Cambridge Healthtech Institute’s Ann Nguyen recently interviewed Tsafi Danieli, Ph.D. and Mario Lebendiker, Ph.D., Heads of the Protein Expression Facility and Protein Purification Facility, respectively, at Wolfson Centre for Applied Structural Biology, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem. They will instruct their upcoming training seminar on Basic Technologies in a Protein Production Lab August 21-22 at The Bioprocessing Summit in Boston.

Translating Protein Expression Research
to Biotech Startup Success and Bioprocess Goals

How and why do good academic ideas in protein expression/production often get lost when translated to the running of a biotech startup?

TD: You may remember from the time when we were graduate students our notes were not always very tidy and organized. Sometimes things that should have been written were missing and things that were not completely relevant to research found their way into our notebooks (our favorite song for preparing RNA, the name of a great pub in the area, etc.). We seldom bothered writing catalogue and lot numbers, we borrowed cell lines, buffers and other reagents from our friends and neighbors, and when it was time to write down the manuscript some of us can clearly remember a moment of panic, when we had to go back and dig in our notes in search of misplaced pages and memory sticks with partial documentation, trying to assemble our data into a decent materials and methods section.

Translating research and procedures from an academic laboratory into a valid process development outline is often difficult. It is difficult for the startup company that suddenly realizes that despite the amazing therapeutic promise of the project, the process is not going to follow the documentation to the letter. It is also difficult to the academic researcher who needs to understand that what worked well for a Science or a Nature paper might not be sufficient for a startup company.

Our facilities are located in an academic institute. However, we serve both academic researchers and biotech companies and often our main task is to bridge the gap between the two worlds. As such, we motivate and train our students to adopt standard operating procedure (SOP) in their work, and help companies obtain the necessary criteria required for recombinant protein manufacturing.

ML: As we will learn during the seminar, each purification project must be adapted to start material and final needs. And needs at the academic level are far to be the same as in the industry level. According to our experience of many years working in this interface between academy and industry, we saw at the academic level a very superficial knowledge of different separation technologies, their potential application, their limitations, scalability and robustness.

Transfer of these type of protocols to a downstream level production may ultimately result in a non-ideal protocol in the best case, till a non-feasible protocol in most of the cases.

What factors most cause protein expression biotech startups to fail?

TD: Manufacturing a recombinant protein is a key factor in the success of the company. When problems relating to productivity, stability and reproducibility are evident at early stages of the process, it is important not to dismiss them and assume that this issue will be resolved at a later stage, by a CMO or a CRO. We believe that a company should put more resources at an early stage, in order to establish the procedures involved in the production of an active and soluble recombinant protein. Understanding the biology of the protein and how it behaves under different expression and purification conditions gives us better chance of overcoming these problems at the manufacturing stage. Too often we see companies that look at manufacturing as a simple way to resolve issues, calculating feasibility by guesstimated productivity, prioritizing other major issues while postponing the actual production optimization to a later stage. We often see that when the time comes and a company needs to deliver, the manufacturing process is the rate-limiting step, and in many cases, timing is everything.

How can understanding the technologies and processes behind successful protein production labs advance the work of bioprocess professionals?

TD: As in many fields, experience is a key factor in solving recombinant protein production problems. Procedures and solutions that took many years to develop are now available as a toolbox in experienced facilities, and can be utilized for a family of problems. Despite the fact that no two proteins are alike, an experienced production lab can deliver better and faster understanding of the problem, and supply more options to try to resolve the problem.

ML: There is not a unique way to purify a protein target. Each purification project must be adapted to start material and final needs. And the goal to success will depend on:

  • Selection or optimization of the best source or best expression conditions (this topic will be discussed by Tsafi during the seminar).
  • Selection and optimization of the most appropriate technique for each step.
  • A good understanding of the protein needs in terms buffer conditions, additives, storing conditions, etc. (last two items will be covered during Mario's talk).
  • Which type of chromatography resin provides the desired performance?
  • How can we select and link chromatography techniques?
  • Every technique offers a balance between resolution, capacity, speed and recovery. So, our seminar will show you that resins should be selected to meet the objectives of each purification step.

We will learn that the input for downstream protocol development will depend on one side on sample specific input, like required purity and quantity, the physical-chemical properties of target and main contaminants, and scouting runs and optimization. But on the other hand, it will depend on general input, based on economy, resources and purification strategy. And this strategy is highly dependent of separation technique knowledge. The understanding and coordination of all these inputs will allow the fastest route to get a product of required purity.

Instructor Biographies:

Tsafi_DanieliTsafi Danieli, Ph.D., Director, BioGiv Excubator & Head, Protein Expression Facility, Wolfson Centre for Applied Structural Biology, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem

Tsafi Danieli is the head of the Protein Expression Core Facility at the Wolfson Centre for Applied Structural Biology at the Hebrew University of Jerusalem, Israel. The core facility functions as a biotechnology research center for the development and implementation of novel technologies in recombinant DNA, molecular biology and protein production. It also operates as a training centre supporting individual research projects and conducting workshops and courses for scientists from academic institutes and from the Biomed & Biotech industry. Dr. Danieli is also the founder and director of “BioGiv”, a specialised university-based center for promoting and supporting entrepreneurs and inventors to translate ideas into new products and bring new technologies to market, while using the infrastructure of the Hebrew University in Jerusalem. Dr. Danieli holds a BSc in Biology and MSc in human genetics from Tel Aviv University, and a Ph.D. in molecular virology from the University of California, San Francisco Pharmacology Department, in collaboration with the Biochemistry Department at Tel Aviv University.

Mario_LebendikerMario Lebendiker, Ph.D., Head, Protein Purification Facility, Wolfson Centre for Applied Structural Biology, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem

Dr. Mario Lebendiker is in charge of the Protein Purification Facility at the Wolfson Centre for Applied Structural Biology, The Hebrew University of Jerusalem. He is actively involved in many collaborations for structural and biochemical studies within the Hebrew University, others Universities in Israel, as well as with biotech and pharmaceutical companies. Dr. Lebendiker received a Ph.D. in Biochemistry in 1982 from the Animal Virology Center (CEVAN), in Buenos Aires University, Argentina. Together with many other laboratories, he found the Protein Production and Purification Partnership in Europe (P4EU) network, a platform for the exchange of information, knowhow and materials between core facility labs in the field of protein expression and purification.

To learn more about Dr. Danieli and Dr. Lebendiker’s training seminar, visit

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