Cure, Create, Innovate: The Future of Research in the UK

Weighing Molecules with Light

Philipp Kukura, the 2019 Blavatnik Awards UK Laureate in Chemistry, opened the symposium with a review of a new optical methodology for studying biomolecules. Kukura’s approach accomplishes a feat unmatched by any preexisting technology—the ability to both visualize and weigh single molecules simply by bouncing light off them. Kukura explained that achieving single-molecule detection with an optical microscope was long considered “hopeless,” due to the fact that until fairly recently, the smallest signal detectable with the most sensitive light microscope was still one million times larger than that of a single molecule. “The right thing to do would have been to accept the impossibility of this task,” he said. “Or you could do what we did, and look at the problem from a different perspective.”

Kukura explained that this new method, called mass photometry, approaches the precision of mass spectrometry and offers the single-molecule detection capabilities of fluorescence. Noting that the human eye is capable of detecting changes in light and color in nature due phenomena at the single-molecule level, Kukura explained that he and his collaborators replicate this feat in the lab, “replacing the light of the sun with a laser, the lens of the eye with a microscope, and the retina with a digital camera.” By shining light on molecules in solution and quantifying the amount of light they scatter, Kukura and his team can both visualize and determine the mass of single molecules in just seconds, opening new avenues for studying biomolecular interactions. “The hope is that this technology will transform the way we study how nature works and what goes wrong in disease,” he said. “We believe it has the potential to change the type of science we can do and the questions we can ask, including applications in drug discovery and optimization.”

Redesigning the World of Polymers

Synthetic polymers have become so ubiquitous that some commentators have dubbed the geologic period that includes the 21^st century “The Plastic Age.” Advances in polymer synthesis have made possible thousands of different types of polymers, yet as 2019 Blavatnik Awards UK Finalist Rachel O’Reilly explained, just six polymer types account for more than 90% of industrial polymer production. Primarily sourced from fossil fuels, today’s plastics are often used for hours but last for centuries, clogging landfills and oceans with staggering amounts of waste. O’Reilly and her collaborators are pursuing methods for creating sustainable polymers based on models found in nature. “Polymers are nature’s greatest invention,” she said, noting that the key materials of life, including DNA, RNA, and proteins, are all polymeric structures.

Natural polymers feature reusable building blocks, and the sequence and stereochemistry of their component monomer units results in complex structures with diverse functionalities. Synthetic polymers tend to have less functionality and their construction is less elegant by comparison, yet O’Reilly and her group are bringing some of the wisdom of natural polymer synthesis into industrial polymer production. She described a newly developed, autonomous system that utilizes the selective recognition of complementary DNA strands to “program” polymer synthesis in the lab. “We’re hoping to use this new approach to explore and understand the influence of monomer sequence in synthetic polymers,” she said.

Nanostructures made from strands of polylactide with opposite stereochemistries interact and undergo a conformal change that can be used to deliver encapsulated cargo, including medications.

Her group is also developing applications for plant-based, highly degradable polymers, such as polylactide (PLA). PLA can be engineered to yield different material properties for novel uses. For example, by careful manipulation of the stereochemistry of the monomer units, isomers of PLA with opposing helicities can be paired to produce functional nanostructures. O’Reilly demonstrated how a cylindrical nanotube consisting of two PLA isomers undergoes a slow conformal change, becoming spherical as the two isomers interact. This process can be controlled and utilized to slowly deliver drugs encapsulated within the nanostructure, a technique O’Reilly has recently begun testing in vivo. Her group is also developing a PLA-based adhesive that shows promise for surgical applications and tissue engineering.

The Key to Unlocking New Molecules

In an ideal world, researchers could identify a medical problem, design an organic molecule to treat it, then produce that molecule at scale and deliver it to patients. In reality, as Igor Larrosa, 2019 Blavatnik Awards UK Finalist, explained, the challenging process of traditional synthesis—an iterative process whereby chemists painstakingly add fragments to an initial compound—often hamper these efforts. In drug development, even promising compounds may be abandoned due to the inefficiency of traditional synthesis. “Unless a molecule shows incredible potency against bacteria, cancer, or another clinically relevant target, this route is not practical for making useful quantities of a drug,” Larrosa said. His lab is exploring new methods for synthesizing complex organic molecules—methods that “break the rules” and enables chemists to explore the effects of structural changes in organic molecules quickly and efficiently.

A highly selective ruthenium-based catalyst allows for precise modifications of existing drug compounds.

The carbon and hydrogen atoms that form the backbone of organic molecules are typically considered “not interesting,” Larrosa explained, as the bond between them is so strong as to render them non-reactive. “But what if we had a tool that allowed us to pick one carbon-hydrogen bond and break it apart?” he asked, describing the process of carbon-hydrogen (C–H) activation, which turns a normally non-reactive site into an area of great interest. He demonstrated how a newly identified reactive species of the element ruthenium is an ideal catalyst for breaking C–H bonds with great precision, allowing chemists to replace hydrogen atoms in organic molecules with the coupling partners of their choice.

In one example, he showed how select hydrogen atoms in the structure of atazanavir, a common antiretroviral drug, can be targeted for C–H activation and replaced with a simple phenyl ring or more complex compounds. Such modifications to existing drugs would be time and cost-prohibitive using traditional synthesis, whereas Larrosa’s method quickly reveals the effects of these changes—such as increased efficacy or reduced side effects. “This unlocks the potential to access hundreds of new and potentially lifesaving medicines,” he said.

Unveiling the Origin of Mass: The Discovery of the Higgs Boson

Konstantinos Nikolopoulos, the 2019 Blavatnik Awards UK Laureate in Physical Sciences & Engineering, offered a glimpse behind the scenes at one of the most exciting breakthroughs in physics in the past century—the discovery of the Higgs boson. In 1964, three groups of physicists proposed a novel particle, the Higgs boson, which became a central component of the Standard Model of particle physics. The Standard Model describes the elementary particles in the universe and the interactions between them. The Higgs boson was an important addition to the model, and was believed to be responsible for giving the other particles their mass. Nikolopoulos explained that physicists had observed every other elementary particle in the Standard Model, including quarks and leptons, but the Higgs boson remained elusive despite decades of efforts to prove the existence—or non-existence—of such a particle that would shed new light on our understanding of the early universe.

Experiments to search for the Higgs boson have been underway in some form since the 1980s at CERN, the European Organization for Nuclear Research. After the 2008 completion of the Large Hadron Collider—currently the world’s largest and most powerful particle accelerator—efforts to prove the existence of the Higgs boson advanced considerably, due in large part to the introduction of ATLAS, the particle detector ultimately responsible for the observation. As Nikolopoulos described the project, which involved 5,500 scientists from more than 180 institutions worldwide, “What we do at CERN is big science in every respect—big experiments, big data sets, and big collaborations.” Their work paid off in 2012, when ATLAS observed the products of a decaying Higgs boson in the wake of a proton collision, an event so rare that Nikolopoulos estimated the odds at “one in one hundred thousand billion.”

The discovery of the Higgs boson completed the Standard Model, but many monumental questions about the universe remain. Among them, noted Nikolopoulos, is the fact that the Standard Model only describes 5% of the matter in the known universe, leaving the composition of the rest of the universe—believed to be comprised of dark matter and dark energy—a mystery for now.

Practical Cryptography

Máire O’Neill, 2019 Blavatnik Awards UK Finalist, began a review of her research in computer hardware security began with a jarring demonstration—a video clip of an interactive, talking children’s doll explaining how it had been hacked by an intern student at O’Neill’s institute. The app-based toy, like many other common Internet-connected devices, including baby monitors, smart door locks, connected home appliances, and even medical devices, contain security vulnerabilities that make them relatively easy targets for computer hackers. O’Neill explained that as costly cyberattacks grow at an unprecedented pace, demand for lightweight, high speed, and cost-effective cryptographic solutions for securing Internet-connected devices is at an all-time high.

Internet-connected devices including children’s toys, smart home appliances, and medical devices often contain security vulnerabilities that computer hackers can easily exploit.

O’Neill reviewed some of her own contributions in this area, including a high-speed optimization of the advanced encryption standard, a widely used encryption algorithm deployed in Skype and Internet security protocols, as well as in Wi-Fi standards and Internet security protocols. Her group is also developing applications for physical unclonable functions, or PUFs, which facilitate computer hardware authentication and combat computer component counterfeiting. Akin to a digital fingerprint, a PUF is a digital circuit that detects minute inconsistencies in electronic chips during the fabrication process, and then uses them to generate a unique identifier for that chip.

In addition to threats from cybercriminals, computer security researchers face a looming difficulty within their own field, O’Neill explained—the inevitable emergence of quantum computers. These computers, which are still experimental, will someday operate exponentially faster than today’s computing technologies and will, theoretically, be able to “break” the mathematics underlying today’s secure systems. O’Neill leads a consortium of academic and industry partners, SAFEcrypto, which is developing cryptographic solutions designed to hold up against the quantum computers of the future. Until then, however, she cautions that device makers and researchers should remain vigilant about present-day security.  “For the true potential of internet-connected devices to be realized, security solutions must be practical, physically secure, and they must be built into devices from the outset of their design, and not as an afterthought,” she said.

Are Black Holes Stable? A Mathematical Proof

Gustav Holzegel, 2019 Blavatnik Awards UK Finalist, closed the session with another story of modern-day scientists solving a decades-old problem. For more than 60 years, mathematicians and physicists struggled to reconcile a series of open questions associated with Einstein’s theory of general relativity. Among them was the black hole stability conjecture—the question of how black holes respond to disruptions, or “perturbations” in the fabric of spacetime. Thanks to contemporary mathematical techniques, pioneered in part by Holzegel, a proof of black hole stability has emerged in recent years.

Holzegel reviewed some of the basic tenets of general relativity, including the concepts that mass curves spacetime; heavier objects create more curvature than those with less mass; and that the curvature of spacetime determines the movement of objects within it. He briefly defined black holes through an analogy, encouraging the audience to envision a rocket achieving the velocity necessary to escape Earth’s gravity. “Now imagine shrinking the Earth to a radius of one centimeter, and keep its mass fixed,” he said. “This results in a much denser object that creates a much stronger curvature [of spacetime]...so dense that the escape velocity you’d need is faster than the speed of light. That’s a black hole.”

The mass of a black hole causes such extreme curvature of spacetime that nothing—not even light—can travel fast enough to escape it.

While the spacetime geometry for a black hole can be mathematically derived from Einstein’s equations, these calculations only apply to a static black hole at a moment in time. A proof of black hole stability requires an understanding of what occurs when a black hole is “perturbed,” or subject to disruption or changes in the fabric of spacetime. Hoelzegel’s studies of black hole dynamics have answered questions about how black holes respond to disruption and regain their stability.

“We poke the geometry of spacetime a little bit here and there,” Holzegel said, which results in “deformations” in spacetime, which according to the Einstein equations, should predictably evolve and ultimately return the black hole to its original state. When a black hole is perturbed, it sends forth ripples in spacetime known as gravitational waves. For a black hole to stabilize, these waves would need to dissipate until their amplitude reaches zero, much the way ripples from a stone tossed into a pond eventually disappear. Yet proving this physical mechanism for stability is a remarkably difficult mathematical feat, one that Holzegel overcame by exploring “remarkable properties” of Einstein’s equations. The result: a proof that gravitational waves do, in fact, disperse to zero amplitude and thus stabilize a black hole following perturbation.

The Shape of Cells: A Journey from Physics to Biology and Back Again

Ewa Paluch, the 2019 Blavatnik Awards UK Laureate in Life Sciences, opened the final session of research presentations with a discussion of her efforts to understand how shape is controlled in biology, a question that she asserts is “fundamentally at the interface of biology and physics,” and cannot be addressed using the tools of biology alone. Quoting the early 20^th-century Scottish biologist and mathematician D’Arcy Thompson, Paluch noted that “the form of an object is a diagram of forces”—that the many shapes of cells are the product of the forces exerted upon them, both from within the cell as well as from the external environment.

For more than a decade, Paluch and her collaborators have paired tools and techniques from biology, engineering, and mechanics to measure the forces that give cells their shape, and to understand how changes in cellular shape contribute to functions including cell division and cell migration. Among their more surprising findings are insights into cellular deformations known as blebs. These bubble-like protrusions, which result when hydrostatic pressure within the cell exerts force on areas of weakness in the cell surface, were long associated with cellular dysfunction and cell death. Paluch’s group, now affectionately nicknamed “The Bleb Lab,” published the first investigations of the mechanics of bleb formation, as well as the first studies showing that blebbing regularly occurs in healthy cells and contributes to critical cellular processes in both health and disease. “During division, when a cell cleaves into two cells, blebs appear at the cell surface and act as pressure valves to stabilize the cell,” Paluch explained. “In cell migration, the pressure that helps cells form blebs can also be used to move cells forward, which is something that cancer cells tend to do.”

Intracellular pressure forces weak areas of the cell membrane to protrude outward, forming blebs. Contrary to longstanding belief, blebs occur in normal, healthy cells and facilitate cellular functions.

Paluch’s studies of bleb formation and function have given way to broader investigations of cell mechanics. Looking to the future, Paluch has trained her sights on trying to understand two processes that she deems “complete mysteries at the moment,”— how cell shape is controlled at the molecular level, and how a cell’s shape relates to its function. “We want to understand the cross-talk between cell fate and cell shape,” she said, noting that this area of research—which stands to transform our understanding of biological processes ranging from development to immune function and even cancer metastasis—can only be accomplished through further interdisciplinary collaborations between biologists and physicists.

Building Models of the World

Most people move through daily life without much thought regarding the neural mechanisms that drive human behavior and actions, but as 2019 Blavatnik Awards UK Finalist Timothy Behrens explained, complex internal models of how we perceive the world to work govern every move and decision that we make. These models, which are rooted in our neural circuity, are a source of fascination for Behrens, who is teasing out the ways in which the brain creates, updates, and maintains these models.

Behrens explained that a strong understanding of the brain’s reward circuits, built over decades of research, has yielded predictive models of human behavior that underlie many artificial intelligence algorithms and shed light on disorders including addiction. He and his colleagues are now attempting to map the neuronal activities that underlie other human behaviors and thought processes, such as problem solving and making inferences.

Building upon prior studies that revealed the neural mechanisms that govern spatial relationships and the concept of “place,” Behrens and a team of collaborators have shown that similar circuitry is responsible for how humans and some animals understand non-spatial, abstract concepts. He showed the results of experiments in which neuronal activity in a rat’s hippocampus, the locus of the brain’s place cells, was monitored as the animal ran a course in search of a food reward. Even when the rat was resting, there were millisecond-long flashes of activity in the animal’s place cells that look identical to the firing patterns associated with actual movement. “He’s not running down the track anymore, but his brain is,” Behrens said. This phenomenon, known as replay, has also been observed in humans and is believed to be involved in making inferences and organizing existing knowledge.  Behrens said that these events “are not replaying old memories, but they are figuring out new things involving your world model.” As an example, Behrens referenced the popular film “Kill Bill,” which features a chronologically scrambled storyline. He explained that replay is likely to be involved with viewers’ ability to reconfigure the story and understand it in real time, even though the narrative was presented out of order.

He noted that in addition to providing a better understanding of normal cognitive processes and informing the development of artificial intelligence algorithms, studies of how the brain creates models of the world may advance treatment and understanding of psychiatric illness. With a steady stream of new analytical tools and techniques to visualize and measure neuronal connections, Behrens believes that “this is a very exciting time to be thinking about the brain.”

Gene Editing in Human Embryos

Kathy Niakan, a  2019 Blavatnik Awards UK Finalist, concluded the research presentations with a report from one of the most exciting—and most sensitive—frontiers of biology: genome editing. Niakan leads the first team in the world to obtain regulatory approval from their government to use genome editing to investigate the functioning of genes human embryos. By studying the earliest stages of human development, their experiments have already yielded important insights into the role of the pluripotency transcription factor OCT4 in human embryogenesis—the first findings in what Niakan hopes will be a body of research that helps illuminate factors that contribute to infertility and miscarriage.

By tracking gene expression patterns over the first seven days of development, a time when a fertilized egg grows from a single cell into a 200-cell blastocyst, Niakan is identifying proteins that are essential for successful embryonic development. To test the function of these genes, she and her collaborators used the genome editing tool CRISPR-Cas9 to inactivate the gene that codes for one such protein, OCT4, in human embryos, then observed their development from single cell to blastocyst.

These experiments revealed that when OCT4 is disabled in human embryos, development fails. Niakan explained that OCT4-disabled embryos often cease dividing before reaching the blastocyst stage, and those that do develop are unable to “hatch” from the protective protein shell that surrounds an embryo prior to implantation. Mouse embryos in which OCT4 has been inactivated still develop normally through the blastocyst stage, a finding that surprised Niakan and validated their approach to this research. “It’s important to understand that there are certain aspects of human biology that can be adequately modeled using other organisms, but sometimes there are effects that are very specific to humans,” she said.

Mouse embryos continue to develop fetal progenitor cells even in the absence of the protein OCT4, while human embryos fail to develop when OCT4 is inactivated. Genome editing in human embryos can help identify genes crucial for human development, which may be different from genes in other species.

Gaining an understanding of the genes that are essential in early embryo development may ultimately improve treatment for infertility. Niakan notes that only one in ten fertilized eggs implanted during in vitro fertilization develops past the first trimester of pregnancy. While many factors influence this success rate, healthcare providers currently rely strictly on morphology to select embryos for implantation.  “If we can understand the key molecular properties of these cells, maybe we can better select embryos for infertility treatment,” Niakan said.

M. Madan Babu, the 2018 Blavatnik Awards UK Laureate in Life Sciences, led the final session of the symposium—a wide-ranging, spirited panel discussion with three of this year’s honorees

Honorees from each discipline discussed the most exciting advances in their respective research areas, with a common theme emerging among them all: the sense that their fields were “on the cusp of revolution,” as Kathy Niakan said. CRISPR-based technologies are an area of great interest in the global research community, and Niakan said that current work to optimize these systems might ultimately give way to truly transformative applications, including therapeutic uses in children and adults.

Konstantinos Nikolopoulos echoed her sentiment. “We are in a very unique time,” he said, explaining that the successful search for the Higgs boson galvanized excitement for the types of discoveries that could be made with future particle accelerators. “We only know about 5% of what the universe is made of, and that leaves 95% to be explored," he said. “We’d like to build larger, more powerful colliders that would give us access to a completely new energy regime.”

For Rachel O’Reilly, the shift toward sustainability in polymer chemistry represents an exciting new chapter in a field that has long been interested in short-term utility rather than the full lifecycle of a material. O’Reilly attributes this shift to societal pressures to address “the plastic problem,” and is hopeful that this pressure continues to be a motivating force to develop highly degradable polymers. “There is no polymer waste problem in the natural world, because the biological machinery is there to break down what nature makes,” she said.

Lab Culture and Diversity

The panelists discussed trends in academia and their own experiences building a lab and overcoming personal and professional challenges.

Babu cited a recent study, published in Nature, which showed that disruptive ideas more often come from small teams of researchers, while larger teams build upon existing ideas. Nikolopoulos and O’Reilly, who both hail from fields where large teams prevail, described their efforts to make individual contributions within the context of a large-scale collaboration, while Niakan, who works with a smaller group, shared her team’s strategy for remaining open-minded and fighting back insularity. “Members of my lab challenge each other’s assumptions because there’s a safety net there—we all feel comfortable talking about things we don’t know about and seeking advice proactively,” she said.  O’Reilly, who noted that large teams are “a badge of honor” for chemists, is pushing back against that trend, encouraging young researchers in her lab to reconsider the idea that “a big team is what equals success.” She also noted the importance of disciplinary diversity within the lab—her team includes mathematicians, biologists, and physicists. “Having them within the group means we have their input from the earliest stages, and we can start with ideas that are a bit more adventurous,” she said.

The panelists addressed the so-called “leaky pipeline” in science, which refers to the precipitous drop in the number of women in the sciences beyond the undergraduate level. There was consensus that many of the same strategies for perseverance necessary for all research scientists are critical for recruiting and retaining women in the sciences—chief among them is a supportive network of family, mentors, or colleagues. The group also noted that the restrictive norms of the academic career track might inhibit young women from pursuing STEM careers. “The culture of what success [in chemistry] looks like isn’t something many young women can relate to,” O’Reilly said. “I think we need to encourage people to think about success in terms of what they want it to be and to promote diversity in career paths so we ultimately become more accepting of people who approach a career in science in different ways.”

Looking to the Future

While the panelists are unquestionably optimistic about the future of their fields, the departure of the United Kingdom from the European Union was viewed as an event that was certain to impact both their individual labs as well as the overall research landscape in the UK.

Every research scientist prioritizes the ability to recruit the best people from around the world, and the withdrawal of the UK from the EU may limit the scope of international collaborations. O’Reilly commented that these partnerships are not only critical for producing quality research, but are personally important for the researchers themselves. “Maintaining a diverse group of people, experience, and culture is so important, and creates a lively environment in the lab,” she said. “It’s also enriching for students as they mature both scientifically and socially.”

As the discussion concluded, the group reflected on the value of awards programs, including the Blavatnik Awards, which, as Babu said, “bring science into the public view.” For Nikolopoulos, public recognition is important as a way to build awareness of key research breakthroughs as well as to spotlight scientists who serve as role models for young people interested in STEM. As O’Reilly reflected on the symposium and her fellow Blavatnik honorees, she commented that, “It’s amazing for us as scientists to see the breadth and depth of other people’s work. It gives me heart—it’s encouraging that there’s this spectrum of activity. This work is some of the most exciting in the country.”