Miracle Cures May Be In Your CellsJoan O'C. Hamilton
From the ancient Aztec to the modern Navajo, many cultures have saved the umbilical cords of newborn babies to use in rituals. If a young company called Biocyte gets its wish, parents in the U.S. soon may embrace a similar rite--potentially with lifesaving consequences. In November, Biocyte said that for $1,500 plus $75 a year, it will freeze and store three ounces of "cord blood" cells extracted from umbilical cords of healthy infants, initially those born at Magee-Womens Hospital in Pittsburgh. If later the child, or a close relative, is afflicted by cancer or other serious disorders, these matched cells could help carry a cure.
It's too early to tell how willing parents will be to pony up. But Biocyte's service is an early indicator of a radical approach to medical treatment that could become common. Called "cell therapy" or "tissue engineering" this new technology springs from dramatic gains in understanding the body's immune system and the role of cells in disease. A dozen small biotech companies are using this new knowledge to pioneer novel ways to handle, manipulate, and deliver human and animal tissues and cells in the body to fight a wide range of ills.
One red-hot area of such research involves stem cells, the lynchpin cells of the immune system that are plentiful in cord blood. They promise to be useful in treating cancer, and ultimately genetic ills. But the action doesn't stop there. Some companies are growing sheets of skin. Others are trying to create a wide variety of "universal" cells that can be transplanted without fear of rejection. Still others are transplanting into the brain and spinal cord cells that ooze useful neurological proteins. Some researchers are even trying to grow organs in petri dishes. This work promises to be expensive and will face thorny regulatory thickets. But it will continue because "the need for this work is so apparent," says Gail Naughton, COO of Advanced Tissue Sciences Inc. (ATS) in La Jolla, Calif., because these treatments address horrible conditions such as organ failure, or severe burns that are now inadequately treated.
Such approaches aren't without precedent. Blood has been banked and transfused for decades, and whole organs have been transplanted since the 1960s. Research into the curative power of fetal cells was making headway until a since-lifted moratorium imposed by the Reagan Administration. But much of what's happening today goes way beyond the progression of transplant research.
The concept behind cell therapy and related techniques is that perhaps only cells are smart enough to correct certain defects in the body. Cells are the engines and brains of many processes. They metabolize nutrients to create energy, pack together to form skin and organs and vital fluids, and manufacture the myriad hormones, enzymes, and other chemicals humans need to survive. Most illnesses occur when these engines break down in some way because of injury or infection, spew harmful proteins, wear out, or grow unchecked, as happens in cancer. Drugs work by prompting desirable changes in cells--such as turning off bad ones. But finding an agent that doesn't cause side effects or disrupt other processes isn't easy.
NO BLOCKERS. The biotech industry was founded on the premise that isolating single proteins made by cells, then gene-splicing them to create large quantities, would lead to better drugs. Genentech Inc.'s human-growth hormone, for example, replaces a natural hormone that some children are missing, and it works well.
But such successes have been relatively rare, in part because plucking single, useful proteins out of the body's complex broth is extremely difficult. It's a bit like sending a football team comprised of 11 all-American quarterbacks out to win a game--with no receivers or blockers. But cell therapy may let scientists accomplish the same goals of healing or replacing cells without micro-managing the process. "Cells have the software to do what we have yet to learn," says Joseph P. Vacanti, a leading tissue engineer and Harvard Medical School researcher.
Proponents of cell therapy point to wound-healing, where gene therapy companies have so far failed to generate drugs based on the isolation of individual protein "growth factors," which stimulate cells to grow. Says Cynthia Robbins-Roth, a PhD biochemist who edits the biotech newsletter BioVenture View: "Everybody has been spending hundreds of millions of dollars to isolate things that don't work well in isolation." By contrast, companies such as ATS, Organogenesis, BioSurface Technology, and LifeCell are testing skin replacements to do that. Most of these products are made of cultured human dermal or epidermal cells that can be transplanted and make their own growth factors in just the right amounts. The products show great promise in healing burns and other stubborn wounds.
"WOUND HEALING." BioSurface Technology Inc. of Cambridge, for instance, is selling sheets of epidermal tissue made by taking a postage-stamp-size piece of a patient's own cells and expanding them ten thousandfold--enough to cover an entire body. Meanwhile, ATS, BioSurface, and Organogenesis are developing other skin-covering products based mainly on cells called "fibroblasts" taken from neonatal foreskin, a discard from circumcisions. From one foreskin, ATS can grow over 1 million four-by-six-inch sheets of dermal skin to treat burns or wounds. "Wound healing is such a complex medical problem, no one knows what factors, in what amounts, over what time," can hasten it, says BioSurface Chief Executive David L. Castaldi. "But the cells are programmed to produce various factors so we don't have to answer those questions."
Engineered human-skin products are the furthest along in human testing and could be the first engineered tissue to seek Food & Drug Administration approval. But numerous other products and techniques are close behind. At Boston's Children's Hospital, in a lab environment designed to mimic the human body and trick cells into growing naturally, Vacanti hopes soon to begin building transplant ears, noses, and other facial features out of human cartilage cells seeded on a polymer mold and grown into the proper shape. Using technology he has licensed to ATS, Vacanti already has grown cow cartilage around special polymers in the shape of a full-size human ear and implanted the ear beneath the skin on the back of a mouse. The skin grows over the structure in 12 weeks and naturally attaches to the ear. This technology could be used to fix genetic facial defects or to repair facial features damaged from accidents or cancer radiation therapy.
Far more commercially important is the attempt by Vacanti and others to grow the cartilage that makes up the meniscus, or lining of the knee. In the U.S. alone, 1.4 million patients a year could benefit. Doctors today can do little but remove damaged cartilage and eventually replace the knee. Organogenesis is working on engineering collagen scaffolds on which to grow skin cells, or fibroblasts, that could become replacement tendons and ligaments. Also in the lab, in a petri dish, Vacanti is trying to grow pieces of a human liver that could someday be transplanted to provide relief from certain liver diseases or as a bridge until entire livers, which are always in short supply, can be located.
In Europe, meanwhile, researchers are using cells from cow adrenal glands encapsulated in special polymer tubing made by Cytotherapeutics Inc. in Providence. In a small number of patients in whom the cells have been implanted at the base of the spinal cord, the treatment appears to relieve severe pain. The key is that the membrane lets desired proteins exit while shielding the cells from the body's destructive immune response.
Next, Cytotherapeutics hopes to attack Parkinson's and Alzheimer's with animal cells wrapped in membranes, then inserted in the brain. CEO Seth A. Rudnick says the membranes should make it possible to mainly use animal tissues, which are easier to get and manipulate than human ones. The company has also supplied the encapsulation technology to researchers transplanting insulin-producing cells in diabetics.
At Cell Genesys Inc., Foster City, Calif., researchers are trying to create so-called universal donor cells by genetically wiping out the regions on various cell types that mark a cell as belonging to a specific individual. If this research pays off, it could lead to an array of transplantable cells that could simply be pulled off the shelf to treat everything from eye damage to cancer--bringing an end to the need for donor-matching.
Companies that see gene therapy as the future of medical treatment are paying close attention to cell therapy--because stable, manipulatable cells will be needed to transfer genes into patients. Drug maker Sandoz Ltd. paid $392 million in 1991 for 60% of Systemix Inc., a Palo Alto (Calif.) company that's working with stem cells for use in cancer treatment and gene therapy. And Baxter International Inc.'s biotech group is looking at several cell and gene therapy approaches aimed at cancer, diabetes, and hemophilia.
Still, there's plenty of uncertainty ever just how cell-tissue engineering companies will make money. Will they sell a product or a service? Will the procedures be practical? How will they be regulated by the FDA, whose commissioner, David A. Kessler, recently published a paper in the New England Journal of Medicine giving notice that the industry will be subject to tight scrutiny by his agency.
Company products could be variously regulated as devices, drugs, or not at all, if the product is the patient's own cells or a straight transplant. "They've got something here, but I'm unwilling to bet on a startup company that has to figure out all this biology and establish a service business," says a prominent Wall Street biotech banker.
To get an idea of how multifaceted business strategies can be in this field, look at what's happening with stem cells. The stem cells that give birth to all the cells of the immune system primarily reside in the bone marrow. For some years now, physicians have used bone-marrow transplants to fight some forms of cancer. First, they use chemotherapy to wipe out cancer cells--and typically, the bone marrow with it. They then transplant donor marrow to restore the patient's immune system. The trouble has been that bone marrow also is loaded with T-cells, which can trigger a rejection response and render the treatment ineffective.
Studies have shown that the freer the stem-cell populations are from T-cells when given to cancer patients, the less toxicity appears to be associated with the transplant. How does a company profit from all this labor-intensive work? Companies such as CellPro, Baxter, Systemix, and Applied Immune Sciences all have technologies designed to pluck out stem cells from the bone marrow and, increasingly, from circulating blood. But CellPro in Bothell, Wash., supplies researchers and companies with equipment to separate out stem cells. Its system could be combined with cord blood stored by Biocyte, for example, to pluck out cord-blood stem cells, which not only can obviate the need for donor marrow but also seem well-suited to deliver genes in gene therapy, for reasons scientists don't yet understand.
Applied Immune Sciences Inc. and Systemix Inc., meanwhile, are building service businesses around stem cells by catering to individual patients. In an industrial park near San Francisco airport sits what Thomas B. Okarma, chief executive of Applied Immune Sciences in Santa Clara, Calif., calls a "hospital for cells." In sterile cleanrooms, technicians are processing blood flown in from AIDS patients in Los Angeles. In a clinical trial, they're testing whether they can bolster patients' immune systems by filtering out infection-fighting white blood cells, multiplying them by adding the growth factor Interleukin-2, then shipping them back for reinfusion in patients. Earlier this year, a similar procedure for kidney cancer patients showed remissions in about one-third of those tested. AIS plans to try the same process for using patient stem cells as a substitute for bone-marrow transplants. Ultimately, Okarma believes AIS can add gene insertion into its current cell treatment process and enable more efficient gene therapy.
Systemix, too, is setting up special centers to process patient stem cells out of circulating blood. Systemix CEO Linda D. Sonntag says advances in gene therapy are moving so quickly that she expects the company will work on using stem cells as a vehicle for gene therapy as its next frontier.
Since most companies are still in the testing phase, few will estimate publicly what they expect the costs of such treatments to be. Bet on this, however: They'll be expensive. So far, cell therapy companies have been careful to target maladies for which other treatments are nonexistent, inadequate, or so expensive that almost anything would be an improvement. Standard bone-marrow procedures today can top $150,000, for example, and the cost of treating severely burned patients, including hospital stays and multiple surgeries, can exceed $200,000. One thing all the companies say they'll do is build cost-effectiveness criteria into their trials. Says ATS Chief Executive Arthur Benvenuto: "If we can't show a cost-saving on the day of launch, we'll scrub the project."
No matter what they cost, these technologies are part of a bet on the head-spinning pace of science. In some cases, interim techniques will be leapfrogged by gene therapy; others will develop into cells and organs that can be ordered off the shelf. But even today, one unspoken premise at Biocyte is that advances in the next decade will provide uses that don't exist today for cells harvested from umbilical cords.