At some point, cells will be the product. Regenerative medicine, the ability to repopulate unhealthy organs and tissues with
healthy cells, is getting closer to the clinic. Mason detects a major change in interest among venture capital groups, who,
he says, "now see some real commercial pressure." For their part, cell-therapy companies are also focusing more on commercializing
the technology as opposed to previous years, when they were mostly researching it. Several biotech companies are either preparing
to enter or are already in clinical trials with cell-based therapies. Geron (Menlo Park, CA), a biotechnology company focusing
on regenerative medicine, is preparing to enter its first clinical trials with a GRNOPC1, a glial-cell product that promotes
spinal-chord repair. And other cell-therapies in the service of regenerative medicine are not far behind.
In preparation for the day cell therapy comes into commercial fruition, process engineers, cell biologists, and equipment
manufacturers are working out the details of large-scale cell culturing to produce cells as end products. One thing they do
know, says Mason, is that for regenerative medicine, "the process is the product. You have to take care of the cell all the
way through the process." In other words, culturing cells on a large scale requires a kinder, gentler process than does culturing
them to produce protein products. And there's the rub.
By it's very nature, industrial-scale manufacturing requires batch handling, bulk movement, and bulk treatment, which is not
necessarily known for its gentleness. And cells, especially the primary and stem cells used in cell therapy, are fragile and
require kid-glove treatment.
Until recently, that kind of treatment could be maintained only when a technician performed all of the harvesting, seeding,
feeding, waste removal, and packaging manually. And that was fine, even for cell therapy. In its initial iteration, cell therapy
involved a patient's donation to himself of his own cells—a process called autologous cell transplant. Healthy white blood
cells, for example, are often removed from patients undergoing high-dose anticancer chemotherapy, which kills all remaining
white blood cells in the bone marrow—including the cancer cells. While the healthy cells remain outside the body, they are
cultured to increase their numbers to a point where they can repopulate the patient's bone marrow once the course of chemotherapy
has been completed. Other organs may also be regenerated by similar autologous transplants. Autodonation of cells sidesteps
the problem of rejection that comes in transplanting cells from one person into another.
Viewed as a manufacturing problem, however, the batch size of an autologous cell dose is very small. Which does not mean the
process cannot be automated. If transplants are being prepared for just one patient, there's little motivation to increase
production scales. But imagine a transplant facility, in which many different cell types harvested from many different patients
are being cultured for reimplantation at the same time. In that case, the challenge for process engineers is the parallel
growth and cultivation of many different cell lines in a sterile, automated setting without contaminating one cell line with
the next. Economies of scale can be realized in this setting by multiplexing the cultivation of cell lines.
The real opportunity to develop a large-scale process comes as researchers consider the possibility of allogeneic transplants.
Here the idea is that it may be possible to create some kind of "universal" cell that can safely be transplanted in many recipients
without concern for rejection. In some scenarios, the cells may be modified as to not express markers that stimulate rejection
by the immune system. In others, cells may be typed in a system similar to blood typing, which allows certain classes of cells
to be transplanted from one group to another without the requirement of an exact tissue match. However it's achieved, the
allogeneic model will require large batches of cells to be cultured for use in cell therapy. And here's where the issues become
As researchers work to invent an industrial process to "manufacture" cells on a large scale, they draw their experience and
knowledge—as well as their assumptions—from two sources. The first is the manual process by which cells have been cultured
for a century. And the second comes from their experience with the bulk processing of cells for bioprocessing. What is emerging
is a process that Mason likes to call "regenerative medicine 1.0," or "RegenMed 1.0," for short.
From manual cell culture, investigators know that the vast majority of cells grow best when they are attached to a solid surface.
They also know that the health of the cells depends on having the proper nutrients in the culture medium, proper gas exchange,
and the proper density. If too many cells crowd the plate, some may be induced to stop dividing and enter a differentiation
stage where they eventually take on the characteristics of the mature cell type. This would be enormously counterproductive,
because cell therapy almost always involves some kind of immature cell type to allow the recipient tissue to continue to regenerate
itself. Cell culture also requires someone to remove spent medium, which is devoid of nutrients and replete with the waste
products of cellular metabolism. It requires someone to recognize whether cells are viable and when the density dictates that
cultures be divided onto new culture plates—a process akin to repotting plants to give them more growing room. Of course,
someone also has to remove the cells in the end, package them, transport them, and then implant them in the patient. All of
these processes have to be automated.
From bioprocessing, scientists already have gained a lot of general knowledge. They know, for example, how to work in a closed
system; they know quality assessment and validation techniques. "There exists a framework in which to do process development
that wasn't there when bioprocessing was developed," says Jon Rowley, director for cell therapy research and development at
Lonza (Walkersville, MD). "A lot of the equipment has been developed, as well," says Rowley. "Sterile connect technology,
for example. We don't have to develop these technologies now from the ground up."
The immediate challenge as Rowley sees it is that "many cells in the cell-therapy world are adherent and don't grow in traditional
[for bioprocessing purposes] suspension systems, which means that that part of the [bio]process is not transferable." The
next challenge is the need to build an adhesion system that limits batch size. A state-of-the-art vessel for bioprocessing
can hold as much as 20,000 L of cell suspension. "There is no 20,000 L culture dish for adherent cells," he says. And then
he notes that with current technology, the highest adherent batch size is 6 L, "a far cry from 20,000," Rowley adds.