Sukhanya Jayachandra, Ph.D., Senior Research Investigator and head of the Cellular Resource Group, Lead Discovery Profiling Compound Management at Bristol-Myers Squibb (BMS), talks to contributing editor Tanuja Koppal, Ph.D., about her cell culture core facility and how it has been impacted by the adoption of automated technologies. She offers advice on why, where, how and which labs should go about automating their cell culture processes and what they stand to gain and lose, in turn.
Q: How did automation get implemented & adopted at BMS?
A: In the late 1990s, the trend in the pharmaceutical industry was to do a lot of high-throughput screening. BMS felt that the net had not been cast wide enough to capture compounds and look at all the small molecule entities for any given drug target. Enormous resources were put in place to automate compound screening and the infrastructure around screening, enabling automated high-throughput screening. If screening was going to be a continuous five- or seven-day operation, and continue for many weeks, it had to be consistent day in and day out. So, in the beginning, automation was required for consistent delivery of the cell lines, reagents and compounds for screening.
Q: Did you think about what aspects needed to be automated and to what extent?
A: Initially we looked to see what could be automated and where the greatest gains could be had. Clearly, automation could be applied to compound delivery; but from a cell culture point of view, could we take some of the scale-up processes and automate them? There were companies in Europe doing so at that time, so we got the first machines to automate one cell line and scaled that up. That was the first version of cell culture automation. In 2000, there was a consortium established with five big pharma companies working with a vendor, The Automation Partnership (TAP), to develop the next generation of mammalian cell culture automation. The designs were well thought out with specifications on what they wanted machines to do. That prompted the second generation of automation and the creation of the SelecT system and the Compact SelecT, which are now the industry standard.
Q: Were there some tasks that could not be automated and some that were more amenable to automation?
A: Almost all aspects of manual cell culture can be and have been automated, except decision-making capability and the thawing of cell lines. Visualization could not be automated, as that requires human intervention to examine cells to determine if they are healthy and of good quality. All the rest of the processes, including the routine care, culture and maintenance of the cell lines and the plating of cells into assay plates, have been automated. Another task that the instrument could not do was retrieve a vial from cold storage (-140°C) and thaw it, because there were neither thaw stations nor an online centrifuge within the system.
Q: How do you go about calculating the return on investment for something like automation?
A: One of these machines, like the SelectT, can do the work of at least four full-time employees (FTEs). Of course, in the first two years there was a learning curve for some of the engineering challenges, but over the years we have really optimized the system. Also it’s a 24/7 operation, which we would clearly not be able to sustain with people. The biggest advantage of a 24/7 operation is the minimal downtime. In the past, Monday was a down day for cell based screening, as cells had to be plated overnight into assay plates. But now the machine is plating and getting assay plates ready on a Sunday and by Monday the cells are ready to go. The same holds true if there is bad weather or if there is a shutdown for some reason. Since these systems are all on backup power, even if people cannot get to the site, the machine runs and there is an uninterrupted workflow.
Q: Are you seeing any other kinds of economic benefits in terms of cost savings from reagents or the cells?
A: Since the same media conditions can be applied to multiple cell lines, you can definitely increase the throughput. As cell lines are processed sequentially, there is no crosscontamination between cell lines. So, over time, you use less material because the waste from manual errors is reduced. However, the machine is not faster than a human. The machine probably takes a little bit longer to process a flask, but it does it more consistently and accurately. Scientists are needed to understand the biology, but once the machine is set up and working, they are resourced to perform other scientific experiments that do not require repetitive tasks, which also cause a lot of ergonomic problems. That is the real benefit.
Q: Have you run into any major snags with equipment that is fully automated?
A: There have been occasional engineering issues, but most of the issues that we run into are biology-related. For instance, certain cell types cannot be automated and some cell types cannot go through the rigors of mechanical handling. We have been able to automate some primary cells but not all. So it all depends on the cell type.
Q: Did you plan the automation around the lab space that you had or did you have to redesign the labs?
A: Luckily for us, when high-throughput screening was initiated at BMS, they built an entirely new wing to the building with certain engineering caveats. With the engineering controls put in place and the right kind of air handling, we have not had major contamination issues over the last ten years.
Q: What kind of personnel training is needed for using automated equipment?
A: There are the super-users who go through extensive weeklong training, and they then train other users. So we do have a super-user who kind of maintains the system and collaborates with the engineering team, in case certain mechanical things go wrong. He or she coordinates all the basic operations and is trained in first-level error recovery.
Q: What would your advice be to those lab managers looking to automate their laboratory protocols?
A: With automation, the key benefit is consistency. However, the biggest challenge is the cost for the capital investment. So the questions are, do you run an operation that needs a high-throughput supply of one particular cell line or multiple cell lines, and what does your budget allow you to do? The investment is not just limited to buying the machine and having a biologist run it. You also need the engineering support to help you back it up. A lot of these systems use special flask types and pipettes that are custom-made for that particular equipment. So there is a certain operating cost associated with these machines, including the service contracts. We’re talking about $200,000 a year going forward on an ongoing basis. If the budget permits, automation is a fantastic thing to have in place, because it helps remove the dayto- day drudgery associated with doing a lot of cell culture. With automation, you can reposition your scientists to do actual experiments, rather than have them sit in a hood, culturing and passaging cells. Culturing cells requires its own skill set but it also involves very routine tasks. If you can afford not to do those tasks, you shouldn’t have to do them.