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Hierarchical Editing Language for Macromolecules (HELM) Project: A Success Story That Opened Doors to Future Collaboration
"The initiative provided me with a fascinating education in areas ranging from collaboration and diplomacy to marketing and PR. From a career perspective, it was a very positive experience." —HELM Project founder Sergio Rotstein, PhD, Senior Director, Pfizer Digital, and Pistoia Alliance Board Member
Boston, US, June 30, 2022: The Pistoia Alliance HELM project set out to provide a computational representation language for the complex biomolecule modalities that are increasingly prevalent across the biopharmaceutical industry. HELM stands for Hierarchical Editing Language for Macromolecules. Scientists at Pfizer first developed the technology 13 years ago, and subsequently worked with the Pistoia Alliance to open source it, enabling the broader industry to benefit from the work. The Alliance was the first membership organization in the life sciences to provide the legal framework that made it possible for competing companies to collaborate on this initiative in a pre-competitive fashion.
The project is a true success story that has helped put the Pistoia Alliance on the map. Companies such as Bristol Myers Squibb, GSK, ChemAxon, and Roche (among many others) contributed funds and staff to the project, while Pfizer donated the technology and led the ground-breaking collaboration. HELM paved the way for many more successful Pistoia Alliance projects, lowering the barriers to innovation and transforming life science and healthcare R&D.
The HELM project – one of the most successful initiatives of the Pistoia Alliance – began as a detective story: the search for a solution to a common and frustrating problem many pharma scientists faced more than a decade ago.
“HELM came to be in 2008 when my team and I were part of a group at Pfizer – the Oligonucleotide Therapeutics Unit (OTU) – that focused on different therapeutic applications of various forms of RNA,” says Sergio Rotstein, Senior Director, Pfizer Digital, and Pistoia Alliance Board Member. “With all the recent successful applications of mRNA in the realm of vaccines, you could say that the OTU was a bit ahead of its time.”
“Our scientists routinely made oligonucleotides that strayed from the building blocks normally found in nature, incorporating chemical modifications and attachments of various kinds. At Pfizer, as it is with every other biopharma company, each molecule needs to be assigned a unique ‘Pfizer Number” which acts very much like a social security number that is associated with each molecule throughout its lifecycle”, Rotstein explains. “In order to determine the uniqueness of each molecule, an exact computational representation is needed.”
There exist several robust computational tools that can work with sequence-based molecules like DNA, RNA, or proteins. Similarly, there exist several tools that enable the atom-based representation of small molecules. “With our unnatural oligonucleotides, however, we found ourselves stuck in the middle: They are far too large to depict on an atom-by-atom basis like small molecules, while their modifications and chemical attachments render them unrepresentable by sequence-based tools,” added Rotstein.
Polymer chemist and software engineer Tianhong Zhang, Director, Pfizer Digital, is credited with inventing this innovative technology. “When we started to focus on biologics,” Zhang recalls, “the issue of assigning a compound identifier to the oligonucleotides became a real challenge in the lab.”
“We needed a tool that allowed us to represent these oligonucleotides precisely,” Zhang said. “We looked around and realized this was a true technology gap in the industry. Absent an existing solution, we had no choice but to create our own.”
Zhang compares creating these molecules to building with Legos. “We needed to define what each of the building blocks was, and how they could be connected, much like vocabularies and grammar rules.”
This innovative system proved to work very well, so Rotstein and his Pfizer team decided to publish it in the peer-reviewed Journal of Chemical Information and Modeling. At the time, they had no idea how profoundly HELM would influence their entire industry in the years to come. Once it sparked the interest of Pistoia Alliance members that were struggling with similar challenges, the collaboration was launched, and the rest is history…
Looking back, Zhang can now see that HELM, in the end, allowed pharma researchers to essentially speak the same language. Before HELM, describing these unusual molecules was a true challenge, creating a barrier within the overall drug-discovery process.
“The language is elegant as it provides a hierarchy, from monomer to polymer to more complex structures, and you can fully identify these constructs,” Zhang explains. “It’s a very flexible notation that can evolve and easily be extended to other biopolymer types.”
When approached by the Pistoia Alliance, Rotstein, Zhang, and the Pfizer team made what at the time was an unusual decision: to share their proprietary and versatile HELM system with other industry scientists.
“It was an easy decision for us to open source our work and disseminate the technology,” Zhang says. “We knew from the start that the problem we had solved was not just a Pfizer problem but rather a problem faced by every company in the biologics space.”
Since the Pistoia Alliance offers member companies a unique legal framework to easily and rapidly spin up new pre-competitive collaborations, Pfizer felt comfortable using this avenue to share the HELM technology. “In the end,” Rotstein recalls, “doors were opened very quickly for all interested companies to join forces.”
A team of around 45 experts from across the industry was quickly formed combined with resources funded through member company contributions. “The enthusiasm was very exciting,” said Claire Bellamy, Pistoia Alliance HELM project manager. “A range of skills were made available, from technical development to marketing specialists. Everyone wanted to work together to get HELM established. The Pistoia Alliance model with a dedicated, experienced project manager enabled that to happen.”
“In addition to mitigating the need for the industry to reinvent the wheel for biomolecule representation, Pfizer benefitted from the release of HELM by influencing the broad adoption of a standard that we were very familiar with, and well-established in our internal infrastructure,” Rotstein said.
As Rotstein and his team presented the HELM project at various conferences and speaking engagements, interest in joining the collaboration grew. “Suddenly, companies were all in,” he says. “They were not only adopting and using HELM, but in many cases enhancing it.”
A perfect example of this were the scientists at Roche, a key contributor to the initiative.
“The underlying HELM data model has been used as a blueprint to design Roche’s registration system for biologics,” said Stefan Klostermann, Expert Scientist, Roche Innovation Center Munich.
While the HELM editor made it both feasible and easy to draw a great variety of complex biomolecules, it was still a bit impractical to try to use it for the routine representation of larger entities such as full-length antibodies.
“To overcome this limitation we collaborated with Quattro / Martinsried on the development of HELM Antibody Editor (HAbE). HAbE automatically assembles and annotates antibodies from their raw sequences. Based on user-configurable rules, even novel complex designs are supported. The antibodies are nicely depicted using standardized building blocks based on the functional domains of the proteins, “ said Klostermann.
Rotstein added: “In addition to adopting the technology, Roche scientists went on to create a very robust antibody registration and analysis system powered by HELM, which they then contributed to the open-source, making it broadly available to the public. By immediately giving back they truly embodied the spirit of the Pistoia Alliance. It’s a beautiful example of how we can all work together to advance science.”
In recognition of this unique cross-company collaboration and significant contribution to the industry, the Pistoia Alliance HELM Project team was honored with a coveted Best Practice Award by Bio-IT World. “The team had worked hard to develop opensource tools and materials: everything our growing adopter community needed,” said Bellamy “So we were very pleased to see the importance of HELM recognized in this way”.
The overall benefit to the pharma industry and ultimately the global patient population is the increased efficiency in bringing new drugs to the market. The pressing need for this type of cross-company cooperation and speed became even more evident when the COVID-19 pandemic hit in 2020.
“When you describe a small molecule or biologic, you want to describe it in a way that doesn’t need any translation,” Zhang explains. “With the HELM format, anyone can understand it. There’s no ambiguity and therefore no miscommunication.”
In the big picture, collaborative projects like HELM allow life sciences researchers to move faster. In other words, when scientists can easily speak the same language and communicate more effectively, it gives them more time to focus on innovation.
That, in the end, is the Pistoia Alliance’s mission: collaborate to innovate. “I feel that this is the true measure of our success: people adopting and using HELM across all of our companies,” Rotstein says.
HELM was one of the first Pistoia Alliance projects that traveled a successful journey from a proprietary solution to a self-sustaining standard, adopted broadly across the industry and accepted by regulatory agencies such as the FDA.
More recently, the long-term maintenance of the standard was transitioned to a dedicated workstream within the International Union of Pure and Applied Chemistry (IUPAC), the universally recognized authority on chemical nomenclature and terminology. “HELM now sits alongside other IUPAC standards like InChI,” said Bellamy. “It is in excellent hands for the long-term.”
Positioning HELM to transition out of the Pistoia Alliance and remain sustainable in the long term is very much in keeping with the Alliance’s principles, as it now enables greater focus on the next set of innovative ideas and projects that will benefit the overall biopharmaceutical ecosystem.
HELM now is available to the pharma and life science industry at www.openHELM.org, and it will be continually refined and updated as new developments unfold. It is the de-facto industry standard for biomolecular representation and an ISO standard additionally leveraged by two important public data repositories (PubChem and ChEMBL) for the representation of peptides.
The original scientists on the HELM team remain close, as collegial collaborators and true friends. With pride, they can clearly see the benefits of being involved in this highly successful collaboration, on both a personal and member company level.
“Personally, I am very thankful for being part of Pistoia’s HELM ecosystem, and to all the colleagues from across industry and academia. I mostly enjoyed the great team spirit and appreciated the diverse thoughts and lively discussions, especially while developing the HELM 2.0 notation. I can only recommend anyone to gain similar experiences by reaching out into Pistoia’s cross-company community of their interest,” said Klostermann.
“When we come together and agree upon our systems, that is a much more efficient process for getting what we need,” says Dana Vanderwall, PhD, Executive Director of Enterprise Informatics, Schrödinger. “Pistoia Alliance is unique in the way it brings people together – both the vendors and the pharma companies together – to create new things like this.” Vanderwall, who is one of the original HELM project team members, now leads the IUPAC committee that will maintain HELM as a public domain standard into the future.
“Sharing resources and collaborating to solve common problems in the industry creates room to build common tools and standards”, Vanderwall says. That, in turn, creates a diversity of experience, background and perspectives.
“Besides merely pooling resources, this kind of collaboration leads to better solutions,” Vanderwall adds. “Every Pistoia Alliance project I’ve participated in has included people that are more experienced and knowledgeable than me, so I have seen great benefits, both personally and for my career.”
Rotstein echoes this positive feeling about his years serving as head of the HELM project, and as a longtime Pistoia Alliance Board member.
“The initiative provided me with a fascinating education in areas ranging from collaboration and diplomacy to marketing and PR.” Rotstein says. “From a career perspective, it was a very positive experience.”
If you are interested in finding out more about this project, please contact ProjectInquiries@PistoiaAlliance.org.
About the Pistoia Alliance
The Pistoia Alliance is a global, not-for-profit members’ organization made up of life science companies, technology and service providers, publishers, and academic groups working to lower barriers to innovation in life science and healthcare R&D. It was conceived in 2007 and incorporated in 2009 by representatives of AstraZeneca, GSK, Novartis, and Pfizer who met at a conference in Pistoia, Italy. Its projects transform R&D through pre-competitive collaboration. It overcomes common R&D obstacles by identifying the root causes, developing standards and best practices, sharing pre-competitive data and knowledge, and implementing technology pilots. There are currently over 200 member companies; members collaborate on projects that generate significant value for the worldwide life sciences R&D community, using The Pistoia Alliance’s proven framework for open innovation.
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