CITY ON A HILL: The Buck Institute is one of six designated training centers for growing stem-cell colonies in California.
The Buck Institute for Aging is set to break ground on a new research center devoted to unlocking the potential of stem cells
By Joy Lanzendorfer
I have two flavors of brain cells here," says Julie Mangada, a postdoctoral fellow at Marin's Buck Institute, as she carries over two petri dishes. "They're called neuronal stem cells or NSBs, which are baby brain cells."
We are standing in the Buck's Zeng Lab beside a microscope. The petri dishes Mangada has brought out of a refrigerator contain the primary thing the lab has been working on: embryonic stem cells that are turning into brain cells.
The first set of baby brain cells Mangada shows me are six weeks old. Under the microscope, they look like triangular blobs with one or two of the trailing veinlike connectors we associate with brain cells.
"So we already have some renegade cells that are differentiating here," Mangada says. "The triangular guys, each one is a cell. And then you can see here," she points to one of the veinlike connectors, "this guy is kind of stretching his arms and legs to bridge this cavern. He's looking for neighboring cells that he can form synaptic connections with."
Next, she shows me brain cells that have been developing for four months. There are millions of them by now, so many that it's hard to get the microscope to focus on them all. Most of the cells are reaching out with the same trailing connectors, called axons and dendrites.
"You see this dense fibrous network throughout here?" Mangada asks. "These little cells are actually forming processes and trying to make connections with all their neighbors."
Getting stem cells to change like this, a process called differentiation, is complex. Behind us is another refrigerator filled with bottles of amino acids, proteins and other solutions that postdoctoral fellows like Mangada have been feeding the petri dishes every day. Most of the stem cells will end up as dopamine-producing neurons that can be used in research for Parkinson's disease.
A patient with Parkinson's slowly loses muscle coordination because of a depletion of dopamine in the brain, which helps with fluidity of movement. If scientists could get good at developing dopaminergic neurons from stem cells, they might be able to transplant them into the brain of a Parkinson's patient, replace the unhealthy cells and cure the disease.
This is the kind of potential stem-cell research promises. It's no wonder, then, that the Buck Institute will soon be breaking ground on a $41 million building devoted entirely to the study of stem cells.
In 2008, the California Institute for Regenerative Medicine (CIRM) awarded Buck a $20.5 million grant for the building. Buck had planned to match the grant by 2009, but the recession slowed things down. Now, however, the funding is back on track, and construction starts June 1.
The new building will be 66,000 square feet and include $1.9 million in equipment. It is the third of five buildings planned for the Buck Institute's Novato campus, which was designed by architect I. M. Pei, who also did the pyramid for the Louvre Museum in Paris. In addition to current stem-cell work, the new building will allow Buck to expand into research related to the aging process or aging-related diseases such as Alzheimer's, Huntington's and even cancer.
A Clue to Aging
At first glance, stem cells seem inconsistent with Buck's mission to fight aging. After all, the existing research building on the campus is devoted to looking at the life cycles of such short-lived creatures as gnats, yeast and worms, and applying that information to human beings.
Stem cells, by contrast, are embroiled in a political controversy that pits where they come from against their life-saving possibilities. But stem cells are also the origins of human development. They can turn into any cell in the body, and from them come all our organs and, in fact, the body itself. Studying this is key to understanding how the body develops and why it stops developing as we age.
"If you take skin cells, they will undergo a process [that] is kind of like aging, and then they will die," says Xianmin Zeng. "But embryonic stem cells do not die. So my view of life when you use this to study aging is, if you look at something that does not age, then maybe you can find some clue to the scientific basis of why aging is happening."
Zeng, originally from China, is developing the stem-cells program with David Greenberg, a vice president and professor at Buck who co-wrote the proposal for the CIRM grant. The building will be an expansion of the Zeng Lab, which she started in 2005 when she came to Buck. Previously, Zeng worked at the National Institutes of Health (NIH), where, among other things, she helped derive a variant of one of the federally approved embryonic stem-cell lines.
There's no doubt that Zeng loves stem cells, particularly stem cells that come from an embryo. While she enjoys developing brain cells for Parkinson's research and drug testing (another advantage of stem cells is that they create an alternative to animal testing because you can put the drug directly on human cells instead of another species), it is really the science that draws her in.
"Of course, there is the basic biology," she says. "Just to look at how cells from a stem cell become neurons, there is a lot of the process to look at. And which genes regulate this process is also interesting. That is my basic interest, developmental biology."
Once scientists understand how stem cells work, they will have a clear picture of how to manipulate them, which can lead to new therapeutic potential. But for now, some things about stem cells are still a mystery.
"We don't fully understand how stem cells go from primitive cells and turn into other types of cells," Greenberg says. "We understand parts of it, but we don't understand what makes one stem cell turn into a brain cell and what makes another turn into a blood cell."
As part of this quest for learning, the new building will also train students on stem-cell research. Buck is one of six designated training centers for growing stem-cell colonies in California, which is one of the reasons postdoctoral fellows like Mangada have an opportunity to learn while doing the work of the lab.
"Most of the people who do the research in the lab are postdocs, which is kind of like finishing school for Ph.D.s," says Mangada, a Petaluma native who did her postdoctoral work at the University of Massachusetts Medical School. "One of the things that's so great here is that you just learn. That's the whole purpose and point of it. You study and expand your repertoire of technical skills."
This December, Buck received an additional $1.6 million grant from CIRM for its research-training program, which will allow it in part to hire six more postdocs or medical students this summer.
The Problem with Embryos
Buck's stem-cell research will use all three types of stem cells: adult, embryo and induced pluripotent stem cells (iPSC). Adult stem cells are found in organs and are only capable of producing cells for that organ. For example, a bone-marrow stem cell can produce all of the 40 different types of cells in peripheral blood, which is what provides your body with a new supply of blood when you need it. Scientists have been working with adult stem cells for years. The first bone-marrow transplant—which is when unhealthy bone-marrow stem cells are replaced with healthy ones—happened in 1968.
But adult stem cells are hard to isolate and purify, and there aren't that many of them. Enter embryonic stem cells. These cells, which come from a human embryo, are much more versatile because they can be manipulated to grow any cell in the body. They could provide scientists with as many of whatever kind of cells they need, which opens up an array of possibilities.
Induced pluripotent stem cells are adult cells, such as skin cells, that have been altered in the lab to look and act like embryonic stem cells. This breakthrough, first done with human cells in 2007, could end the debate over stem-cell research, because iPSCs do not require the use of an embryo.
"It's still in the infancy of the iPSC cells, but the potential is huge," says Zeng. "If [you need] a stem-cell transplant, you can get the cells from your own body. That means your immune system would not reject the cells. In the medical field, it would be a huge plus, because the patient won't need immunal suppression. If you suppress the immune system, you are subject to a lot of infections and other diseases."
But iPSCs are only three years old. At this point, it takes many attempts to get even a few adult cells to revert to the embryonic state, which means that the production of iPSCs is inefficient and expensive. Also, there are problems with shutting off the genes that prompt the cells to revert. Two genes in particular stop cell division, which is one of the body's defenses against cancer. That means that tissue derived through iPSCs could be pre-cancerous.
"We're loaded with mutations," says Judy Campisi, a professor on genome maintenance, aging and cancer at Buck. "These genes' job is to make sure you don't have runaway proliferation of mutated genomes. So, if you want to improve the efficiency of the iPSC, you can kill those genes, but then you give rise to these stem cells that are pre-cancerous. It's going to be a tension between getting good healthy stem cells that are not cancerous and getting the efficiency up to make iPSCs work."
DISHIN' IT: A fluorescent microscopic image of neural precursors generated from human embryonic stem cells. The neural cell bodies are visible in red and the nuclei in blue.
Why It's Not a Baby
For the time being, embryonic stem cells have the best potential for research. Many opponents of stem-cell research believe that embryonic stem cells come from aborted fetuses. That is not true. Embryonic stem cells come from in vitro fertilization centers.
When two people try to get pregnant through in vitro fertilization, the doctor often creates more embryos than will be implanted into the woman's uterus. The couple can then pay to store the embryos for use at a later date. If they decide not to store them, they have the option of donating the embryos to medical science, which can then go to stem-cell research. If not, the embryos are discarded.
The term "embryo" here refers to a "hollow microscopic ball of cells called the blastocyst," according to the NIH. The blastocyst is between five to eight days old. An aborted fetus could not be used for embryonic stem-cell research; by the time a woman knew she was pregnant, the fetus would already be too developed to be useful.
"The confusion comes from the definition of embryo," says Erik Forsberg, executive director of WiCell Research Institute, which has provided NIH-approved stem-cell lines to facilities like the Buck Institute. "It is confusing to people new to the field, because people call fetuses embryos. These embryonic stem cells are typically pre-implant embryos that are seven to eight days old. They are less than 1,000 cells, smaller than a head of a pin." Still, some opponents believe that life begins as soon as a sperm fertilizes an egg, and this belief has informed public policy. In August 2001, President Bush drew what is referred to as the "Bush line" by saying that no federal funding could be used for new stem-cell lines developed after that date. If scientists wanted to receive federal funding, they had to use one of the 21 embryonic stem-cell lines previously approved by the government. These lines came from all over the world, including Sweden, Israel, San Francisco and WiCell in Wisconsin.
The Bush line made everything complicated.
"There was confusion about whether the same equipment could be used," says Greenberg. "If you buy a microscope with a fed grant, could you look at stem cells under it that were not NIH approved? The implication was that you had to duplicate a lot of things—equipment, even buildings. CIRM took a lot of that away."
In 2004, California voters passed Proposition 71, which created CIRM to distribute $3 billion in funding to stem-cell research. The Buck Institute would not have the new building without Prop. 71. In fact, given the complexities and lack of reliable funding, the institute might not have even looked into studying stem cells at all.
Incidentally, while President Obama is friendlier to stem cells, government change is slow. The NIH is setting up new guidelines, but in the meantime, federal funding for stem-cell research remains difficult.
Cancer & Stem Cells
Perhaps because of its location in Marin County, which has one of the highest breast-cancer rates in the country, the Buck Institute may look into the relationship between stem cells and cancer. New information suggests that stem cells may play a role in why cancer sometimes comes back.
"You have a tumor mass, and you can apply radiotherapy or chemotherapy or even surgery on the tumor," Campisi says. "That will usually kill off the tumor cells for some period of time. A big problem in cancer therapy is that after a period of time, the cancer comes back. The question is, why? The idea is that for at least some cancers, there is a stem cell that is slowly replicated, so it's not very susceptible to chemotherapy."
While radiation and chemotherapy are killing the cancerous cells, the stem cell is lying dormant. After awhile, it starts slowly cycling and renews itself, dividing so that there are new cancer cells and new stem cells.
But the extent the stem cell plays here is still unclear. For one thing, cancerous stem cells have only been identified in certain types of tumors. For another, scientists don't know how much new tumors are fueled by stem cells and how much they are caused by mutation.
It's questions like these that make stem-cell research complicated. On one hand, stem cells may give us new clues to longstanding scourges like cancer, but on the other hand, they carry new complexities to be addressed.
Which is exactly why we need to study them, says Campisi.
"I think we're learning more and more," she says carefully. "I am a little bit optimistic. We'll get there eventually."
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