Professor Shirley M Tilghman OC FRS, Princeton University Lect

‘Laying the Foundations for 21st Century Scientific Progress’

Professor Shirley M Tilghman OC FRS, Princeton University

Lecture given at the Royal College of Physicians, 8 October 2015, on the occasion of the 60th anniversary of the Wolfson Foundation

It is a great honour to have been asked to give one of the Wolfson Anniversary Lectures this evening. The mission of the foundation – its commitment to supporting excellence in science and medicine, health and disability, education and the arts and humanities throughout the UK and Israel – is inspiring indeed. What is truly gratifying to me as a scientist is the support that the foundation provides for scientific infrastructure, a critical part of the ecosystem that is so often ignored as a priority by philanthropic organizations and government funding agencies alike. And as a former university president, let me just say, “Bless you, bless you, bless you” for recognizing the need to refurbish laboratory space! As the great British geneticist Sydney Brenner reportedly said, “Progress in science depends on new techniques, new discoveries and new ideas, probably in that order.“ Without the buildings, laboratories, computers and scientific equipment that the Wolfson Foundation makes possible, the capacity of your great universities to be engines of innovation would be greatly diminished.

Now I have been handed a challenging remit by Paul Ramsbottom – to reflect on future trends in the fields of science and technology. When contemplating this task, I am reminded of the following quote

‘Prediction is risky – especially about the future.’ - ?

– a quote that has been attributed to everyone from Niels Bohr and Albert Einstein to Dan Quale, the former Vice President of the United States who is best remembered for being unable to spell the word “potato”.

‘Laying the Foundations for 21st Century Scientific Progress’. Professor Shirley M Tilghman OC FRS, Princeton University. Lecture given at the Royal College of Physicians, 8 October 2015, on the occasion of the 60th anniversary of the Wolfson Foundation.

1 But irrespective of who gets credit for this deep insight, predicting the future is indeed risky, especially so when the subject is scientific discovery, for the simple reason that Mother Nature is consistently surprising us. From Copernicus banishing Earth from the center of the universe…. to Darwin making monkeys of our ancestors…. to Einstein’s warping of time and space, science has always found a way to upend our preconceived notions about the natural world.

What I can predict with absolute certainty is that the questions that will be addressed by the next generation of scientists are profound, and their solutions will be of lasting benefit to our future wellbeing.

Let me illustrate that point with a question I often ask young students when I am trying to inspire them to study science – How did the universe begin? What existed before the Big Bang, if anything? That always gets their attention. After all, every society in human history has created an origin myth for itself – stories that form the basis of religious belief – which implies that there is an innate human hunger to understand where we have come from. Yet we do not understand the first thing about the ultimate origin story – how space and time came into existence, and an unstable form of energy exploded at the instant of the Big Bang to create the first particles of matter.

Our expanding Universe

2 We now have a map of that early universe, compliments of NASA’s Wilkinson Microwave Anisotrophy Probe that measured the cosmic microwave background radiation of the Big Bang - and from those measurements the team was able to accurately date the age of our universe – 13.8 billion give or take a few million years - and confirm that it is expanding at an accelerating rate. Amazing progress. Yet we can still account for just 4% of the matter in our universe with the atoms and molecules with which we are familiar. The rest has been given the enigmatic placeholder names of dark matter and dark energy – stand-ins until these forces are identified by the next generation of brilliant young scientists. If I were 18 years old today, I would surely be a cosmologist.

These fundamental questions on the origin of the universe are matched in importance by those that will be tackled by the next generation of neuroscientists exploring the complexity of the human brain.

The Human Brain as Complex Machine

It has become a cliché to say that the brain is the most complex machine in the universe, but the reason it is a cliché is that it happens to be true. The numbers alone are staggering – there are 80-100 billion neurons in the human brain, and they are connected to one another by upwards of 100 trillion synapses.

3 The Complexity of Neuronal Connections

Embedded in the number, topography and strength of those connections lie the answers to another set of profound questions that have been posed for millennia by philosophers and natural scientists alike. What is human consciousness and how did it evolve? How did language arise, and why can someone speak a dozen languages and not be terminally confused? What is the cellular and molecular basis for memory? Why do you forget where your car is parked but a scent can recall instantly a moment from childhood? What is the basis for creativity, and does the brain encode the creativity of a chess champion differently from that of a composer? If I were 18 years old today I would surely be a neuroscientist.

Let me offer one more opportunity to motivate that wide-eyed 18-year old, eager to take on the world by tackling a grand 21st century scientific challenge. And this is one on which the future of the planet depends.

4 Global Warming – an unprecedented rise in atmospheric CO2

I needn’t tell this audience that in the last 50 years we have experienced an unprecedented rise in CO2 levels in the environment, leading to a rise in global sea levels of 17 cm, and temperature increases on land and in the oceans.

Global Land and Ocean Temperature Anomalies in July 1880-2015

5 The impact of these changes in the atmosphere are far-ranging and threaten human health and well-being in many ways, through more extreme fluctuations in weather, decreased air and water quality, declines in agriculture productivity, damage to fragile ecosystems – coral reefs in the oceans and Arctic habitats in the tundra – and ultimately the loss of coastal cities. In response to these immense threats, geologists will be building more sophisticated climate models to help anticipate the changes ahead; engineers will be developing cost-effective renewable energy sources; material scientists will be discovering new batteries that can store energy indefinitely; biologists will be studying the adaptation of threatened animal and plant populations; and environmental scientists will be developing mitigation methods to scrub the atmosphere of heat-trapping gases. If I were 18 years old I would surely want to work on sustaining the future of the planet.

So I hope I have persuaded you that my first prediction – that there will be no dearth of important, and challenging problems for the next generation to solve – is – no pun intended – a no-brainer. The End of Science – which has been predicted with surprising regularity throughout the 20th century, is well beyond the foreseeable horizon.

The issue I would like to explore with you this evening – a question for all stakeholders in the scientific enterprise, including government funding agencies, philanthropies, research institutes and research universities, scientists and the lay public – is the steps we must take to ensure that the staggering impact of scientific progress we have experienced in the 20th century will continue apace in the 21st century. What are the ground conditions that are critical to scientific progress?

That question was posed to Vannevar Bush, an MIT-educated engineer - and parenthetically no relation to the Bush political dynasty – who rose to become science advisor to Presidents Franklin Roosevelt and Harry Truman in 1945.

Vannevar Bush, The Architect of U.S. Science Policy 1945

6 Fully aware of the powerful role that science played during World War II, Roosevelt asked Bush to lay out a strategy that would ensure that scientific discovery would flourish in the postwar era. Bush’s blueprint – Science the Endless Frontier – was immensely wise and has had a lasting impact on the direction of science in the US and elsewhere. Bush’s first great insight – he emphasizes it throughout the report – is that fundamental research is the foundation on which all scientific progress rests. It is the initial investment that must be made by each generation if research is to pay dividends for the next.

The rationale for supporting basic research has largely rested on economic arguments, of the kind proposed by the economist and Nobel laureate Robert Solow, who showed that the predominant driver of GDP growth over the past half century has been scientific and technological advancement. But I would argue there is an equally compelling argument that deep curiosity about the world around us is one of the things that defines us as human, and that citizens of a rich and developed society like yours and mine have an obligation to engage in scientific inquiry, just as we have a moral obligation to support creativity in the arts. I will confess to you, however, that when I tried out this second argument on members of the US Congress as I sought additional funding for science, I was met with blank stares at best, and contempt at worst. I quickly retreated to the safety of American economic hegemony, which clearly resonated more loudly as a rationale for federal investment.

Whichever argument you favor, investing in basic research is always going to be risky, for the simple reason that its dividends are almost always unpredictable. As Bush himself wrote: “One of the peculiarities of basic science is the variety of paths which lead to productive advance. Many of the most important discoveries have come as the result of experiments undertaken with very different purposes in mind”. Over time we have learned that it is unwise to search only in predictable places, for new knowledge often depends upon serendipity and good luck, as well as deep intelligence. Freedom of inquiry, which is one of our most cherished organizing principles, is not just a moral imperative in science, it is a practical necessity.

One of my favorite examples of the unpredictability of discovery is the work that led to the founding of the biotechnology industry. Two scientists – Werner Arber in Switzerland and Hamilton Smith in the US were studying the immune response of simple bacteria to infection by viruses. It is hard to imagine a more esoteric subject of inquiry – yet their efforts led to the discovery of restriction enzymes, which recognize foreign DNA inside the bacteria and by digesting it selectively, efficiently destroy the invader. Those enzymes became the tools that made it possible to splice unrelated pieces of DNA together, led to the founding of the first biotech company Genentech, and within a relatively short period of time, the development and sale of human protein pharmaceutical, insulin, to treat diabetes.

7 Unexpected dividends – the founding on the Biotech industry

Without Arber and Smith’s work an entire industry would not exist today, and we would not have Herceptin to treat breast cancer, or Epogen to treat anemia or Humira to treat rheumatoid arthritis.

Likewise, as a recent report of the American Academy of Arts & Sciences pointed out, the iconic iPhone did not arise like a phoenix out of the brain of Steve Jobs, but is the product of many fundamental discoveries in electrochemistry, liquid crystals, integrated circuits, signal compression and thin-film metallic multilayers, most of which was conducted in research universities. Without this ground-breaking work, much of which was conducted without any anticipation of commercial reward, the wireless revolution would not have occurred, and we would not be living today under the tyranny of our smart phones.

Bush envisaged science as a vibrant research ecosystem, in which the government provided the funding for fundamental science, and the private sector took responsibility for converting discoveries into products. Today all developed nations recognize the value of supporting basic discovery, although the level of investment varies from country to country (table 1), with Korea and Switzerland currently expending almost 1% of GDP on basic research, and you will note that the UK is an outlier on the other side, with just 0.18% of GDP devoted to fundamental research. If you look at total R&D expenditures (table 2), Israel, Japan and Korea top the list, devoting over 3% of GDP to the entire spectrum of research and development. China is an interesting data point – it is increasing its investments in R&D at a breakneck pace, but it is starting from a very low base, and it will be some time before those investments pay off for them.

9 Table 1: Basic research expenditure as a % of GDP – 2013

Table 2: Total R&D expenditure as a % of GDP – 2013

It is common to pay lip service to the central role of basic research in economic progress and future prosperity, and you may be wondering why I am harping on such an obvious point. The reason is that over the last decade I have observed in both the US and the UK a perception among many scientists that the pendulum that swings along the continuum between basic and applied science has shifted dangerously in the direction of applied research. The cause is almost certainly the persistent after shocks of the Great Recession of 2008-9, which have had a depressing effect on total funding in both countries.

10 As total R&D funding has either flattened, or in the case of the US, actually declined, it is human nature to seek short term, clearly demonstrable outcomes over uncertain and unpredictable longer-term benefits when allocating scarce resources. Scientists are not immune, nor unresponsive, to this message. Once the perception that short-term outcomes are preferred by funders takes hold in the scientific community, scientists become more risk averse, which leads to less innovative work, and ultimately the quality of science declines. If there is one metric I would watch closely in the coming years, it is degree to which fundamental research continues to thrive. Are we continuing to generate the seed corn for the next explosive crop of scientific discoveries?

There is an important role for philanthropic organizations like the Wolfson Foundation to play in this ecosystem. Large government agencies tend to be risk averse even in the best of times. By their willingness to make large bets on big ideas, this is a moment when private charities can have an outsized impact on the future progress of science.

If we return for a moment to the three scientific challenges I spoke about at the beginning of this talk and ask what ground conditions they will require in order to flourish in the next decade, several common threads stand out for me. First and foremost, none of the problems resides squarely within one of the traditional scientific disciplines, but will require scientists with very different perspectives to make progress. Interpreting the human brain is going to require the expertise of biologists, chemists, physicists, computer scientists, mathematicians and engineers. Understanding the origin of the universe will likewise require engineers, mathematicians and computer scientists, in addition to physicists and astrophysicists – and a rich mix of theorists and experimentalists. Organizing our institutions and funding mechanisms so that teams of scientists that bring deep expertise from their own branches of science to bear on a single important question will be essential for the 21st century.

I began to appreciate how difficult this might be at one of the first meetings with Rafael Vinoly, the architect who designed the genomics institute laboratory that I founded at Princeton. He asked each faculty member what they would like their space to look like, and received completely different answers from each one. The molecular biologists were basically seeking an atmosphere that encouraged Brownian motion - open spaces with lots of avenues on which students and faculty could collide and interact. The physicists looked aghast – they wanted completely closed spaces with no windows and no corridors that might get in the way of their sensitive measurements. The potential for a failure to communicate was high.

That lesson was reinforced once I became president of Princeton. The most exciting scientific proposals that crossed my desk involved multiple departments – proposals in neuroscience, biophysics, computational biology, machine learning and artificial intelligence, quantum computing, water resources, renewable energy, chemical biology – but structurally we were organized along traditional departmental lines. Developing the university governance structures and establishing cultural norms that would accommodate multidisciplinary programs without compromising the standards by which we hire and promote faculty or undermining coherent teaching programs was an ongoing challenge.

11 Interdisciplinarity also raises pointed questions about the best approach to educating the next generation of scientists. The tension over whether to privilege breadth or depth in science education is always going to be present. For myself I am convinced that depth must come first – that one’s ability to contribute to a team of scientists depends first and foremost on bringing the deepest possible understanding of one’s own discipline to the table. But that is not enough – students must acquire the vocabulary and the mindset that will allow them to seamlessly integrate into an environment in which Brownian motion and reclusiveness are able to productively co-exist.

At Princeton David Botstein, a distinguished geneticist, established a curriculum for undergraduates that he called the Integrated Science curriculum, in which 1st and 2nd year students were introduced to the fundamental concepts and ideas of modern science by a team of molecular biologists, physicists, chemists and computer scientists. When they were designing this curriculum, the faculty were surprised to learn how much redundancy exists among the introductory courses – students were learning about energy transfer not once but three times in chemistry, physics and biology. In the new curriculum they encountered it once, and studied how it applied to a variety of problems. Once through the first two years the students were ready to concentrate in one of the disciplines, but with a multi-disciplinary habit of mind. Students who have gone through this program are sought after by every major graduate program in the country, and to David’s delight, they enter graduate school at much higher rates than the rest of the science students at Princeton. Purposefully preparing students for their scientific future has really paid off.

The quality of scientific discovery is crucially dependent on attracting talented and committed students. As former Harvard president James Bryant Conant said over 60 years ago, “In every section of the entire area where the word science may be properly applied, the limiting factor is a human one. ……So in the last analysis the future of science in this country will be determined by our basic educational policy”. Vannevar Bush made the same point when he wrote “The most important single factor in scientific and technical work in the quality of the personnel employed.”

Are we attracting the most promising students into STEM fields? One piece of evidence that we are not is the chronic under-representation of women in science and technology, which unless you have spent the last few months on the International Space Station, you will know has been hotly debated in the academy and the press here in the UK. If we are restricting the pool of talent from which we draw future scientists, either intentionally, or unintentionally, we guarantee that the full potential of scientific progress on our lives will be significantly less than it could have been.

Furthermore I would argue that bringing more women and other groups currently under-represented into STEM fields will strengthen the entire enterprise by expanding the diversity of scientific problems being pursued. Although I risk being accused of invoking a stereotype, it is likely that the scientific interests of women are not completely coincident with those of their male colleagues. I am not suggesting that women conduct scientific inquiry differently from men – the scientific method is universal – but it has been my own experience that the problems that intrigue women about the natural world are not always exactly the same as those that attract men. There are certainly innate differences between males and

12 females – only the profoundly unobservant would challenge that claim – and indeed there are clearly documented differences that affect everything from spatial perception to maternal behavior. The issue is how those differences, independent of social and cultural factors, affect the likelihood that an individual would aspire to become a scientist, and their likelihood of succeeding. Finally there is a significant body of social science research that documents the ways in which diverse teams are more effective at innovation and decision-making. By enlarging the tent, we will not only raise the overall quality of the pool, but we will expand the range of problems under study, innovation and effectiveness of the and consequently strengthen the entire research enterprise.

Low participation fields for women: Computer sciences and engineering, 1991–2010 USA

Over my career there has been significant progress in the inclusion of women in the scientific enterprise, especially in life sciences and chemistry. However progress has not been uniform. At a time in our two countries where the total number of students pursuing degrees in science and technology is on the rise, and women’s enrollment in university is significantly outpacing men, it is disheartening to see the stubbornly persistent gap in critically important fields like computer science, physics and engineering.

What is even more frustrating is that a gap is already evident by the time students finish secondary school, as you can see from the slide above illustrating the percentage of women taking A-levels in the sciences this year. The numbers are not so different in the US. Of special concern is the low participation of women on both sides of the Atlantic in computing, a field on which so much of modern science increasingly depends. That gender gap put at risk the progress that has been made in biology, for life sciences research is increasingly coming to depend on quantitative approaches. Two of the fastest growing fields of biology are computational biology and bioinformatics, both of which require deep expertise in maths and computing.

There is no silver bullet to guarantee that women are being given every opportunity to pursue careers in STEM. Indeed a growing body of work in psychology suggests that as we have reduced all the obvious barriers to entry, we are coming smack up against the phenomenon of unconscious bias, the insidious consequence of the fact that the brain cannot process information quickly enough, and therefore often relies on what feels safe and familiar when making quick decisions. It is going to take fresh approaches to change the fact that when most people close their eyes and think “scientist”, the image of a white male in a lab coat with a pocket protector and government-issued crooked glasses comes immediately to mind.

14 Technology drives Scientific Progress

I began this talk with an observation from Sydney Brenner that technology is key to accelerating scientific discovery. If one plots the pace of scientific progress over the last century, it would look like a step function, with periods of relative stasis where knowledge is being consolidated and refined, followed by sharp inflection points, in which progress suddenly takes off like a rocket. Inflection points happen when there is a new way to ask an old question; when doors that were closed to scientific inquiry sudden open. In my own career the genesis of every inflection point was the arrival on the scene of a new technology, not a new idea. The development of restriction enzymes by Arber and Smith made it possible to isolate from the complex maze of the mammalian genome a single gene, whose structure and function could now be interrogated. After the British embryologist Martin Evans developed a way to grow mouse embryonic stem cells in culture in the 1980s, Oliver Smithies and Mario Capecchi in the U.S. capitalized on their fundamental work on DNA recombination to develop a way to modify the mouse genome at will, changing the conduct and pace of mammalian genetics. The human genome project would never have been conceived without the development of the polymerase chain reaction or PCR by Kary Mullis in 1983 and it would have been stillborn had major funding agencies on both sides of the Atlantic not heavily invested in developing faster, cheaper ways to sequence DNA. Today the gene editing technology called CRISPR/Cas9 is revolutionizing genetics yet again.

Although I have used examples from my own field of genetics, the argument that technology development is critical to scientific progress is obviously generalizable. The Long Hadron Collider at CERN turned the

15 Higgs boson from a theoretical possibility into a reality; seismometers that measure ground vibrations have made it possible to study and anticipate earthquakes and volcanic eruptions; a revolutionary way to prepare brain tissue called Clarity has made it possible to visualize brain activity as never before; the list goes on and on. It is not by chance that when President Obama asked a group of neuroscientists to craft a vision for a major Brain Initiative, their top recommendation was to invest in new technology.

The lesson to take away for the future is that government agencies and philanthropies like the Wolfson Foundation need to be sure that they are supporting the scientists and engineers who are working on the development of new technology. It is every bit as important, and as Sydney Brenner said, perhaps even more important, than supporting those who are breaking new conceptual ground.

It will also be critical for the future that we collaborate, not just among scientists, but across institutions and countries to ensure that access to the most ground-breaking technology is readily available to those who can take full advantage of it. The physicists have taught us a great deal about the benefits that come from this kind of collaboration - very costly linear accelerators, satellites, telescopes, space vehicles and beam sources are routinely funded by a combination of government agencies, philanthropic organizations, for-profit companies and academic institutions themselves, and involve multi-country collaborations. Physicists have also learned how to assign credit within large projects – no easy task – so that young scientists can build highly successful careers and gain individual recognition while participating in a large team.

Most of the technology I have mentioned is specific to one discipline or another. The technology that is becoming essential across all disciplines is that ubiquitous new buzz word: “big data”. It has been my experience that every serious research university is hearing the drumbeat from faculty for bigger faster better ways to conduct high performance computing and to store its output. Whether they are developing global climate models or seismic models of the earth’s crust, analyzing digital surveys of the solar system, developing a circuit map of the human brain or extracting new knowledge from thousands

16 of whole genome sequences, the rate of data generation is unrelenting and is threatening to overwhelm our networks, storage devices and retrieval systems. This is both a magnificent challenge to human ingenuity and a major source of financial burden to those of us trying to support the creativity of scientists and engineers. Of course the challenge of managing big data is not restricted to science; it is now affecting every aspect of modern life, from the corporate world to the arts, and we have a great deal to learn from internet companies such as Google and Amazon, whose business plans require that they manage unimaginable amounts of information. But as we look toward the future of science the development of new computational algorithms and hardware to manage big data is going to be crucial to progress.

During this lecture I have identified some of the ground conditions that are necessary to guarantee that the future of science is as bright as its past. I have highlighted the importance of asking deep and fundamental questions, and taking on society’s most pressing problems; attracting into STEM a broadly diverse talent pool, and preparing them to succeed in a scientific milieu that is increasingly multidisciplinary; supporting the development of new technology as a key to progress and learning to work together to take full advantage of that technology, and collectively managing the tsunami of information that is coming our way.

But so far I have left out the most important stakeholder – the public, on whose support the entire edifice depends. Whether it is Sir Isaac Wolfson being inspired to endow this extraordinary foundation in 1955 or the British citizen whose taxes help to fund your universities and research councils, they are expressing their confidence that scientific research can lead to better lives for all. In return, they rightfully expect the generation of new ideas and the discovery of new knowledge, the exploration of complex issues in an open manner and the preparation of the next generation of scientific leaders. They also rightfully expect that we sincerely engage with them when new discoveries pose significant challenges to longstanding cultural norms. One need only look back to the early days of genetically modified food to appreciate that greater engagement of the public and transparency would have gone a long way to dispelling the fears of critics. Today the possibility of germline genome editing in humans, a specter raised by CRISPR/Cas9 technology, is being approached far more adroitly on both sides of the Atlantic, with scientists leading the way in calling for public discussion and further scientific exploration before proceeding with human experimentation. We know that our society can adapt to change – just think about how quickly the initial fears of and resistance to in vitro fertilization were overcome – but change will not occur if scientists are failing to engage in the discourse the most important stakeholder – the public.

Perhaps you can tell that I am an optimist. I have confidence that by unleashing the creativity of the next generation of brilliant young people, and with thoughtful leadership from philanthropies, government, academia and industry, the future of science is bright indeed. In fact I suspect that the best is yet to come. Thank you all for coming this evening.