The future of Cryo-EM in Pharma [event highlights]

“The trend with Cryo-EM in pharma is moving towards: More structures. More targets. More modalities.”
— Mazdak Radjainia, Senior Stuff Scientists, Thermo Fisher Scientific

Cryogenic electron microscopy (Cryo-EM) is one of the fastest-growing structural determination techniques in structural biology. In our article 5 fast-growing techniques in structural biology, we summarized the general advantages and applications of this technique, but how does this really look like in practice?

Can Cryo-EM really drive rational drug design and the discovery of more complex and safer drugs in the future? The answer is – yes, but we are not quite there yet, even if rapidly getting closer!

To elaborate on this, at our third Discngine Labs event we invited domain experts from pharma:

  • Chiara Rapisarda, Group Leader in Cryo-EM , Sanofi

  • Gerhard Fischer, Principal Scientist, Lab-Head Cryo-EM, Boehringer Ingelheim

  • Giovanna Scapin, Chief Scientific Officer, NanoImaging Services (ex Merck)

  • Mazdak Radjainia, Sr. Staff Scientist, Thermo Fisher Scientific

to share how Cryo-EM is making a difference in their work, their experiences from various drug discovery projects and what they expect from the technique in the future. The discussion lasted for more than one hour and was led by Gabriella Jonasson, 3decision product owner, that managed to incorporate the curiosities of the audience into the discussion and create a very friendly atmosphere.

In this article, you will find some of the key takeaways from the event. For the full discussion and details, please watch the replay.

 
 

Key takeaways

The event started with good news from one of the Cryo-EM microscope vendors – Thermo Fisher – about the improvement of microscope speed power (currently 10x faster than 3 years ago) and data acquisition software. Those technical advancements enable scientists to maximize productivity through higher structure throughput and reduced time-to-structure. One example comes from joint industry and academia efforts on developing SARS-CoV-2 antibodies therapy. In a single microscope session, scientists produced 12 different SARS-COV-2 spike-Fab complexes. (You can find more examples on their dedicated website page).


What is the current added value of Cryo-EM?

The biggest impact of cryo-EM is mainly, but not only, in the early stages of drug discovery, such as target selection and hit finding. Cryo-EM enables access to many hard-to-analyze protein complexes. One recent example, among others, is the structural determination of the inactive states of GPCRs, which otherwise wouldn’t be possible to obtain.

Picture from the Discngine Labs event “The Future of Cryo-EM in Pharma”.

The crucial advantage of Cryo-EM is that it allows the view of the entire protein complexes, rather than just one domain. This is very important for having an idea of the mechanism of action of future potential drugs. The technique is therefore a very good fit for the studies of new modalities (e.g. degraders, RNA, gene, and cell therapies). With the full picture and in-depth understanding of complex disease mechanisms, you can optimize your design strategy and proceed more efficiently and precisely.

Moreover, Cryo-EM is also useful in later, more advanced drug discovery stages (confirmation of the binding mode, for example) and even outside the R&D development.



What is still missing?

Sample preparation is a limiting step for cryo-EM analysis in many different ways. Then, the throughput of data analysis, especially for bigger targets, can be very long. For example, the structure of more flexible complexes can take up to 1-2 months to resolve.
There are also fewer tools for Cryo-EM than for X-Ray to determine whether the data are true or not. If the resolution of structures is lower, then the fitting of small molecules is not 100% reliable (however it is important to know that the resolution of resolved Cryo-EM maps coming directly from the experiment is higher quality than those coming from X-Ray).

Bottlenecks are also found in computing power and especially in the storage capacity of the big cryoEM data – something often underestimated.
Then, what happens with all of this if you can’t afford your own microscope?

“Combined image storage and data processing are about 1.5 terabyte a day per microscope in our facility”
— Giovanna Scapin, Nanoimaging Services

Where are we going with Cryo-EM?

We are just getting started with Cryo-EM in the industry, it might be 10 years behind the X-Ray, but it is probably developing faster because we can reuse a lot of knowledge from existing techniques.

The Cryo-EM is going in two main directions from a technical point of view:

1. More automation: The goal is to accelerate the parts in which human intervention is minimal and automate the determination of the structure so that scientists can spend more time looking at the structure and ideating

2. More speed: Make the process faster



The rest of the discussion where panelists mention the final structure storage and sharing, the optimization with Alpha Fold structures, challenging modalities, education, cost etc. you can find in the replay by clicking the button below.