The Language of the Universe: A Journey Into Atomic Structures

Understanding atomic structures serves as a cornerstone of chemistry and biology. This knowledge is important from a practical perspective and has profound implications for various fields, from medicine and materials science to environmental studies and energy production. Unsurprisingly, the #LINO23 Agora Talk about the future of biotechnology was packed, and most of the talk focused on imaging.

A Cold Look at Atomic Structures

Understanding atomic structures is akin to understanding the language of the universe. It allows scientists to predict how substances will behave under different conditions, design new materials with desired properties, and manipulate chemical reactions to achieve specific outcomes. But to understand any language, you must first have an alphabet, and the alphabet of chemistry is not easy to decipher.

Nobel Laureates Johann Deisenhofer, Joachim Frank, Hartmut Michel and Kurt Wüthrich took the stage to talk about their perspectives and how they see the past, present, and future chemical imaging. Hartmut Michel started out with an overview of the field.

Understanding of atomic structure is the prerequisite for understanding mechanisms of action, drug design, and virtual screening, Michel explained. There are five main methods though which this is done, the Laureate continued:

• X-ray crystallography;
• nuclear magnetic resonance spectroscopy;
• electron crystallography;
• neutron crystallography;
• single particle electron cryomicroscopy.

Each of these methods comes with its own set of advantages and challenges. X-ray crystallography, for instance, is well established, but requires crystals, and an X-ray source that can be very expensive. Similarly, neutron crystallography requires huge crystals, and is even more expensive. With electron crystallography, you need 2D crystals, and it often causes strong radiation damage. But Michel specifically emphasised the latter method:

“We have the single particle electron cryomicroscopy which seems to revolutionise the field. If you have a look at the atomic structures deposited in the protein bank, it’s clear that it used to be all X-ray, but now, single particle electron cryomicroscopy is coming up,” Michel noted, adding that X-ray crystallography and cryomicroscopy dominate the newly added structures for this year.

In addition, if you look at the type of proteins deposited, it’s mainly complexes of drugs which are novel, not just single particles – which makes it all the more impactful.

Cryo-EM is particularly exciting because it doesn’t require the crystallisation of molecules and you only need tiny amounts of materials. In the method, samples are rapidly cooled at extreme temperatures to prevent the formation of ice crystals and preserve the natural shape of the samples. The samples are then visualised with an electron microscope.

“I think cryo-EM has been so successful because it enables the visualisation of molecules in their native states, and that is very different from those methods in which the molecules are essentially forced into a crystal arrangement,” adds Joachim Frank. “It is truly something unique.”

This is why cryo-EM has become a major method in structural biology, helping researchers visualise and the inner workings of various biological structures in a way that was not possible previously. Of course, the field of X-ray crystallography hasn’t been still, either.

Progress on All Fronts

Between 1970 and now, the intensity of X-rays one can generate with synchrotons or free electron lasers has increased by 11 orders of magnitude, notes Johann Deisenhofer.

“That generates a very, very different situation from what we lived through in the early 1980s, with months of data collection. Now, they are talking about seconds of data collection. It also changes the requirement that we have for crystals, because in the old days, we needed big crystals, so big that you can see them with your eyes, but nowadays, the talk is about 10 microns or so,” the Laureate told the audience.

These crystals will not be used for months, they will be used for just one single exposure of X-rays. They will then be destroyed during that exposure, but will have enough time to diffract the X-rays and give a diffraction pattern. “So essentially, you no longer need to wait for big crystals anymore,” Deisenhofer explains.

If you’ve been paying attention, there’s one method that wasn’t addressed: Nuclear Magnetic Resonance (NMR) spectroscopy. That’s because the Laureates saved the topic for Kurt Wüthrich, who developed NMR methods for studying biological macromolecules.

Wüthrich emphasised not just NMR and its applicability, but also the importance of using these methods in conjunction.

“We have now talked about different disciplines in structural biology. But what’s important is that we all work together,” the Laureate adds, recalling a paper published alongside Deisenhofer in 1976. “These were not unimportant papers at the time, and they combined crystallography results and NMR results, as well as results from molecular dynamics.”

After the brief technical introduction, Wüthrich also took a moment to allude to an earlier panel on diversity and referenced an article from a German newspaper on diversity in science. “I must say that as a male scientist, I have a feeling of discrimination when I’m here, in the climate that this meeting is being held.”

At the Q&A section, this led to a heated moment. But despite this moment being out of scope of the session, some good also came of this: it’s important that we have these conversations, and perhaps, it’s also useful to have them publicly.

Splicing and Dicing

Being able to visualise chemical structures also enables researchers to solve more complex and deeper questions. At the Next Gen Science Session on Genetics, Biochemistry and Cell Biology, Young Scientists presented an impressive array of research that they’re working on.

Johanna Gassler, from the Institute of Molecular Biotechnology of the Austrian Academy of Sciences, discussed the role of NFIB in pluripotency. While this receptor is known to play an important role in pluripotency, its role in earlier stages of embryonic development was not clear. Now, the work of Gassler and colleagues showed that NFIB is a pilot transcription factor and plays a big role in totipotency – the ability of an isolated cell to produce a healthy individual.

Cameron Griffiths, from University of Virginia, focused on a different problem: heart infections. Most viral heart infections resolve, but some can become chronic and potentially lead to heart failure. The challenge in studying these infections is that their symptoms are similar to other viral infections and heart biopsies are risky and infrequently performed. So Griffiths gathered data from RNA-seek, a comprehensive, open-source RNA-sequence pipeline. He found data from around 1,000 patients and found that the presence of a virus in the heart might not result in a uniform response but could lead to different adaptations in different patients. Using a clustering algorithm, they identified three distinct clusters among the patient hearts with viruses, and this clustered data could hold information about upcoming heart failure.

Yu-Chi Sun, from New York University, looked at ion channels, pore-forming proteins that help control the small voltage gradient across the membrane of all living cells. Much of physiology is about maintaining homeostasis through negative feedback regulation, similar to a thermostat controlling temperature, explains Sun. Something similar is happening to ion channels, but how exactly this negative feedback happens is not well understood. To study this, Sun and her colleagues analysed changes in ion channel splicing under varying activity levels. They found widespread splicing changes in ion channels involving physiology, and Sun mentioned that this is possible thanks to BARseq, a method she worked on developing that can detect short RNA sequences which makes it ideal for splice variants. In the future, she intends to investigate how these splicing variations are related to mental health conditions.

These are just some of the groundbreaking work presented by Young Scientists. No doubt, science is developing at an accelerated pace, thanks in part to tools (like imaging tools), and in part, to international collaboration. Both the Agora Talk and the Next Gen presentations offered a fascinating deep dive into the world of future biotechnology. Undoubtedly, we’re bound to see even more breakthroughs.