July 03-07, 2023

Abstract

When the laser was invented in 1960, people were wondering what is going to be the use of it. Today we know that lasers are used almost everywhere. Since laser’s invention, researchers have endeavored to create more and more intense laser pulses that goes together with creating shorter and shorter pulses.

The duration of laser pulses has, over the years, been reduced from ms (10-3 s) to fs (10-15 s) and eventually to sub-fs entering the attosecond (10-18 s) temporal scale. As the characteristic times of motion increase with the size of the moving object, short pulses allow the study of ultrafast dynamics occurring in the microworld. Indeed for the investigation of phenomena with ps or fs duration, like molecular or atomic processes in gases, liquids and solids, only laser based techniques can be used, as electronics are not fast enough. Femtochemistry made it possible using fs lasers to “see” how atoms move in a molecule during a chemical reaction. Attosecond pulses can now be used, as the fastest ever “camera”, for capturing ultrafast electron dynamics, like the evolution of atomic coherences or charge migration in large molecules, as well as electron-electron correlation times.

THigh intensity lasers are used in relativistic and ultra-relativistic interactions with matter. Such interactions lead to very compact particle accelerators and novel radiation sources. Electrons have been accelerated to 7.8 GeV over an acceleration length of 20 cm. Lasers produce 100 MeV scale protons from laser-film interactions. Table top coherent XUV and soft x-ray sources are based on laser-gas and laser-surface interactions, in a process known as high order harmonic generation, while 100 keV scale betatron radiation is co-emitted in laser electron acceleration sources. Recently, non-linear Compton scattering between an electron and several hundred laser photons has been demonstrated, inaugurating laser induced QED phenomena.

In addition to curiosity driven physics, compact and user-friendly, high-power, ultra-short pulse laser systems are used in many industrial, medical and other practical applications. Because of the minimal thermal energy deposition by a fs laser when interacting with materials, it causes negligible collateral damage beyond the targeted interaction volume, providing high precision and controllable material processing. High-aspect-ratio holes that are required for stents can be drilled with fs lasers. fs lasers are in clinical use in refractive surgical procedures or in changing the properties of matter like converting electrical insulators to conductors, acting as ultrafast optical switches.

The journey towards high peak power, short pulse lasers seemed, by the mid-1980s, as having reached the end of the road. For short pulses it was no longer possible to increase their intensity without destroying the amplifying material. At that time the new technique, known as chirped pulse amplification, CPA, came to overcome the bottleneck. A short laser pulse is stretched it in time, amplified and squeezed back generating high peak power ultrashort pulses. The CPA-technique has revolutionized laser science and applications. It is used in all high-intensity lasers and a gateway to new research areas and applications in physics, chemistry, medicine and industry.

This year’s Onassis Lectures are dedicated to the science and applications of extreme light. The lead speaker is Gerard Mourou, co-inventor (with his at that time PhD student Donna Strickland) of CPA. The individual presentations will cover a wide range of topics related to current and future applications of high peak power, ultra-short pulse lasers.

July 25-29, 2022

Abstract

Biological systems have evolved over billions of years, with natural selection favoring the re-shaping of molecular structures and metabolic pathways that enhance survival in a continuously fluctuating chemical environment. Yet these solutions, optimized for fitness rather than human utility, are often suboptimal for applications in areas such as efficient chemistry, renewable energy, and medicine.

Directed evolution—a methodology inspired by natural selection but conducted in the laboratory—enables scientists to engineer proteins, enzymes, and even entire metabolic pathways with enhanced or novel functionalities. This approach involves iterative rounds of mutation and selection to traverse the vast "fitness landscapes" of molecular function. Initially laborious and time-consuming, directed evolution has become a central strategy in modern biotechnology, thanks to significant advances in high-throughput screening, rational design, and computational modeling.

The pioneering work of Frances Arnold, awarded the Nobel Prize in Chemistry in 2018, demonstrated that laboratory evolution can reliably outperform rational design in engineering complex molecular functions. Her contributions established directed evolution as a transformative force across chemistry and biology.

Beyond individual enzymes, synthetic biology has emerged as a complementary field, aiming to build and rewire entire cellular processes. Researchers are designing new-to-nature metabolic pathways, including those capable of capturing and converting CO2, offering novel solutions to climate and sustainability challenges. Advances in membrane biology, minimal cell design, and the recreation of basic metabolic modules have further expanded the scope of cellular engineering. Recent work has also broadened the focus of re-engineering biology beyond catalysis to the fine-tuning of protein conformational landscapes and dynamic regulation. Insights from statistical thermodynamics and free-energy landscape theory are reshaping our understanding of how allosteric networks evolve and adapt, balancing affinity, efficiency, and environmental responsiveness. Strategies now aim not only to optimize catalysis, but also to reprogram internal communication networks and the dynamic behavior of proteins, enabling the design of more adaptable and responsive molecular systems.

Technological innovations have further reshaped the landscape. Ultrahigh-throughput methods, such as droplet-based microfluidics, allow millions of enzyme variants to be screened rapidly, accelerating the exploration of protein sequence space. Concurrently, developments in real-time biosensing and wearable molecular monitors are beginning to bridge the gap between engineered biological systems and direct clinical or industrial applications.

Artificial intelligence has entered the field as a powerful accelerator. Large-scale protein language models and AI-driven structure prediction tools are enabling the in-silico design of functional biomolecules at an unprecedented pace, opening vast new territories for synthetic biology and biotechnology.

This year’s Onassis Lectures are devoted to the advances, challenges, and future prospects of re-engineering biology through directed evolution and synthetic cellular pathways. The series will highlight groundbreaking technologies and conceptual innovations, featuring presentations from world leaders in enzyme engineering, synthetic metabolism, minimal cell construction, thermodynamic modeling of protein evolution, and AI-driven biological design.

July 16-20, 2018

Abstract

The sequence of bases in DNA constitutes an organism's genetic code. This means that it contains within it all the information which may be called upon in the future -at the right time and place - to direct the biochemical processes that contribute to the organism's morphogenesis and to the regulation of its overall metabolism. However, this stored information, as such, represents a static state. By analogy, it resembles the notes of a music score, which come to life – and their melody is perceived – only when the score is executed by the orchestra.

Something similar happens with the information stored in DNA, which remains static until it is “activated” (transcribed) through dedicated and specific biochemical steps. The first stage in this expression is the transcription of the gene from the DNA to RNA molecules (messenger, mRNA) through the action of protein enzymes (DNA-dependent RNA polymerases). The nucleotide-sequence code in the mRNA is then translated within the ribosome into the amino acid code, that is, into sequences of amino acids (the building blocks of proteins) that yield specific protein molecules, such as a multitude of metabolic catalysts (enzymes), structural proteins, etc., but also to some regulatory, non-protein-coding RNAs.

All forms of life (with few exceptions) consist of several hundreds of different cell types each designed to perform specific tasks, which contribute to the overall functioning of the organism. The remarkable diversity in cell specification within one organism is achieved via the precisely regulated expression of a subset of the genes in each cell type.

Transcription of eukaryotic genes is a multistep process that involves the ordered assembly of large multiprotein complexes in gene regulatory regions. The main components of the transcription machinery are Transcription Factors (TFs), possessing sequence-specific DNA binding activity and serve as anchor points for the recruitment of general transcription factors (GTFs), components of the Mediator complex and RNA-polymerase-II, the enzyme complex that catalyzes mRNA synthesis. The mechanism of activation has been a focal point in the field for several years.

A significant breakthrough in our understanding came from the seminal discoveries of Roger Kornberg who was awarded the Nobel Prize in Chemistry in 2006. His studies, combining advanced biochemical and structural analyses of RNA Pol-II and associated complexes, enabled a dynamic interpretation of the different stages of the transcription process, by providing molecular understanding of promoter recognition, mechanism of initiation, the structural basis for accurate selection of an incoming nucleotide to the DNA template and the mechanism by which the newly synthesized RNA strand is separated from the DNA template.

Roger Kornberg's pioneering discoveries engendered much subsequent research in the field aimed at understanding of how transcription is regulated during the cellular differentiation processes of normal development or by external and internal signals and how this process becomes uncontrolled and leads to appearance of various diseases. Another speaker in these Lectures and a pioneer in the field of transcription is Robert Roeder who fifty years ago discovered that there exist three types of DNA-dependent RNA polymerases, each specialized to a different domain of transcription.

The individual presentations will cover critical enzymatic stages in the transcription of eukaryotic cells within the cell nucleus, in the mitochondria, on the link between transcription and the correction of 'faults' in the genome, and on examples of specialized, tissue-specific transcription regulation. New data will be presented that correlate dynamic shifts in the 3-D organization of the nuclear genome with the correct (in place and time) genetic transcription as well as with epigenetics. Recent technological developments will also be presented which enable us to investigate transcription mechanisms at the level of single molecules and with millisecond-time resolution.

Clarification: Although the substrate of the enzymatic process of transcription is chromatin, the 2018 lectures will NOT deal with issues of chromatin structure, assembly, remodelling, etc. It is hoped that these important topic, will be addressed separately at a future time.