With the aim of treating conditions such as diabetes, Alzheimer’s and some types of cancers, the University of Michigan’s stem cell research program has advanced exponentially over the past eight years, making it a state leader in the area.

The growth follows the passage of a controversial 2008 state proposal, Proposal 2, which allowed the use of human embryos for stem cell research under certain conditions. The proposal has prompted a huge spike at the University in research projects and funding for stem cells  — an area of study that today, researchers say, remains with opportunities to grow, but also still faces some controversy on campus and beyond.

What a stem cell does:

To understand what stem cell research means for the University, it’s first important to understand what it is. Stem cells are cells that have the capacity to produce different kinds of cells in a given tissue as well as make copies of themselves — making them uniquely useful in research.

Ivan Maillard, associate professor of cell and developmental biology, is one of several at the University who utilizes stem cells in research. Maillard’s research focuses on blood-forming stem cells — cells that create other cells in the blood system and allow for normal production of blood cells. Blood-forming stem cells are adult stem cells typically retrieved out of individual tissues.

“(Stem cells) have the potential to be used themselves as a treatment for patients,” Maillard said. “The only ones that are actually routinely used as a treatment for patients are the blood-forming stem cells. The other types of stem cells have the potential to be useful in other conditions, especially conditions where the organs become damaged by disease or other conditions and ideally, you would need to replace the cells in the damaged organ by new cells. You can consider using stem cells as a way to do that in the future.”

Along with helping develop treatments, stem cells have also been used to provide information about human biology and replace cells in a damaged organ.

There are several different types of stem cells —adult stem cells are found in individual tissues as stem cells that have already chosen which type of cell to become. Embryonic stem cells, on the other hand, are found in the embryo only at early stages, when the embryo consists of just a few cells. Usually, to be used for research, embryonic stem cells are kept at this young state to prevent them from growing into adult cells, according to MStem Laboratories, the center for stem cell research at the University.

Gary Smith, the director of the MStem Cell Laboratories, said his lab primarily focuses on making human embryonic stem cells for single-gene disorders, such as muscular dystrophy.

“What we do is make the embryonic stem cell line from the embryo, grow it, characterize it, and then with documentation, we submit them to the National Institute of Health,” Smith said. “They review all of the documentation and then accept them — every line we’ve made has been accepted on the NIH registry … any researcher in the country can get the stem cell lines from the University of Michigan and work on them with federal funds.”

The cells are typically derived from fertilized embryos of couples who created them for reproductive purposes yet no longer need them. The embryos are either discarded as medical waste or donated with consent for research needs.

Maillard said the potential to help the patients he interacts with on a daily basis motivates his research, which often uses stem cells for bone marrow transplants as an effective treatment in many cases.

“I work with these patients,” Maillard said. “I see them in the clinic and I see their problems. I see the ones that we can help, and I also see the limitations of the field. I see the patients that we are not able to help enough and I want to be part of the solutions that we’re going to bring to these patients.”

State proposal on stem cell research

The Michigan Stem Cell Amendment, more commonly known as Proposal 2, was passed by the state’s electorate in 2008. It expanded use of human embryos in research so long as the embryos were created for the purposes of conceiving children and were not suitable for implantation or would be otherwise discarded unless used for research. The proposal also required that donations were made from consenting couples who voluntarily sought out fertility treatment.

Following the passage of this legislation, the University announced the opening of the A. Alfred Taubman Medical Research Institute Consortium for Stem Cell Therapies in 2009. The institute was intended to facilitate the development of new stem cell lines. At the same time, President Barack Obama issued an executive order lifting restrictions placed on embryonic stem cell research by former President George Bush.

In 2015 alone, the National Institutes of Health gave $445 million in grants for human non-embryonic stem cell research nationally. The NIH also funded $180 million in human embryonic stem cell research last year. According to the organization’s spending report, nearly $4.2 million out of that total went to the University.

The University was able to develop the state’s first human embryonic stem cell line, or group of stem cells cultured in vitro, in 2010 through the Consortium for Stem Cell Therapies. In 2012, it was announced that the University’s first human embryonic stem cell line would be added to the National Institutes of Health’s national registry.

Maillard noted that while he does not directly work with embryonic stem cells, he thought 2008’s Proposal 2 affected the stem cell research field as a whole.

“(Proposal 2) has expanded the potential of researchers at the University to derive new lines of embryonic stem cells for research purposes,” Maillard said. “It has ensured that this remains something that was possible in Michigan in general and at the University of Michigan in particular.”

However, there is also still significant controversy surrounding the research. There are many groups opposed to stem cell research, such as Concerned Women for America, a national interest group that has decried federal and state measures to make the research legal. Because the group believes that life begins at conception, they see research like that performed at the University destructive to human life.

At the University itself, there is also dissent from parts of the student body. LSA junior Rachel Crawford, vice president of Students for Life, said the organization only supports adult stem cell research.

“We do oppose all embryonic stem cell research because it destroys that human embryo,” Crawford said. “In order to procure any kind of stem cells from an embryo you have to destroy it.”

Crawford said many believe a moral question remains as to whether it should be permissible to create the excess human embryos to begin with, due to the fact that genetically mutated embryos, sometimes donated for research, often have to be discarded.

“In the past years, adult stem cells have been used to treat more than 70 conditions but never had a condition treated by using embryonic stem cells yet,” Crawford said. “A lot of the strains that they create from them often have to be discarded because of genetic mutation.”

Maillard said from a scientific perspective, the research is justified in using embryos that otherwise would have been discarded.

“The reality is that there is not a single embryo that is used for research unless it has already been decided that it would be otherwise discarded,” Maillard said. “All the embryos that are used in research would otherwise be discarded as medical waste.”

Jason Spence, assistant professor of cell and developmental biology, works with both embryonic and induced pluripotent stem cells. Induced pluripotent stem cells, or IPs, are grown in a dish and potentially have the ability to become any human tissue.

Spence said he began working with human pluripotent stem cells around 2006, and has multiple goals for his research, including figuring out how to take a cell that has not chosen what cell type it wants to become and coax it to become a differentiated cell. In his lab, Spence hopes to ultimately coax these cells into lung or intestinal tissue.

In discussing his work, he emphasized that he and his colleagues strictly adhere to the ethical and legal standards set in place that are required to work with embryonic stem cells.

“The federal government has a very strict set of standards and regulations for working with human embryonic stem cells, and all of the different cell lines that we work with have to be on a special registry with the federal government,” Spence said. “The cells being on this federal registry ensures that all the ethical standards and guidelines have been met in generating those cell lines.”

Many of these guidelines include information about consent, donation eligibility and use of funding. Additionally, all of the stem cell lines that make it on the NIH registry have to meet federal guidelines confirming the embryos were, in fact, donated.

During his time at the University, Spence said, he has seen several technological advances in the field occur. In addition to the capability to differentiate cells, drug screening can now be done on stem cell types that can help identify new drugs that could affect a diseased cell by using a similarly diseased cell in a dish.

Smith, with MStem, said the University lab has produced more stem cell lines for diseases than any other university or academic institution in the country. He added that the lab has created nearly 40 different stem cell lines, many of which are the only ones in the world.

Many times, people who donate the embryos are those who have diseases in their family, and even already have a child affected with the disease, he noted.

“It is something that affects their families,” Smith said. “Because of that, and because I think that donation is really important, what we’ve tried to say is this isn’t strictly a research project, we are actually going to apply the things we know from human in vitro fertilization in an embryo culture to making the best opportunity to produce those stem cell lines available.”

Even beyond Proposal 2, the path hasn’t been entirely clear for the research.

Smith said the conversation and controversy stemming from research like his, even after Proposal 2, remains complicated.

Before Proposal 2, when it was illegal in the state of Michigan to derive human embryonic stem cells, Smith said the lab did not do any embryonic stem cell derivation. Smith said even today, the federal Dickey-Wicker Amendment remains, denying federal funds to make lines to connect individual stem cells for further study, acting as another barrier limiting research. Only once a stem cell line is on the NIH registry can any researcher obtain federal funds to work on that line.

“For us, every line we’ve made has been accepted on the registry,” Smith said. “While we can’t get funds to make the line, we can make it so that any researcher in the country can obtain that line and then get federal funds to work on it.”

However, because the majority of the work done in the MStem lab is non-profit due to government regulations, obtaining financial resources can often be difficult. Much of MStem’s plan for sustainability includes philanthropy, development and partner foundations or pharmaceutical companies.

“There are many pharmaceuticals who are starting to see this as a great intermediate pathway before they go to clinical trials,” Smith said. “Even if they do have an animal model that they’re testing on, still being able to have a human cellular model to be able to test a potential pharmaceutical on, really has potential to save huge amounts of money.”

Unlike Smith, Spence said he can receive federal funding because much of his research uses induced pluripotent cells. A majority of Spence’s research program is funded by the NIH, but he said he has received funding from outside sources such as the March of Dimes and Bill and Melinda Gates Foundation.

Because there are more than 300 types of single-gene disorders that are tested for in embryos, Smith said the goal of his lab is to use knowledge of human embryology to understand these diseases. He said the lab is glad to distribute the stem cell lines to other labs, to allow for faster progress in researching them, than might occur if the lines remained at the University alone.


Future of stem cell research at the University

Moving forward, University researchers are planning to move into multiple areas of stem cell research.

One of those researchers is Max Wicha, professor of oncology and internal medicine, is the founding director of the University’s Comprehensive Cancer Center. Wicha stepped down from the position a year ago to focus on his research looking at cancer stem cells. He currently sees breast cancer patients one day a week.

Wicha recently received an Outstanding Investigator Award, of which he will be allotted $6.5 million to use in any area of his choosing for cancer research. He said the ultimate goal of his research is to develop new drugs and ways of treatment to target these stem cells in cancer patients.

“We used to think that all of the cells in a cancer were the same, and that basically in order to cure cancer you would have to kill all of the cells in the cancer,” he said. “About 15 years ago, we made the discovery that that wasn’t true at all.”

Wicha said the grant he received enables him to work with a diverse group of collaborators to develop treatment for patients as well as to monitor patients while they are on clinical trials.

Though the funding helps make Wicha’s research easier to accomplish, he noted that there are still many challenges along the way for stem cell research.

There was a big advance in stem cell research when Proposal 2 was passed, he said, but prior to that, many researchers left the University and the state to conduct their embryonic research in other states where it was legal.

He said now that this research can be conducted at the University, there is promise for breakthroughs.

“It’s very exciting now that we’re making some more dramatic progress now than we have ever seen before,” Wicha said. “The time is right to be able to do this cross-cutting research.”


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