A number of events held throughout the week at the 70th Lindau Nobel Laureate Meeting focused on aspects of biological research from a big-picture perspective – where we’ve been, the current state of the art, and what the future may hold for the field. The various lectures and Agora Talks covered topics as diverse as structural biology, color pattern evolution in animals, vaccination, and super-resolution fluorescent microscopy.
Structural Biology and Its Key Role in the Life Sciences
A trio of Agora Talks on Tuesday tackled the latest trends in structural biology, the study of how biological molecules are built. Imaging techniques, which are used to view molecules in three dimensions, remain at the core of structural biology research. How molecules are assembled gives insight into how they function and interact.
Robert Huber, who received the 1988 Nobel Prize in Chemistry for determining the three-dimensional structure of a photosynthetic reaction center, kicked off the session with an overview of the past and present of structural biology.
“We learned to use the full spectrum of electromagnetic radiation for imaging, from X-rays to radio waves,” Huber said. “We have the tools to see and image small molecules and eukaryotic cells with these different methods.”
He noted all the diverse imaging techniques available within the structural biologist’s wheelhouse today, and how they can be synergistically combined. For example, the complementary approaches of single-particle cryo-electron microscopy (cryo-EM) and X-ray crystallography increases the range of possibilities. While X-ray crystallography is still the method of choice to observe structural information from proteins, for instance, cryo-EM provides unique information regarding changes in conformation.
Next, Kurt Wüthrich – recipient of the 2002 Nobel Prize in Chemistry for the development of nuclear magnetic resonance (NMR) spectroscopy – made a brief statement about imaging macromolecules in solution, which are under the regime of Brownian motion.
Random motion is averaged out in single-molecule approaches like cryo-EM and causes unwanted artifacts. This issue does not affect X-ray crystallography, since Brownian motion is suppressed for molecules in crystals. However, he mentioned that new single-molecule techniques are being created that eliminate such artifacts.
Lastly, Hartmut Michel summarized the three most impactful methods in the field – X-ray crystallography, NMR spectroscopy, and cryo-EM – and their integral role in the development of new drugs. Michel received the 1988 Nobel Prize in Chemistry along with Huber. He mentioned how structure-based drug design directs the discovery of a drug lead, which is a compound with a certain affinity for a target. From there, more research is needed to convert a drug lead into a drug that will be both effective and tolerated by the human body.
In her Agora Talk on Tuesday, Christiane Nüsslein-Volhard spoke about the vivid colors and patterns that appear throughout the animal kingdom.
“We enjoy beauty of animals in the same way that we enjoy arts and music,” said Nüsslein-Volhard, who received the 1995 Nobel Prize in Physiology or Medicine for discoveries concerning the genetic control of early embryonic development. “The products of art are made by humans for humans, but how about the colors, ornamentations, and melodies of animals?”
Beauty is a term rarely uttered by biologists today in a scientific sense. However, the founder of modern biology, Charles Darwin, actually contemplated how animals perceived one another’s beauty. He believed that animals, like humans, assess things like ornaments and melodies on the basis of their own cognitive experiences.
In her own laboratory, Nüsslein-Volhard studies the physical basis of color and patterns in vertebrates. Colors are most rich and variable in fish, amphibians, and reptiles, where different kinds of pigment cells are deposited in superimposed layers beneath the skin. She uses zebrafish as a model to understand the genetic basis of color pattern variation in vertebrates.
Sixty Years of Structural Biology
Richard Henderson began his esteemed career in structural biology 55 years ago, culminating in a much-deserved 2017 Nobel Prize in Chemistry for the development of cryo-EM. His lecture traced the history of the field from five years before his involvement to the present era, where cryo-EM is regarded as a highly revolutionary technique for the generation of 3D images of biomolecular structures at near-atomic resolution.
“In the 1950s, there weren’t really techniques powerful enough to determine structures,” said Henderson. “So what people did was model building based on the best information they could glean from a variety of techniques.”
For instance, Linus Pauling and Robert Corey discovered the alpha-helix and beta-sheet, which are now known to form the backbone of tens of thousands of proteins, back in 1951. They deduced these fundamental building blocks based on studies of small molecule crystal structures.
In the decades that followed, experimental methods to determine structures finally started to emerge – most notably, X-ray crystallography and NMR spectroscopy. Today, X-ray crystallography has grown to produce over 10,000 structures per year, all of them being deposited into the Protein Data Bank (PDB), a database for the three-dimensional structural data of large biological molecules.
“Electron microscopy was developing in parallel, but it had a fairly slow start because the quality of electron microscopes was not very good,” he said. “Biological structures got destroyed by the electron beam.”
From the 1980s to the 1990s, improvements in electron microscopy such as higher energy electrons, better vacuums, and more stable stages led to much higher resolutions. Then, the advent of cryo-EM – which involved the flash-freezing of samples in non-crystalline ice – allowed for the preservation of the natural structure of biological specimens and reduced damage from the electron beam. Cryo-EM is responsible for over 2,000 PDB depositions made each year, many representing unstable or flexible assemblies whose structure cannot be determined any other way.
Ada Yonath, who received the 2009 Nobel Prize in Chemistry for studies of the structure and function of the ribosome, foresees a life-saving application for cryo-EM: the development of next-generation antibiotics.
“Antibiotics are fantastic, but there are problems with them,” she said. “The main problem is resistance, and we are trying now to fight against it.”
Resistance to antibiotics is one of the biggest public health challenges of our time. A growing number of infections – including pneumonia, tuberculosis, and gonorrhea – are becoming more difficult to treat as the antibiotics typically used against them are becoming less effective. The problem is accelerated by the misuse and overuse of antibiotics.
Yonath’s lecture on Thursday reviewed her past work uncovering the structure of a ribosomal subunit from bacteria with X-ray crystallography, as well as the close relationship between ribosomes and antibiotics.
“[Ribosomes] are universal, which means they function in a very similar way in all cells, regardless of the source,” said Yonath. “It can be bacteria, it can be flower, it can be cockroach, it can be human – they do the same thing, the decoding and the production of the protein in the same way.”
Because of the fundamental role played by ribosomes, many antibiotics target them. Over 40 percent of clinically useful antibiotics target protein biosynthesis, mostly by paralyzing the ribosome. Yonath believes that cryo-EM can identify specific structural features of ribosomes which are unique for each pathogenic bacteria. With this information, novel, targeted antibiotics can be designed.
Lastly, another set of Agora Talks on Wednesday covered the area of cell biology, or the study of the structure, function, and behavior of cells. Martin Chalfie, who received the 2008 Nobel Prize in Chemistry for the discovery and development of green fluorescent protein, first discussed the many lingering questions that still remain unanswered in cell biology. And he feels that there is no better time to investigate these questions than today.
“For other fields – maybe in theater, music – people talk about the golden age, or the real peak of understanding and accomplishments,” said Chalfie. “I feel that right now is the golden age of science. We always are at the peak of what we can do, and of course, it always gets better.”
So many aspects of cell biology are ripe for new discoveries, such as specialized cells and evolution, cells in distress and disease, cell signaling and metabolism, and many others. He is highly optimistic about the future of the field, given that so many advanced tools now exist to study the function and interaction of cells.
“New techniques like CRISPR and super-resolution microscopy will allows scientists to go back to the fundamental questions and look at them deeper, with greater resolution and greater understanding,” he said.
Randy Schekman took a different approach with his Agora Talk, specifically tailoring his wise words of advice to the young scientists in the audience aiming to do research in cell biology. He spoke about how to plan a future career in cell biology, as well as how to best represent your work in the form of publications. Students will often ask him what to study, since it seems like everything in cell biology has already been discovered.
“One of the downsides of being a Nobel Laureate is somehow believe that you have a vision into the future as a result of that,” he said. “Of course, that couldn’t be farther from the truth.”
Schekman emphasized that students need to challenge themselves to pursue new avenues in research. He finds that young scientists tend to stay in their lane, where they feel most comfortable, but that path often doesn’t lead to groundbreaking work.
“The only way that you will succeed at a high level is if you challenge yourself by identifying things that have not been done, not simply improving on things that have already been done,” he said. “It is your opportunity, going forward, to make a difference.”