became our friend even though thousands of kilometers are dividing us. During the Lindau Meeting, we had some deep conversations over a glass of red wine. We talked about the important things in life: for example, about what it means to grow old. Those moments were quite touching. I also took her out on a motorcycle tour once to show her the surroundings. A few months later, Dissaya came back to Lindau to stay with us for a two-week vacation. She also invited us to her wedding a few years ago; unfortunately, we weren’t able to go.

 

After the interview with Mr. Heller, we asked Dissaya to also comment on her experience with her host family.

Dissaya Pornpattananangkul: Before meeting with the family, I was only expecting to exchange experiences with the local people. The first time I arrived in Lindau by train, Mr. Heller was there waiting to pick me up. From that moment onwards, my host family took care of me so well. They showed me many places in Lindau. It was one of the most valuable experiences abroad for me. Staying with the host family, I gained a family in Lindau for life. […] The whole time I was there, every moment was very special. Mr. Heller took me out to ride a motorcycle in the mountains. The view was fantastic. It was really one of the most beautiful sceneries I have ever seen.

 

Alumna Dissaya at the motorcycle tour. Photo/Credit: Courtesy of Mr. Heller

Alumna Dissaya at the motorcycle tour. Photo/Credit: Heller

We thank the Lindau host families for their engagement as well as the open and interesting conversations.

The Hungry Brain

Gut brain Axis Feature Credited

 

Under normal, healthy conditions we eat whenever we are feeling hungry. In addition to the feeling of hunger, we also often have an appetite for a specific kind of food, and sometimes we simply crave the pleasure a certain food like chocolate or pizza may provide us. This pleasure is part of the hedonic aspect of food and eating. In fact, anhedonia or the absence of experiencing pleasure from previously pleasurable activities, such as eating enjoyable food, is a hallmark of depression. The hedonic feeling originates from the pleasure centre of the brain, which is the same one that lights up when addicts ‘get a fix’. Hedonic eating occurs independently of the gut-brain axis, which is why you will keep eating those crisps and chocolate, even when you know, you’re full. Hence, sayings like “These chips are addictive!” are much closer to the biological truth than many realise.  

But how do we know that we are hungry? Being aware of your surrounding and/or your internal feelings is the definition of consciousness. And a major hub for consciousness is a very primal brain structure, called the thalamus. This structure lies deep within the brain and constantly integrates sensory input from the outside world. It is connected to cognitive areas such as the cortex and the hippocampus, but also to distinct areas in the brainstem like the locus coeruleus, which is the main noradrenergic nucleus in the brain and regulates stress and panic responses. Directly below the thalamus and as such also closely connected to this ‘awareness hub’ lies the hypothalamus.

The hypothalamus is a very complex brain area with many different functions and nuclei. Some of them are involved in the control of our circadian rhythm and internal clock – the deciphering of which was awarded the 2017 Nobel Prize in Physiology or Medicine. But the main task of the hypothalamus is to connect the brain with the endocrine system (i.e. hormones) of the rest of the body. Hormones like ghrelin, leptin, or insulin are constantly signalling your brain whether you are hungry or not. They do so via several direct and indirect avenues, such as blood sugar levels, monitoring energy storage in adipose cells, or by secretion from the gastrointestinal mucosa.

There are also a number of mechanosensitive receptors that detect when your stomach walls distend, and you have eaten enough. However, similarly to the hormonal signals, the downstream effects of these receptors also take a little while to reach the brain and be (consciously) noticeable. Thus, the slower you eat, the less likely you will be to over-eat, because the satiety signals from hunger-hormones and stomach-wall-detectors will reach your consciousness only after about 20 to 30 minutes.

Leaving the gut and coming back to the brain, the hypothalamus receives endocrine and neuropeptidergic inputs related to energy metabolism and whether the body requires more food. Like most brain structures, the hypothalamus is made up of several sub-nuclei that differ in cell-type and downstream-function. One of these nuclei, the arcuate nucleus of the hypothalamus, is considered the main hub for feeding and appetite control. Within it there are a number of signalling avenues that converge and that – if altered or silenced – can induce for instance starvation. Major signalling molecules are the Neuropeptide Y, the main inhibitory neurotransmitter GABA, and the peptide hormone melanocortin. The neurons in the arcuate nucleus are stimulated by these and other signalling molecules in order to maintain energy homeostasis for the entire organism. There are two major subclasses of neurons in the arcuate nucleus that are essential for this homeostasis and that, once stimulated, cause very different responses: activation of the so-called POMC neurons decreases food intake, while the stimulation of AGRP neurons increases food intake. And this circuit even works the other way around: researchers found that by directly infusing nutrients into the stomach of mice, they were able to inhibit AGRP neurons and their promotion of food intake.

Given this intricate interplay between different signalling routes, molecules, and areas it is not surprising then that a disrupted balance between all of these players could be detrimental. Recent studies identified one key player that can either keep the balance or wreak havoc: the gut microbiome

 

Bacteria colonising intestinal villi make up the gut microbiome. Picture/Credit: ChrisChrisW/iStock.com

Bacteria colonising intestinal villi make up the gut microbiome. Picture/Credit: ChrisChrisW/iStock.com

 

The gut microbiome is the entirety of the microorganisms living in our gastrointestinal tract, and they can modulate the gut-brain axis. Most of the microorganisms living on and within us are harmless and in fact are very useful when it comes to digesting our food. However, sometimes this mutually beneficial symbiosis goes awry, and the microbes start ‘acting out’. For instance, they can alter satiety signals by modulating the ghrelin production and subsequently induce hunger before the stomach is empty, which could foster obesity. They can also block the absorption of vital nutrients by taking them up themselves and thereby inducing malnutrition. A new study which was published only last month revealed that Alzheimer patients display a different and less diverse microbiome composition than healthy control subjects. Another study from Sweden even demonstrated that the specific microbiome composition occurring in Alzheimer’s patients induces the development of disease-specific amyloid-beta plaques, thereby establishing a direct functional link between the gut microbiome and Alzheimer’s disease – at least in mice. Similarly, the composition and function of the microbiome might also directly affect movement impairments in Parkinson’s disease. In addition, there is also mounting evidence that neuropsychiatric diseases such as anxiety or autism are functionally linked to the microbiome

Moreover, even systemic diseases such as lung, kidney and bladder cancers have been recently linked to the gut microbiome. Albeit, in this case, not the disease development and progression seem to be directly related to our gut inhabitants. Instead, the researchers found that if the microbiome of the cancer patients was disrupted by a recent dose of antibiotics, they were less likely to respond well to the cancer treatment and their long-term survival was significantly diminished. It seems that the treatment with antibiotics disrupts specific components of the microbiome, which then negatively affects the function of the entire composition. 

While the cause or consequence mechanisms between these different afflictions and an altered microbiome have not been solved yet, it seems certain that it is involved in more than digestion. Hence, the already intricate gut-brain axis is further complicated by the gut microbiome, which not only affects when and what we eat, but can also determine our fate in health and disease.  

Richard Thaler: No Regular Economist

Richard Thaler of the University of Chicago has been awarded the 2017 Nobel Prize in Economic Sciences “for his contributions to behavioural economics”. This column, written by his first behavioural collaborator, provides a personal perspective on the development of three key areas of research to which the new laureate has been a major contributor: people’s limited rationality, their perceptions about fairness, and their lack of self-control.

 

A bowl of cashew nuts inspired Thaler to a thought experiment in behavioural economics. Picture/Credit: Altayb/iStock.com

A bowl of cashew nuts gave Thaler the idea of performing a thought experiment on self-control. Picture/Credit: Altayb/iStock.com

 

Behavioural economist Richard Thaler is the 2017 recipient of the economics Nobel Prize. Yet, despite having been president of the American Economic Association (AEA) in 2016, he is no regular economist. In fact, Stanford economist and past AEA president Robert Hall once characterised Thaler as his “favourite offbeat economist”.

The award marks Thaler’s transition from the fringe to the mainstream. But it is instructive to look back at the time when his views were regarded as offbeat by mainstream economists. To be sure, Hall is a mainstream economist and an excellent one at that. As chair of the Business Cycle Dating Committee of the National Bureau of Economic Research (NBER), Hall often makes the call on when the US officially enters and exits recessions. His academic work teaches us how to establish equitable and efficient consumption taxation in a world of rational actors.

By contrast, Thaler’s academic work teaches us to beware of the limits of assuming that the world is populated by rational actors. The Royal Swedish Academy of Sciences identified the following three areas to which he has been a major contributor: limited rationality; perceptions about fairness; and lack of self-control.

In the mid-1970s, I began to work with Thaler on two of these issues and eventually applied his insights to the third. With this as context, I would like to provide a personal perspective on how these three key ideas developed.

Before getting down to details, I need to say something about what Richard Thaler does better than any other economist: he constructs simple and incisive thought experiments. Most economists, including me, are trained to think in terms of formal models. Thaler is more of a qualitative thinker. As I will explain, he is able to pierce through the formality to get right to the soft spot of where those models are unrealistic in key ways.

Lack of Self-Control

Cashew nuts are calorie-rich – and I like them a lot. I have in my office a bowl of cashews, which look very tempting, but fortunately for me, these cashews are not real, but ceramic. I got them as a souvenir at a gathering to celebrate Thaler’s 70th birthday. There is a self-control story behind the cashews.

In the 1970s, Thaler and his wife threw a dinner party for some friends. Before they served dinner, they placed a large bowl of cashews in front of their hungry guests. The guests began to devour the cashews and soon realised that continuing to do so would interfere with their ability to enjoy dinner. But they couldn’t stop. The cashews were too tempting. So they begged Thaler to take the bowl away.

What would you do if you were really hungry, the cashews were in easy reach and you knew that continuing to eat them would ruin your dinner? To a neoclassically trained economist, asking that the cashews be removed is puzzling – and Thaler was trained as a neoclassical economist.

Classical Greek philosophers taught that rational human beings choose the best means to achieve their desired ends. The neoclassical approach formalises ‘choosing the best’ as a problem in mathematical optimisation. In the neoclassical approach, people are assumed to optimise without effort. If they think that eating more cashews is not optimal, they don’t need somebody else to prevent them from doing so; they can costlessly choose to do something other than eat more cashews.

Thaler realised that his dinner guests were not acting rationally in the face of temptation, at least not rationally in the sense of being neoclassically rational. He engaged in one of his thought experiments, asking himself what would prevent him from reaching for more cashews when he didn’t want to eat more cashews. That question led him to think about an internal dialogue within his brain between the part of his brain that was ‘planning’ to stop eating cashews and the part of his brain that was actually ‘doing’ the reaching and eating.

Like Thaler, my interest in self-control also stemmed from issues about eating. But in my case, it was because I became intrigued by my wife’s research on the role of healthcare professionals in treating eating disorders – not as compelling as the cashew story!

In any event, Thaler and I managed to find each other and began to collaborate on a formal economic model that would capture how people make decisions when their internal planners and doers fail to agree (Thaler and Shefrin 1981, Shefrin and Thaler 1988).

Limited Rationality

Some credit unions offer a programme called Christmas Clubs. People who join such a club regularly deposit funds during the course of a year into a special account, with the goal of having a balance at year-end that will fund their Christmas gifts.

When Thaler and I first worked on our self-control model, Christmas Clubs were more popular, offered by many banks and, moreover, did not pay interest, even though interest rates on savings accounts were much higher than they are today. This meant that people who used the clubs to save for gifts earned less interest than they could have by just using a regular savings account.

From a neoclassical perspective, someone who joins a Christmas Club and forgoes interest is operating in the interior of his or her budget set, a clear violation of neoclassical rationality. Were these people that stupid?

Some people choose to have too much of their income withheld to pay income tax, in order to get a large tax refund. Less money withheld means more money to invest for a return. Do people not understand the time value of money? Are they that stupid? How about you? Would you withhold at the lowest rate allowable by law?

In a neoclassical world, the answer to the previous two questions is yes, people are that stupid. But hold on a minute. In a world where planners need to deal with difficult doers, which can lead to a lack of self-control, it might be perfectly sensible for people to join Christmas Clubs and for people to have too much tax withheld in order to receive large tax refunds.

Both behaviours might lead to higher savings than would otherwise occur and, if higher savings is the goal, then such behaviours might be eminently reasonable. In theory, the behaviours might not be neoclassically rational, but in practice they might well be ‘good enough’; and as the late economics Nobel Laureate Herbert Simon noted, going for what’s good enough is “satisficing behaviour” that is “boundedly rational”.

Christmas Clubs and tax over-withholding are not foolproof. People can rob their Peters to pay their Pauls. Someone with a severe self-control problem might borrow heavily during the year using her credit card, to the extent that when the year-end arrives, she finds herself compelled to use the proceeds from her Christmas Club to pay her credit card balance rather than to purchase gifts. Perverse? Yes. Boundedly rational? I don’t think so.

People need enough impulse control to prevent perverse behaviour. There are at least three ways for doing so:

  • The first way is using willpower. Of course, if willpower were easy to exert, then there would be no need for Christmas Clubs or tax over-withholding.
  • The second way is through external enforcement: no credit cards at all, which raises all kinds of issues, not the least being the consequences of not having a credit history.
  • The third way is through internal enforcement, using habits.

Planner-doer theory suggests that people segregate their wealth into separate ‘mental accounts’, such as take-home pay, liquid assets, future income and home equity. Mental accounting habits are ‘pecking order’ rules that specify the order in which different accounts are accessed.

Many people find it easiest to spend first from take-home pay. If they wish to spend more than their take-home pay, the first place they go is to their liquid assets (such as checking or savings account balances, bonds and stocks). If these are insufficient, then people can borrow or, as a last resort, dip into their home equity by borrowing or selling their property.

Mental accounts can be somewhat arbitrary. Their levels are not finely tuned. Therefore, following mental accounting rules can lead people to appear as if they are not operating at the margin. But operating at the margin is not the goal – someone can operate at the margin and overspend very easily.

Thaler pointed out that people use all kinds of mental accounts. One of his thought experiments involves a person who mows their own lawn, but would never mow any part of their neighbour’s lawn for compensation.

Thaler suggests that such behaviour is unlikely to involve operating at the margin by setting marginal benefit equal to marginal cost. By this he means that the property line is arbitrary and, in a neoclassical sense, he might be right. But people might use boundaries as rule parameters, just as much as they use boundaries to separate types of wealth (take-home pay, liquid assets, etc.).

Thaler wrote: mental accounting matters (Thaler 1980, 1985). Now mental accounting might not be neoclassically rational. But given the limits of the human mind, it might be sensible – and good enough. Moreover, striving for perfect rationality might be counterproductive, with the end result being an outcome that is not good enough.

Perceptions of Fairness

In the late summer of 2017, a series of hurricanes struck the Caribbean, the Gulf of Mexico, Houston and Florida. After Hurricane Irma, which struck Florida, local residents registered over 8,000 complaints of price gouging with the state Attorney General’s office. These complaints mostly related to excessive prices being asked for water, ice, food and fuel.

Why are Florida residents complaining about price gouging? Do they not realise that keeping a lid on prices in these circumstances means that demand will exceed supply and that, as a result, some would-be purchasers will be rationed? Do they not realise that keeping a lid on the prices of these items lowers incentives to increase supply? From a neoclassical point of view, preventing the increase of prices to perceived gouging levels, irrationally induces rationing and insufficient supply.

Thaler, together with his colleagues Daniel Kahneman and Jack Knetsch, suggest an alternative way of thinking about market clearing prices (Kahneman et al. 1986a, 1986b). The alternative stems from Thaler’s concept of ‘transaction utility’ – the psychological pleasure or pain associated with how good of a deal a person associates with a transaction.

In the fairness framework, people have notions of reference transactions that they deem to be ‘fair’. Media reports indicate that some Florida hotels doubled their hotel rates in the wake of Hurricane Irma. Paying double for the normal price of a hotel room generates the experience of loss – negative transaction utility, if you like – if there is no corresponding increase in the costs that the hotel incurs as a result of the hurricane.

According to the fairness framework, hotels that charge double but do not incur higher costs are acting unfairly. In contrast, hotels that charge double to cover higher costs and do not reap additional profits as a result are acting fairly.

These are the rules of fairness that people follow. Fairness matters, just as mental accounting matters. Many people would rather be rationed and arrange for alternative accommodation than be gouged. If they feel pain from perceived unfair treatment, it is by no means obvious that the maintenance of fair prices that do not clear markets is necessarily irrational.

Conclusion

Psychologist Daniel Kahneman received the 2002 economics Nobel Prize for his work on ‘prospect theory’, a way of understanding how people make decisions under conditions of risk and uncertainty. The Royal Swedish Academy of Sciences noted that Kahneman had done this work together with the late Amos Tversky. Prospect theory, first published in 1979, was foundational for the development of behavioural economics and finance. That said, without Thaler, I am not sure that prospect theory would have had the traction it ultimately had.

There is much to say about Thaler’s accomplishments, beyond the three specific issues discussed above. Thaler was the first economist to reach out to Kahneman and Tversky, and he did so in the mid-1970s. It was Thaler who saw the connection between his fledgling thought experiments, such as the lawn-mowing example, and prospect theory.

 

Richard H. Thaler. Picture/Credit: By Chatham House, CC BY 2.0

Richard H. Thaler. Picture/Credit: By Chatham House, CC BY 2.0

It was Thaler’s entrepreneurial talents that found ways to bring open-minded economists together with Kahneman, Tversky and their psychology colleagues. In part, he did so through his efforts to secure support from the Sloan Foundation, the Russell Sage Foundation and eventually the NBER.

It was Thaler who wrote an ‘Anomalies’ column for the Journal of Economics Perspectives, which regularly piqued economists’ interest about the shortcomings of neoclassical thinking.

It was Thaler who, together with Shlomo Benartzi, ingeniously applied our work on self-control to help people save more, through their Save More Tomorrow (SMT) programme.

And it was Thaler who, together with Cass Sunstein, extended insights gained from SMT to develop ‘nudging’, the idea of using ‘choice architecture’ based on behavioural insights to induce people to make better decisions. This concept has had widespread influence in both US and UK public policy.

Richard Thaler’s accomplishments certainly merit his being awarded the 2017 economics Nobel Prize. For those accomplishments, we are all the better.

 

References

Kahneman, D, J L Knetsch and R H Thaler (1986a), “Fairness and the Assumptions of Economics”, Journal of Business 59(4): S285-300.

Kahneman, D, J L Knetsch and R H Thaler (1986b) “Fairness as a Constraint on Profit Seeking: Entitlements in the Market”, American Economic Review 76(4): 728-41.

Shefrin, H M and R H Thaler (1988), “The Behavioral Life-Cycle Hypothesis”, Economic Inquiry26(4): 609-43.

Thaler, R H (1980), “Toward A Positive Theory of Consumer Choice”, Journal of Economic Behavior and Organization 1(1): 39-60.

Thaler, R H (1985), “Mental Accounting and Consumer Choice”, Marketing Science 4: 1999-214.

Thaler, R H and H M Shefrin (1981), “An Economic Theory of Self-Control”, Journal of Political Economy 89(2): 392-406.

 

This article was first published by VoxEU.

Immunotherapy: The Next Revolution in Cancer Treatment

Over the past 150 years, doctors have learned to treat cancer with surgery, radiation, chemotherapy and vaccines. Now there is a new weapon for treatment: immunotherapy. For some patients with previously incurable cancer, redirecting their immune system to recognise and kill cancer cells has resulted in long-term remission, with cancer disappearing for a year or two after treatment.

 

Lymphocytes attacking cancer cell. Credit: selvanegra/iStock.com

Lymphocytes attacking a cancer cell. Credit: selvanegra/iStock.com

 

Cancer immunotherapy has been used successfully to treat late stage cancers such as leukaemia and metastatic melanoma, and recently used to treat mid-stage lung cancer. Various forms of cancer immunotherapy have received regulatory approval in the US, or are in the approval process in the EU. These drugs free a patient’s immune system from cancer-induced suppression, while others engineer a patient’s own white blood cells to attack cancer. Another approach, still early in clinical development, uses antibodies to vaccinate patients against their own tumours, pushing their immune system to attack the cancer cells.

However, immunotherapy is not successful, or even an option, for all cancer patients. Two doctors used FDA approvals and US cancer statistics to estimate that 70 percent of American cancer deaths are caused by types of cancer for which there are no approved immunotherapy treatments. And patients that do receive immunotherapy can experience dramatic side effects: severe autoimmune reactions, cancer recurrence, and in some cases, death.

With such varied outcomes, opinions vary on the usefulness of immunotherapy. Recent editorials and conference reports describe “exciting times” for immunotherapy or caution to “beware the hype” about game-changing cancer treatment. Regardless of how immunotherapy could eventually influence cancer treatment, its development is a new revolution in cancer treatment, building on detailed biochemical knowledge of how cancer mutates and evades the immune response. Academic research into immunotherapy is also being quickly commercialised into personalised and targeted cancer treatments.

 

T-cells (red, yellow, and blue) attack a tumour in a mouse model of breast cancer following treatment with radiation and a PD-L1 immune checkpoint inhibitor, as seen by transparent tumour tomography. Credit: Steve Seung-Young Lee, National Cancer Institute\Univ. of Chicago Comprehensive Cancer Center

T-cells (red, yellow, and blue) attack a tumour in a mouse model of breast cancer following treatment with radiation and a PD-L1 immune checkpoint inhibitor, as seen by transparent tumour tomography. Credit: Steve Seung-Young Lee, National Cancer Institute\University of Chicago Comprehensive Cancer Center

Checkpoint inhibitors

Twenty years ago, James Allison, an immunologist at MD Anderson Cancer Center, was the first to develop an antibody in a class of immunotherapy called checkpoint inhibitors. These treatments release the immune system inhibition induced by a tumour. The drug he developed, Yervoy, received regulatory approval for the treatment of metastatic skin cancer in the US in 2011. By last year, Yervoy and two newer medications had reached 100,000 patients, and brought in $6 billion a year in sales.

In general, immunotherapy tweaks T-cells, white blood cells that recognise and kill invaders, to be more reactive to cancer cells. Tumours naturally suppress the immune response by secreting chemical messages that quiet T-cells. Cancer cells also bind to receptors on the surface of T-cells, generating internal messages that normally keep the immune system from attacking healthy cells.

One of those receptors is called CTLA-4. Allison and his colleagues blocked this receptor on T-cells with an antibody, and discovered that T-cells devoured cancer cells in mice. Since then, other checkpoint inhibitors have been developed and commercialised to block a T-cell receptor called PD-1 or its ligand PD-L1, present on some normal cells as well as cancer cells.

In the US, PD-1 and PD-LI inhibitors have been approved to treat some types of lung cancer, kidney cancer, and Hodgkin’s lymphoma. And the types of potentially treatable cancers are growing: Currently, more than 100 active or recruiting US clinical trials are testing checkpoint inhibitors to treat bladder cancer, liver cancer, and pancreatic cancer, among others.

 

CAR-T

Another type of cancer immunotherapy, called CAR-T, supercharges the ability of T-cells to target cancer cells circulating in the blood. In August, the first CAR-T treatment was approved in the US for children with aggressive leukaemia, and regulatory approval for a treatment for adults came in October.

To produce CAR T-cells, doctors send a patient’s blood to a lab where technicians isolate T-cells and engineer them to produce chimeric antigen receptors, or CARs. These CARs contain two fused parts: an antibody that protrudes from the surface of a T-cell to recognise a protein on cancerous B-cells (commonly CD-19) in the blood and a receptor inside the T-cell that sends messages to cellular machinery. When the antibody binds to a tumour cell, it activates the internal receptor, triggering the CAR T-cell to attack the attached cancer cell.

In clinical trials, some patients treated with CAR T-cells for aggressive leukaemia went into remission when other treatments had failed. But several high-profile trials had to be suspended because of autoimmune and neurological side effects, some leading to patient deaths.

To improve the safety of CAR-T treatment, researchers are now engineering “suicide switches” into the cells, genetically encoded cell surface receptors that trigger the cell to die when a small molecule drug binds them. If doctors see a patient experiencing side effects, they can prescribe the small molecule drug and induce cell death within 30 minutes.

Other safety strategies include improving the specificity of CAR T-cells for tumour cells because healthy cells also carry CD-19 receptors. To improve CAR-T tumour recognition, some researchers are adding a second CAR, so that the engineered cell has to recognise two antigens before mounting an attack.

 

As seen with pseudo-coloured scanning electron microscopy, two cell-killing T-cells (red) attack a squamous mouth cancer cell (white) after a patient received a vaccine containing antigens identified on the tumour. Credit: Rita Elena Serda, National Cancer Institute\Duncan Comprehensive Cancer Center at Baylor College of Medicine

As seen with pseudo-coloured scanning electron microscopy, two cell-killing T-cells (red) attack a squamous mouth cancer cell (white) after a patient received a vaccine containing antigens identified on the tumour. Credit: Rita Elena Serda, National Cancer Institute\Duncan Comprehensive Cancer Center at Baylor College of Medicine

Neoantigens

 A third type of immunotherapy aims to target mutated proteins that are a hallmark of cancer. Cancer cells display portions of these mutated proteins, called neoantigens, on their surface. Researchers are studying how to use tumour-specific neoantigens in vaccines to help the body mount an immune response targeted at the cancer.

Results from two recent small clinical trials for patients with advanced melanoma suggest that neoantigen vaccines can stop the cancer from growing, or in some cases, shrink the tumours with few reported side effects. But it’s too early in clinical development to know if the vaccines will extend the lives of cancer patients.

There are two steps to making a neoantigen vaccine: first, identify mutated proteins unique to most of a patient’s cancer cells and second, identify portions of those proteins that could most effectively stimulate an immune response.

To identify mutated proteins, researchers sequence the genome of cancer cells and compare it to the sequence in healthy cells. Next, they identify which mutations lead to the production of altered proteins. Finally, they use computer models or cellular tests to identify the portions of proteins that could be the most effective neoantigen.

This last step of predicting neoantigenicity is the most challenging part of developing a new neoantigen vaccine. Lab experiments to confirm the activity of multiple neoantigens are time consuming, and current computer models to predict antigenicity can be inaccurate due to low validation.

A few principles of cancer biology also make developing neoantigens for long-lasting treatment difficult. Some cancers may have too many mutations to test as potential neoantigens. Cancer cells also continue to mutate as tumours grow, and some cells may not display the neoantigens chosen for a vaccine. Finally, cancer cells may naturally stop displaying antigens on their surface, as part of their strategy for evading an immune response.

However, identifying neoantigens can still be useful as cancer biomarkers. Or if used in a vaccine, they may be most effective in combination with other drugs: a few patients in the small clinical trials whose cancer relapsed after the trials responded to treatment with a checkpoint inhibitor.

Cancer has been a common topic in Nobel Laureates’ lectures at many Lindau Meetings. Learn more about these lectures, as well as Nobel Prize winning research related to cancer, in the Mediatheque.

Resistant Bacteria vs. Antibiotics: A Fiercely Fought Battle

Antibiotics are an integral part of today’s medicine, not only to treat a strep throat or an ear infection – they also play a huge role in routine operations like appendecotomies or cecareans, and they are indispensable as co-treatment for many chemotherapies.

If you take an antibiotic today, it has most probably been developed and approved of in the last century. And since “bacteria want to live, and they are cleverer than us,” as Nobel laureate Ada Yonath describes them succinctly, many pathogens have become resistant to these common drugs. In September 2017, the World Health Organization (WHO) published an urgent appeal to increase funding for research into new antibiotics: not enough new drugs are in the ‘pipeline’ to combat the growing problem of multi-resistant strains. Currently, an estimated number of 700,000 patients die from infections with these strains every year – and this death toll might rise.

The WHO and other experts are especially concerned about multi-resistant tuberculosis that causes about 250,000 deaths per year, and less than half of all patients receive the necessary treatment that can take up to 20 months. The problem is that disrupted treatment inevitably leads to more resistances. Another very worrisome development is the emergence of multi-resistant Neisseria strains that cause the STD gonorrhoea. Neisseria gonorrhoeae are gram-negative bacteria, meaning that their surface is not coloured by gram staining. This resilient surface is also the reason why it is hard to treat gonorrhoea infections in the first place, even without resistances. Only this year, there have been several outbreaks of this multi-resistant variant around the world.

 

Antibiotic resistance tests: the bacteria in the culture on the left are sensitive to all seven antibiotics contained in the small white paper discs. The bacteria on the right are resistant to four of these seven antibiotics. Photo: Dr Graham Beards, 2011, CC BY-SA 4.0

Antibiotic resistance tests: the bacteria in the culture on the left are sensitive to all seven antibiotics contained in the small white paper discs. The bacteria on the right are resistant to four of these seven antibiotics. Photo: Dr Graham Beards, 2011, CC BY-SA 4.0

 

This brings us to another problem: resistant bugs travel fast. No matter where they develop, with modern travel they can spread around the world within days. The WHO also published a list with 12 pathogens that pose the greatest risks. This list includes Neisseria as well as the well-known and much-feared ‘hospital bug’ methicillin-resistant Staphylococcus aureus, or MRSA.

 

Imaging technologies help to develop new drugs

Relief from this dire situation might come from unexpected sources, like the technology honoured by the Nobel Prize in Chemistry 2017: cryo-electron microscopy, or cryo-EM. With the help of this new method, researchers can ‘see’ “proteins that confer resistance to chemotherapy and antibiotics”. This method was difficult to develop, and it leaned heavily on the experiences from X-ray crystallography and classic electron microscopy.

Often in research, being able to ‘see’ something is the first step of understanding its function, hence the strong interest in imaging technology in the life sciences: if a researcher can ‘see’ the workings of a resistance-inducing protein, he or she can start working on strategies to inhibit this process. Cryo-EM is especially good at depicting surface proteins, i.e., the location where infections or gene transfers usually start.

At the same time, optical microscopy is moving ahead as well, being able to ‘watch’ proteins being coded in living cells.  The Nobel Prize in Chemistry 2014 was dedicated to the breaking of the optical diffraction limit. Stefan Hell developed STED microscopy, American physicists Eric Betzig invented PALM microscopy, and both were awarded the Nobel Prize, together with William E. Moerner, “for the development of super-resolved fluorescence microscopy”. Shortly after receiving the most prestigious science award, Stefan Hell combined STED and PALM microscopy to develop the MINFLUX microscope: the very technology that can show proteins being coded. All these methods together will result in a “resolution revolution” that may contribute to the development of new classes of antibiotics.

 

Nobel laureate Ada Yonath during a discussion with young scientists at the 2016 Lindau Nobel Laureate Meeting. Photo: LNLMM/Christian Flemming

Nobel laureate Ada Yonath during a discussion with young scientists at the 2016 Lindau Nobel Laureate Meeting. Yonath has been studying bacterial ribosomes for many years. Photo: LNLM/Christian Flemming

Nobel Laureate Ada Yonath, who was awarded the 2009 Nobel Prize in Chemistry “for studies of the structure and function of the ribosome“ with X-ray crystallography, is currently researching species-specific antibiotics. Her starting point is that many antibiotics target bacteria’s’ ribosomes, “the universal cellular machines that translate the genetic code into proteins.” First, her team studied the inhibition of ribosome activity in eubacteria, i.e., ‘good’ bacteria. Next, she extended her studies to ribosomes from multi-resistant pathogens like MRSA. Her goal is to design species-specific drugs, meaning specific to a certain pathogen. These will minimise the harm done to the human microbiome by today’s antibiotics, resulting in a more efficient cure and a lower risk of antibiotic resistance, because fewer bacteria are affected.

 

Finding new drugs in unexpected places

Another attack strategy is to look for new antibiotic agents in places that never seemed very promising. For example, in 2010 the Leibniz Institute for Natural Product Research and Infection Biology in Jena (Germany) published a new antibiotic agent found in the soil bacterium Clostridium cellulolyticum. It belongs to the group of anearobic bacteria, a group that has long been neglected in the search for antibiotics. “Our research shows how the potential of a huge group of organisms has simply been overlooked in the past,” says Christian Hertweck, head of Biomolecular Chemistry. Just recently, scientists at the Imperial College London and the London School of Hygiene and Tropical Medicine have treated resistant Gonorrhoea bacteria with Closthioamide, the agent from Jena. They found that even small quantities were highly effective in the Petri dish; clinical trials will follow.

Yet another research strategy is to make antibiotics more ‘resistant’ to resistance formation. For instance, it has taken 60 years for bacteria to become resistant to vancomycin. Now, researchers at The Scripps Research Institute (TSRI) have successfully tested an improved version of vancomycin on vancomycin-resistant Enterococci that are on the WHO list of the most dangerous pathogenes. This improved drug attacks bacteria from three different sides. The study was led by Dale Boger, co-chair of TSRI’s department of chemistry, who said the discovery made the new version of vancomycin the first antibiotic to have three independent ‘mechanisms of action’ to kill bacteria. “This increases the durability of this antibiotic,” he said. “Organisms just can’t simultaneously work to find a way around three independent mechanisms of action. Even if they found a solution to one of those, the organisms would still be killed by the other two.”

 

Drug resistance can ‘jump’ between pathogens

Unfortunately, researchers and bacteria are not the only combatants, and this fiercly fought battle is not confined to clearly marked battlegrounds. Increasingly, multi-resistant bacteria can be found in our food, mostly due to the use of antibiotics in animal farming, and even in our natural environment. One such troubling example is Colistin, an antibiotic from the 1950s, which had never been widely used in humans due to toxic side-effects; however, in recent years it has been rediscovered as a last-resort antibiotic against multi-resistant bugs. Since it is an old drug, it’s also inexpensive and widely used – on pig farms in China.

As expected, Colistin-resistant bacteria developed in pigs, which was first discovered and published in 2015. But what makes this resistance perilous is the fact that the relevant gene is plasmid-mediated, meaning it can spread easily from one bacterium to another, possibly even from one species to another. In 2015, this resistance gene, called mcr-1, was also found in pork in Chinese supermarkets and in a few probes from hospital patients. Only 18 months later, 25 percent of hospital patients in certain areas in China tested positive for bacteria with this gene: resistances start spreading at unprecedented speeds.

Another highly disturbing example are large quantities of modern antibiotics and antimycotics found in the sewage from pharmaceutical production in India. In warm water, many bacteria find ideal conditions not only to live, but also to adapt to these novel antibiotics by quickly becoming resistant. Already travellers returning from some developing countries are considered a potential health threat, because many of them are unwitting carriers of multi-resistant pathogenes.

Since the discovery of Penicillin in 1928 by Nobel Laureate Alexander Fleming, the battle between bacteria and antibiotics is fierce and ongoing. This battle is fought in the laboratories, the hospitals and doctors’ offices all over the world, with some people seeming about as determined and creative as their opponents.

But resistance-breeding grounds like Chinese pig farms or sewage pipes from pharmaceutical companies present yet another battleground and call for a strategy that needs to be innovative as well as multifaceted. Only last week, a United Nations ad-hoc group met in Berlin to discuss these challenges. To sum it up: most of us do not live next to Indian sewer pipes, but the resistant bacteria bred there may reach us all.

 

Sign by the US Centers for Disease Control and Prevention CDC how antibiotic resistances occur - you use them and you lose them. But in this graph, large-scale pollution with resistant bacteria is not even included. Image: Centers for Disease Control and Prevention, 2013 Public Domain

Sign by the US Centers for Disease Control CDC how antibiotic resistance occurs: “you use it and you lose it”. Sewage pollution with resistant bacteria from pharmaceutical production is not included in this graph. Image: Centers for Disease Control and Prevention, 2013 Public Domain