Children’s Hospital Boston was one of the first three research centers in the world to take an ordinary cell from the body and genetically “reprogram” it to a pluripotent state, creating a robust, self-perpetuating line of induced pluripotent stem cells (iPS cells) able to form all of the tissues of the body. This advance, a key milestone in stem cell research, was cited as the Breakthrough of the Year in 2008 by the journal Science.

The Children’s researchers, led by In Hyun Park PhD in the lab of George Q. Daley, MD, PhD, Director of Stem Cell Transplantation, reprogrammed skin cells from a volunteer donor by inserting just four genes known as Oct4, Sox2, Klf4 and Myc. Their report, published in Nature in 2007, was also the first demonstration that reprogramming could work in cells taken directly from a living person, rather than banked cells.Today, the study of iPS cells is an important and active area of our research. In August 2008, Children’s established the first collection of iPS cells from patients with specific diseases, including:

• Type I diabetes
• Down syndrome
• Gaucher disease
• Huntington disease
• Severe combined immunodeficiency
• Lesch-Nyhan syndrome
• Muscular dystrophy
• Parkinson disease

These new disease-specific iPS cell lines, developed from the cells of patients ranging in age from 1 month to 57 years old, have been deposited in a new core facility established by the Harvard Stem Cell Institute. By manipulating them in the lab, researchers can track the earliest development of different diseases in a Petri dish. Many of these new lines are under active study at Children’s, and are already beginning to yield new insights into their respective diseases, from premature aging to congenital heart disease to cancer. Some of these observations may change how these diseases are treated in the future. Children’s researchers are working to create additional lines specific to other diseases.

Safety and efficiency:
Children’s researchers are actively seeking ways to make iPS cells safer and the process of creating them more efficient. In animal studies, for example, some of the reprogramming genes and the viruses used to introduce the genes have been observed to cause cancer. Children’s researchers are currently investigating safer viruses as well as non-viral delivery strategies.

They are also seeking to better understand the reprogramming process itself, and the many variables that influence it. For example, the Daley Lab is exploring the role of telomeres, the tips of chromosomes that regulate a cell’s longevity, to see how reprogramming affects them.

Improving the efficiency of reprogramming is a top priority, since under current methods, only one in several thousand mature cells actually reprograms fully. Daley and colleagues are working to make iPS lines from different kinds of cells (skin, blood, and more) and investigating whether iPS lines made from different sources form one cell type more readily than another.

Recent advances:

• The Daley Lab, with collaborators, recently won a $1.7 million National Institutes of Health grant to do a comprehensive comparison of the properties of iPS cells and embryonic stem cells (ES cells) derived from various sources. One goal of this project is to determine whether iPS cells are functionally equivalent to ES cells.
• Thorsten Schlaeger, PhD, of Children’s Stem Cell Program has developed a battery of quality-control tests scientists can use when creating iPS cells. Previous tests often used markers that couldn’t reliably distinguish true iPS cells from cells that are only partially reprogrammed. Schlaeger’s work, published in Nature Biotechnology in 2009, created a much-needed standard of analysis in the field.

Related work:

The Stem Cell Program is also actively researching embryonic stem cells (ES cells) from several different sources. Click on the Embryonic Stem Cells link on the right side of this page to learn more.

Spotlight

• Capturing the origins of immune disorders

  Children with severe immune deficiencies cannot pet a cat, play in a sandbox or even hug a parent without risking life-threatening infection. Learn more about how iPS cells are helping researchers understand these diseases and investigate new treatments.

• iPS cells, Down syndrome and cancer

  The late cancer researcher Judah Folkman, MD, proposed that people with Down syndrome rarely get cancer because their extra copy of chromosome 21 gives them an extra dose of genes that block the growth of blood vessels, preventing cancers from growing. This idea has now been proven right, thanks to iPS cells derived from a patient with Down syndrome. Read more.

• Modeling congenital heart defects

  Children’s Hospital boston cardiologist William Pu, MD, is using induced pluripotent stem cells
  to understand how gene mutations prevent the heart from growing normally. With support from a National Heart, Lung, and Blood Institute Recovery Act grant, Pu’s lab is seeking to make iPS cells from patients with the heart defect Tetralogy of Fallot, which will then be used to create heart muscle cells. In the process, Pu’s team can observe how heart malformations develop, which may suggest ways to prevent or treat them.

• Stem cells and aging

  The creation of iPS cells from patients with a rare premature aging disorder brings surprises—and the possibility of treating their devastating disease.

• Quality control

  The production ofinduced pluripotent stem cells (iPS cells) is often imprecise, yielding many incompletely reprogrammed cells. Thorsten Schlaeger, PhD, of Children’s Stem Cell Program has developed a battery of tests to ensure that he has the real thing: pure pluripotent stem cells. Schlaeger’s work creates a standard of analysis in the field. Read more and click here to see image.