Monday, July 21, 2008 | Ed Baetge and the team of scientists he has led for seven years have had setbacks and disappointing days, but the prospect of finding the cure for Type I diabetes makes their research too tantalizing to give up. Especially now that Baetge believes that they’re on the brink of a medical breakthrough that could stave off the disease in humans.
“I’m convinced we’re going to do it,” Baetge said. “It’s going to take some time, but we can do this.”
Baetge is the chief scientific officer for Novocell, Inc., a San Diego biotechnology company. Earlier this year, Novocell researchers were able to convert human embryonic stem cells into insulin-making cells that stopped diabetes when implanted in mice.
The achievement raised the hope that the embryonic cells that have been converted into insulin producers could one day be injected into the bodies of diabetics to replace cells that should produce insulin but don’t because they have been killed by a faulty immune system. If it works, a one-time implantation therapy could relieve patients of the need to give themselves as many as four injections of insulin daily.
Scientists within the diabetes research community have said the research is promising in theory, but that they’re not holding their breath for it to become a feasible therapy anytime soon. One obvious problem that has arisen is that a small number of mice developed tumors from the cell implantation process. But both Baetge and Dr. Steven Chessler, a biomedical researcher at the University of California, San Diego, said the cancer can probably be eradicated with a more stringent cell purification process in which contaminated cells that trigger cancer are weeded out of the cell pool.
However, Chessler and other researchers who reviewed Novocell’s work in Nature Biotechnology, an industry journal, said the final step Novocell used in the process to convert the embryonic stem cells into insulin-producers — the step that made the therapy successful in mice — entails greater risks in humans, meaning it would be difficult to get through the Food and Drug Administration.
Also, as in most cell-based therapies, questions remain whether Novocell’s therapy can be perfected, and if so, how long it will take. Baetge said he hopes to be in human clinical trials within three or four years. Chessler is more skeptical.
“Novocell’s work is probably the most promising in the field,” Chessler said, adding, however, that he was surprised by Baetge’s timeline. “I think it will take a lot longer than people imagine” for the research to give rise to a patient treatment.
In June, Novocell’s research was validated when it became the first company to receive a business grant — nearly $50,000 — from the California Institute of Regenerative Medicine, the state’s stem cell agency. Normally the agency, created in 2005 to dole out $3 billion in stem cell research grants over the next 10 years, grants money to academic research institutions. An agency spokesman said Novocell was a worthy recipient because it is often companies “that most directly bring therapies to the marketplace — not academia.”
Novocell is one of a handful of local companies and institutions doing research based on the use of stem cells. At the La Jolla-based Burnham Institute for Medical Research scientists are exploring the strategy of using stem cells as factories to make hormones or proteins the body is not making. In Oceanside, International Stem Cell Corp. has produced an alternative to natural embryonic stem cells through the production of stem cells that act like embryonic ones but are derived from unfertilized, rather than fertilized, human egg cells which can’t become a complete human.
But Novocell is plunging ahead using embryonic stem cells, which are politically sensitive and hard to come by because they have to be extracted from a days-old embryo. They’re considered the gold standard in cell-based therapy research because they can potentially be forced to morph into any type of cell in the body. They could be used to create a plentiful source of the functional insulin-making cells that diabetics lack and other cells that could replace those in the body that have been damaged by disease.
Beta cells, a certain cell found in the pancreas, normally produce insulin, a hormone that moves sugar from food throughout the body where it’s used as an energy source for movement, growth, repair and other functions. Type 1 diabetes occurs when the body’s immune system attacks and kills beta cells, rendering the pancreas unable to produce insulin. When the sugar hits the bloodstream, a healthy pancreas automatically makes the right amount of insulin needed to transport the sugar. But when the beta cells are destroyed, no insulin is produced and the sugar stays in the blood instead, where it can wreak havoc on vital organs.
In Baetge’s laboratory, the insulin-making cells kept blood sugar in check in mice after the mice’s own insulin-making cells were destroyed by scientists.
“It absolutely cured its diabetes,” Baetge said of the converted embryonic stem cells’ affect on a diabetic mouse used in trials.
But a small number of the mice developed tumors in the process, prompting some concern that the cells wouldn’t be suitable for use in people. Baetge said his team is creating purified cells, meaning they aren’t expected to trigger cancer, which will be tested in small animals, then larger animals, such as monkeys, before human clinical trials begin. Also, researchers need to grow huge numbers of the cells for trials and eventually for patient therapy. Each patient would need to have between 500 million and 1 billion converted cells implanted for a successful therapy.
Baetge’s research team has already cleared at least one giant hurdle.
In 2006, Novocell reported that its scientists had been successful at programming, or “coaxing,” human embryonic stem cells into becoming insulin-making cells in Petri dishes. The achievement was lauded in the science community because the cell conversion was quicker and produced more cells than previous tries by other researchers, an important feat for scientists needing plenty of cells for scores of trials.
Still, there was one problem. In laboratory experiments, the converted cells, unlike natural beta cells, didn’t alter the amount of insulin they secreted when different amounts of sugar was added to them, a vital requirement for the implantation therapy to be viable. Essentially, if the converted cells Novocell produced couldn’t automatically alter the level of insulin they omitted in response to the amount of sugar they encountered, the research would be moot and a cure, as envisioned by Baetge, would be out of reach.
“It was the only problem, but it was a big one,” Baetge said. The finding “definitely didn’t make my day.”
Baetge decided to rethink things. He noticed that the converted cells weren’t fully mature and behaved more like beta cells in a human fetus, which also don’t respond to glucose until after the baby is born. The insulin-making cells his team had created had been derived by taking embryonic stem cells and adding or taking away specific growth factors in a process that simulated the progression that cells in an embryo go through to become a pancreatic cell, a process that takes between 16 and 20 days. Basically, scientists had tried to replicate the uterus environment in the Petri dish, but something was missing.
“There’s something we can’t mimic in that final maturation stage in a living thing that makes the cells functional,” Baetge said. “We put the cells in mice and they responded.”
Baetge realized that the converted cells weren’t working because they weren’t getting the final growth signals necessary to turn into functional insulin-making cells in the dish. So the researchers decided to use the mice themselves to force the converted cells to make insulin. Rather then implanting the insulin-making cells into the mice, they implanted “precursor” cells that were one step short of being the insulin producers. The result was just what Baetge was hoping for.
The mice’s living bodies aptly provided the correct signals that forced the implanted precursor cells to transform themselves into working insulin-making cells in about three months, sending the diabetes into remission. To test the results, scientists extracted the implanted cells from the mice after about 100 days. Blood sugar levels shot up, indicating that the implanted cells were in fact keeping the disease at bay, a finding that has bolstered the prospect that the same process could be successful in human patients.
On the other hand, the success of the precursor cells also presents the biggest complication of the therapy.
The Food and Drug Administration might not allow the transplant into humans of cells that have to mature in the body because of concerns about adverse effects, such as tumors, that could arise if the process isn’t completely predictable. Chessler, the UCSD researcher, said that within the diabetes research community at large, the goal is to completely manufacture insulin-secreting cells for implantation in a Petri dish, a process that wouldn’t carry such risks.
“Unless Novocell proposes to put the more immature cells into people, as they did in mice, the signals that triggered the maturation of the immature cells into more mature, insulin-secreting cells will have to better understood to accomplish this long-term goal,” Chessler said.
A controlled laboratory is the best way to make the cells in a regulated fashion and avoid irregularities after they are injected into diabetics, he said.
Outside of San Diego, scientists are already experimenting with transplanting cells from the pancreas of deceased organ donors into people with Type 1 diabetes with some success. In some instances, the transplants have relieved the patients of the need to give themselves daily injections of insulin, but the effect wears off for most recipients within two years.
Also, donor organs are too scarce to provide cell replacement therapy to more than a very small percentage of diabetics. Technology that would allow doctors access to cells that are grown in a lab would make the treatment more widely available.