By Peter Ephross
The problem Bernhard Palsson faced was how to create outside the body the conditions that occur naturally inside it. Resting on his promising solution is the well-being not only of the 15,000 to 20,000 patients who receive bone marrow transplants each year, but also of thousands of patients with other cellular and genetic disorders.
Bone marrow produces all the circulating blood cells. Transplantation of bone marrow, one of the earliest forms of cellular therapy, is used in treating a variety of cancers ranging from testicular and ovarian to lymphoma and leukemia. To protect the marrow from being damaged by chemotherapy or radiation therapies, it is removed from patients before treatment, preserved during therapy and then returned to re-establish bone marrow function.
Unfortunately, bone marrow transplants are both very expensive, costing from $80,000 to $150,000, and very uncomfortable. But if chemical engineer Bernhard Palsson has his way, these transplants will soon become easier and cheaper. Along with hematologist Steven Emerson, his former U-M colleague, Palsson developed cell culture procedures that allow for the growth of human marrow outside the body in devices called "bioreactors" that Palsson designed, built and tested in his laboratory on North Campus.
Palsson's bioreactors automated the previously tedious and labor-intensive regimen required to process the cell culture. The performance of these devices was so promising that in 1989, with the University's help, Palsson, Emerson and Michael Clarke, a U-M molecular hematologist, established in Ann Arbor one of the nation's first tissue-engineering companies, Aastrom Biosciences, Inc. The company, which separated from U-M in 1992, has set out to design, develop and manufacture the scientists' Cell Production System (CPS) as its principal product.
"What we can do is take a small amount of bone marrow, inoculate it into one of these bioreactors and grow a transplantable dose of cells," explains Palsson, who is leaving Michigan to join the new
bioengineering department at University of California-San Diego in January.
Using the CPS eliminates the need to have the patient undergo general anesthesia and an operating room procedure during which about one liter of bone marrow is sucked from the patient's hip. "The alternative that the CPS provides is local anesthesia, and a simple draw from the hip that takes about
five minutes and can be performed in a doctor's office," says Palsson. The CPS may cut the cost of a transplant by more than half. In addition to making it easier to harvest the marrow from the patient, adds Palsson, the CPS may decrease the amount of time it takes the cells to readjust to the body's environment after transplantation by as much as one-third, eliminating expensive care in the hospital.
The ability to use cell culture approaches to grow bone marrow was first developed for mouse bone marrow in England in the 1970s. During the 1980s, however, attempts to apply this method to humans failed because the human bone marrow cultures died after six to eight weeks.
The research that ultimately led to the CPS began soon after Palsson, a native of Iceland, arrived at Michigan in the fall of 1984 after earning his PhD from the University of Wisconsin-Madison. His early research focused on mathematically describing red blood cell metabolism and the production of the therapeutic proteins from animal cell lines.
As a part of this research, Palsson's lab had already built a series of bioreactors that could grow mammalian cells that produce and secrete proteins of therapeutic value. His lab had put significant effort into studying metabolism, growth and protein-production rates in cell culture systems.
"But developing bioreactors systems for bone marrow was a much more difficult challenge than I faced earlier," Palsson says, "because the product was the cells themselves, not the proteins that the cells made." Making a cell bioreactor required not only a fundamental understanding of the complex dynamics involved in blood's feeding, oxygenating and protection of tissue, but the ability to mimic the processes in an artificial environment.
Why were tissue engineers succeeding with preserving mouse marrow cultures but not with human ones? Palsson's calculations showed that where mouse cell cultures could survive on a weekly feeding of a solution of nutrients and animal serum, a culture of human bone marrow stem cells (stem cells are the cells that all blood cells originate from, and they start the long process of forming mature blood cells) required daily feeding. Although the research was complicated, even Palsson was surprised by the simplicity of the result showing that "we could get the culture to be much more pro
ductive by adjusting only one critical variable."
Palsson and Emerson then went to the laboratory with this and other findings. In less than a year and a half, with Emerson concentrating on cell biology and Palsson on optimizing cell culture systems and designing bioreactors, they confirmed the validity of their approach to growing human
bone marrow outside the body. Their rapidly fed cultures of bone marrow stem cells could be sustained for up to half a year.
Being able to replicate bone marrow stem cells is the "holy grail" of cellular hematology, the science of blood cells, because it opens a series of important clinical applications. According to Terry Papoutsakis, professor of chemical engineering at Northwestern University, the CPS is likely to have a "profound impact on the clinical treatment of a large number of patients," and not just cancer patients but those with other disorders such as sickle cell anemia and AIDS.
Perhaps the most important clinical application will be in gene therapy of blood disorders through insertion of a "healthy" gene into a target cell, leading to healthy progeny of all the blood cell lineage from the stem cell, and thus a cure for a number of ailments.
It will be a couple of years before Aastrom's products will be ready for the market, Palsson says. However, preliminary results from a study performed at the Anderson Cancer Center in Houston and presented this month at the annual meeting of the American Society of Hematology in Seattle were positive. If full clinical trials do succeed and Aastrom markets the CPS, the University will have a shining example of what is called technology transfer: shepherding research done at universities into the private sector.
"In the United States, high-powered graduate schools churn out scientists willing to take a chance at hundreds of small venture-funded start-ups"---Wall Street Journal, Nov. 29, 1995
Michigan played a vital role throughout the development of Aastrom Biosciences (the two A's stand for "Ann Arbor," while "strom" is from stroma, the name for the type of stem cells used to grow bone marrow cells).
"When I arrived here in 1984, there was an entrepreneurial and
interdisciplinary atmosphere prevailing in the Engineering School," Bernhard Palsson says. He credits the creative environment to James J. Duderstadt, who was then dean of the School of Engineering and now U-M's president, and Charles Vest, who was associate dean of academic affairs at the time and is now president of the Massachusetts Institute of Technology.
"Interdisciplinary work among faculty members is often paid lip service," Palsson says, "but Duderstadt and Vest strongly supported and enabled the interdisciplinary environment that led to the collaboration between Steve Emerson and me."
Duderstadt and Vest fostered technology transfer and interdisciplinary research in many ways, Palsson says, one of which was to help establish the Cellular Biotechnology Laboratories located in the Dow Connector Building on North Campus. The labs were not assigned to any particular faculty member; instead, they served as a home for interdisciplinary work between faculty in engineering on one hand, and life and clinical sciences on the other.
Once their cellular engineering experiments confirmed their initial calculations about the feasibility of growing human bone marrow stem cells outside the body, Emerson and Palsson contacted the U-M Intellectual Properties Office (IPO), one of the University offices responsible for technology transfer.
"We want to put technology to work in the public sector so that it does not lie fallow on the laboratory shelf," says current IPO director Robert Robb. His predecessor, Robert Gavin, played a critical role in the establishment of Aastrom, Palsson says. Gavin helped Aastrom attract investments from a venture capitalist firm and from the State of Michigan Pension Fund.
The U-M retains patent rights and a percentage of Aastrom's stock. Today, after a few more rounds of investment, Aastrom has close to 50 employees in its 20,000-square-foot facility on Domino's Farms just northeast of Ann Arbor.
Palsson took a leave of absence from U-M to serve as Aastrom's vice president for developmental
research. As the company has grown and succeeded with its major goals, he has weakened his ties to it, but he retains a share in Aastrom and will continue to help it as needed.
Biotechnology is a risky field; many companies fail to live up their original promise. But in the past year, Aastrom has received three key patents and has passed the first round of clinical testing necessary to have its products approved by the FDA. The second round of testing, which will test
the efficacy of the products, will begin next year.
The CPS may prove to be critical to the delivery of cell therapies other than bone marrow transplantation. In the fall, Aastrom announced a $25 million dollar partnership with the French pharmaceutical firm RPR Gencell. Overall, estimates the Wall Street Journal, the drug industry has invested about $14 billion in biotechnology since 1990.
"The CPS has the potential to become a big ticket product," Palsson
says. "Cellular therapy is a therapy of the future. Producing cells on site in this sort of automated fashion is needed, and few companies are paying attention to it."
. . . December 1995
