Personalized Proteins

A quantum leap in the control of proteins’ function is changing the rules in the worlds of pharmaceuticals, vaccines, and enzymes used in the industry, enabling to quickly improve the stability and activity of any protein. This technological breakthrough offers genuine hope for millions worldwide

Prof. Sarel Fleishman and his team at the Weizmann Institute’s Department of Biomolecular Sciences lab who work on the planning of proteins are leading a real revolution in the field of protein engineering. The results are yielding a new generation of industrial enzymes, pharmaceuticals, and vaccines, and developing new possibilities for contending with the environmental crisis.

A Molecular Structure at the Click of a Button

Protein sciences have been researched for almost a century, and in the past 40 years, laboratory studies have been conducted to physically analyze proteins via mutations that influence the proteins’ structure, stability, and function. However, despite all the efforts, the significant molecular complexity of proteins continues to pose a challenge for scientists. A characteristic example of this complexity is the fact that many of the mutations which increase the protein’s activity, significantly impair its stability, or vice-versa. Consequently, the enhancement of a single protein requires an intensive process of trial and error to find satisfactory solutions in numerous parameters.

This novel approach integrates several scientific paradigms, including bio-informatic, physical-atomistic calculations, and AI tools to predict proteins’ structure. “We create a physical-atomic model of the protein that is, in fact, a large complex molecule”, Prof Fleishman explains. “Using this model, we calculate the influence of each mutation and, even combinations of mutations, on the structure and function of the protein. Due to the considerable complexity of producing the protein in a live cell, physical calculations alone do not accurately predict the mutations’ influence and we have therefore combined atomistic calculations and bioinformatic-evolutional calculations. We examine all the mutations in natural proteins with a similar function that have been created over hundreds of millions of years of evolution and construct a statistical model that prioritizes mutations according to their frequency. The integration of atomistic and evolutionary tools enables solvingproblems at the forefront of protein engineering that impeded other paradigmsand expedites and enhances the results of protein optimization processes.

The Bio-convergence based models enable, with a click, to transform any sequence of amino acids into the molecular structure of a protein, so that it is even possible to calculate the structure of antibodies with a satisfactory level of precision. These antibodies are extremely complex proteins which the human immune system produces to combat infection. Such a feat was impossible even only a few years ago.

Instead of investing years of trial and error in searching for combinations of mutations, the new methods mean that it is possible today to simultaneously calculate an optimal combination of dozens of mutations, usually without compromising between desired qualities such as activity and stability.

Innovative Malaria Vaccine

One of the lab’s significant successes resulting from the new technologies is the enhancement of a new vaccine against malaria, a disease that claims the lives of half a million people a year in Africa, most of them children. The calculative tools developed have facilitated more stable versions that can be integrated into an effective low-cost vaccination platform. The calculation process takes only several hours, and its high precision means that a characterization of the best protein can be achieved in just a few weeks. This capability is a game changer in the field of vaccines, especially for diseases that affect underdeveloped areas.

Another successful development achieved by the combination of different disciplines is an enzyme that breaks down a diverse range of nerve gases four-thousand-times more efficiently than the previous version, using calculations that take only a few hours.  

One of the lab’s important goals is to enable all researchers to have access to calculative tools. “The immense diversity of problems in the field of protein engineering is way beyond the capacity of a single laboratory”, Prof. Fleishman explains, “and it is therefore critical to make the tools accessible for academics with different fields of expertise. We invest extensive effort in making the tools accessible via the websites of the Weizmann Institute where researchers from all over the world can submit proteins with details of their requirements at the click of a button. Behind the scenes, the Institute’s high-performance computer servers run the lab’s algorithms according to the researchers’ specifications and, several hours later, send back sequences to be tested. Thus far, over one hundred articles have been published and more than fifty patents have been submitted by academics worldwide – all based on our calculations”.

Pharmaceuticals from Personalized Proteins and Enhanced Agricultural Crops

The technologies developed in the lab have already generated promising startups in Israel that demonstrate the huge potential of computational research in the field of proteins. The first company, ‘Scala Biodesign’, was founded by two of the lab’s graduates – Dr. Adi Goldenzweig and Dr. Ravit Netzer – who also developed some of the lab’s methods. The company focuses on designing personalized proteins to significantly accelerate the development process of pharmaceuticals and to lead innovative solutions in the chemical and pharmaceutical industries.

The second company, ‘Infinite Acres’, works on enhancing agricultural crops. According to Prof. Fleishman, “the studies are also gaining great interest among giant companies in the fields of pharma and chemistry because the technologies developed in the lab enable these companies to work faster and on a wider scale than in the past”. Nevertheless, bridging the gap between the lab and the “real world” remains a huge challenge that poses many problems.

This is where the Innovation Authority comes into the picture and plays a critical role in this process. The Authority assists in establishing contacts and collaborations that allow to translate the scientific findings into practical solutions. “The Innovation Authority maintains a long-term view and preserves Israeli leadership in these fields, despite the daily challenges”, Prof. Fleishman notes. The Innovation Authority’s support enables the lab and the startups to compete in the global arena, despite their physical distance from the large development centers. “Thanks to this support, we meet the industry after gaining a significant track record and, therefore, interest in our developments”.

Giant Libraries of Billions of Synthetic Antibodies

Prof. Fleishman believes that it will soon be possible to design proteins for almost any biomolecular purpose. In practice, we will have the ability to change how we treat diseases, produce food, and even contend with environmental challenges.

Until then, and with the assistance of new funding from the EU, the lab is already working on the next generation of technologies for discovering medicinal antibodies – a new method for planning giant libraries of billions of synthetic antibodies that are pre-calculated to be stable and active in order to minimize the effort required in optimizing antibodies for medicinal use. The algorithm will change how antibody-based medicines are developed, will lower the cost, and accelerate the development of life-saving drugs.

The aging population and the spread of infectious diseases are igniting our tremendous interest in finding effective, low-cost, and swift methods to develop vaccines. Together with a combination of advanced science, breakthrough technology, and institutional support, Israel is leading the way to a healthier future for us all.