ANN ARBOR—University of Michigan researchers have created the state’s first human embryonic stem cell lines that carry the genes responsible for inherited disease. The achievement will enable scientists here to study the onset and progression of genetic disorders and to search for new treatments.

With this accomplishment, the U-M joins a small handful of U.S. universities that are creating disease-specific human embryonic stem cell lines.

“All our efforts are finally starting to bear fruit,” said Gary Smith, co-director of the U-M Consortium for Stem Cell Therapies and leader of the cell-line derivation project. “Creating disease-specific human embryonic stem cell lines has been a central goal of the consortium since it was formed two years ago, and now we’ve passed that milestone.”

One of the lines carries the genetic defect that causes hemophilia B, a hereditary condition in which the blood does not clot properly. The other carries the gene responsible for Charcot-Marie-Tooth disease, a hereditary neurological disorder characterized by a slowly progressive degeneration of the muscles in the foot, lower leg and hand.

If embryos are created for reproductive purposes but are found to be unsuitable for that use because they carry disease, Michigan law allows those embryos to be donated for research instead of discarding them. At that stage of development, the donated embryos consist of a cluster of cells about the size of the period at the end of this sentence.

“These are the first of many disease-specific human embryonic stem cell lines that researchers at the U-M Consortium for Stem Cell Therapies intend to develop,” said consortium co-director Sue O’Shea, a professor of cell and developmental biology at the Medical School.

In the months and years ahead, donated embryos will be used to create cell lines that carry the genes responsible for myotonic dystrophy, Huntington’s disease, Rett syndrome, spinal muscular atrophy and Tay-Sachs disease, for example.

“This announcement puts the University of Michigan at the very forefront of stem cell research,” said Dr. Eva L. Feldman, director of the U-M’s A. Alfred Taubman Medical Research Institute.

“We will be one of the few institutions in the country to be creating embryonic stem cell lines targeted at understanding and treating specific inherited diseases,” Feldman said. “These stem cell lines hold so much promise for medical science, and for this reason, they will be of tremendous interest to researchers around the world.”

The consortium will distribute samples of the new lines to researchers across campus and to collaborators statewide. In addition, U-M researchers intend to submit the lines to the U.S. National Institutes of Health for inclusion in the national registry of human embryonic stem cell lines that are eligible for federal research funding.

The two new U-M lines would be the only lines on the federal registry to carry the genes for hemophilia B and Charcot-Marie-Tooth disease. There are currently three disease-specific lines on the federal registry, which contains 91 human embryonic stem cell lines.

These are the second and third human embryonic stem cell lines created by U-M consortium researchers. The first line was announced in October and was derived from a genetically normal five-day-old embryo created for reproductive purposes but no longer needed for that use and donated to the university.

The creation of all three lines was made possible by Michigan voters’ November 2008 approval of Proposal 2, a state constitutional amendment permitting scientists here to derive human embryonic stem cell lines using surplus embryos from fertility clinics.

The amendment also made possible an unusual collaboration that has blossomed between the University of Michigan and a company that describes itself as “the leading global provider” of pre-implantation genetic diagnosis (PGD) tests, Genesis Genetics of Detroit. PGD is a testing method used to identify days-old embryos carrying the genetic mutations responsible for inherited diseases.

Genesis Genetics performs nearly 4,000 PGD tests annually at its Detroit facility. Under the arrangement between the company and the university, patients with embryos that test positive for a genetic disease now have the option of donating those embryos to the U-M Consortium for Stem Cell Therapies if they have decided not to use them for reproductive purposes and the embryos would otherwise be discarded.

The agreement was worked out between U-M’s Smith and Dr. Mark Hughes, founder and president of Genesis Genetics and a pioneer in the field of pre-implantation genetic diagnosis.

“This is an example of two Michigan leaders “U-M and Genesis Genetics” joining forces to advance medicine by thinking outside the box,” said Smith, a professor of obstetrics and gynecology at the Medical School.

“This is an innovative collaboration and one that did not happen overnight,” Smith said. “This is an arrangement that’s been worked on for more than two years.”

During a PGD test, a single cell is removed from an eight-celled embryo. The other seven cells continue to multiply and on the fifth day form a cluster of roughly 100 cells known as a blastocyst.

The U-M consortium received the first disease-affected blastocysts through Genesis Genetics in November and began trying to establish a human embryonic stem cell line—a collection of millions of genetically identical cells generated from a single embryo.

“These are very precious cells, and it would be unconscionable not to take advantage of such an opportunity for medical science and the cure of disease,” Hughes said.

Genesis Genetics has a similar arrangement with Stanford University. Until the Michigan constitutional amendment passed in November 2008, Hughes said he “hadn’t even imagined that I could work with a top-flight institution right down the road, like the University of Michigan, because the state didn’t allow such work.”

Once the two new lines were established, various tests were performed to confirm that the cells displayed traits of normal embryonic stem cells. Conducting those tests is called characterizing an embryonic stem cell line. The characterization tests were completed this month.

Hemophilia B, also known as Christmas Disease, is the less common form of the disorder and is caused by the lack of clotting Factor IX. Charcot-Marie-Tooth disease is one of the most common inherited neurological disorders, affecting one in 2,500 people in the United States. People with CMT usually begin to experience symptoms in adolescence or early adulthood.

“The creation of these cell lines will provide a new tool that will help the international scientific community improve the treatment of these diseases,” said Sean Morrison, director of the U-M Center for Stem Cell Biology.

The U-M cell-line derivation project was approved by the university’s Human Pluripotent Stem Cell Research Oversight Committee and the Medical School’s Institutional Review Board. Both committees are composed of physicians, scientists, ethicists, attorneys and community members who concluded that the project would be conducted ethically, legally and to the benefit of patients.

“This scientific breakthrough demonstrates the wisdom of the voters of Michigan, who realized the importance of stem cell research for the health and well-being of the state,” said A. Alfred Taubman, founder and chair of the A. Alfred Taubman Medical Research Institute.

“We have become global leaders in the science of stem cells,” he said. “We are producing tools that can be of immeasurable aid to scientists studying such disorders as hemophilia and Huntington’s disease. And we are just beginning to scratch the surface of this new scientific frontier.”

Contributors to the A. Alfred Taubman Medical Research Institutute’s Consortium for Stem Cell Therapies include the Taubman Institute; the Office of the Executive Vice President for Medical Affairs; the Office of the Medical School Dean; the Comprehensive Cancer Center; the Department of Pediatrics and Communicable Diseases; the Office of the Vice President for Research; the School of Dentistry; the Department of Pathology; the Department of Cell and Developmental Biology; the College of Engineering; the Life Sciences Institute; the Department of Neurology; and U-M’s Michigan Institute for Clinical and Health Research.

Related Links:

• Stem cell research
• A. Alfred Taubman Medical Research Institute
• NIH Human Embryonic Stem Cell Registry