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Engineered Blood

How induced pluripotent stem cells may eventually pave the way for stem cell therapies.

Blood: It's ubiquitous throughout the human body, accounting for almost 10 percent of our body weight. When we cut ourselves, our blood stem cells kick on, generating the specialized white cells, red cells and platelets we need to survive. Yet, despite the abundance of blood in our bodies, scientists can't get enough of it. Literally. The blood stem cells that are so good at replenishing our supply of lost blood cells inside the body refuse to do so outside the body. But with no way to grow blood stem cells in the lab, scientists have been unable to study diseases of the blood, such as leukemia, sickle cell disease and aplastic anemia. Until now.

Elias Zambidis, M.D., Ph.D., assistant professor of pediatric oncology and member of the Johns Hopkins Institute for Cell Engineering. Elias Zambidis, M.D., Ph.D., assistant professor of pediatric oncology and member of the Johns Hopkins Institute for Cell Engineering.

Scientists first looked to embryonic stem cells, which have the potential to become any cell type in the body. But, says Elias Zambidis, M.D., Ph.D., an assistant professor of pediatric oncology and member of Johns Hopkins Institute for Cell Engineering (ICE), it's a hard job convincing embryonic stem cells to become the blood stem cells required by the adult body.  "How can we coax stem cells to become different cell types? That's the holy grail question," says Zambidis, whose lab is working to recreate the human blood system from its earliest fetal stages. Researchers are now to the point that they can get embryonic stem cells to produce more of themselves, but they still don’t know how to get them to differentiate into specialized cell types.

Lenzhao Cheng, Ph.D., member of the Johns Hopkins Institute for Cell Engineering. Lenzhao Cheng, Ph.D., member of the Johns Hopkins Institute for Cell Engineering.

Stymied scientifically and politically, scientists working with embryonic stem cells turned their attention toward fancier pursuits: the genetic alteration of adult cells to resemble embryonic stem cells. They were stunned. Known as induced pluripotent stem cells, or iPS cells for short, these reprogrammed cells enabled scientists to grow blood stem cell lines in the lab for the first time. It turns out that, at least with cells, experience matters. Even though it's hard to distinguish iPS cells from embryonic stem cells, they have managed to retain some basic memory, Linzhao Cheng, Ph.D., says another ICE member. "In a way, the reprogrammed cells just go back home."

In a series of papers published in the past 18 months, Cheng and his lab showed that human iPS cells may indeed become medical technology's newest frontier. Starting with the protocol established for creating iPS cells three years ago by Shinya Yamanaka in Kyoto, Japan, Cheng and his colleagues added an extra viral protein or a household chemical to the mix. That halved the time it takes to make iPS cells, from about a month to two weeks. They can derive human iPS cells from patients or healthy donors using cells found in their skin or marrow or simply from their blood.  Human iPS cells from several types of diseases, such as sickle cell anemia and myeloproliferative disorders have been generated.  In a separate publication, the Cheng lab also demonstrated the feasibility to make gene editing in human iPS cells: they can either create a mutation for laboratory research or correct a mutation (such as one causing sickle cell anemia) for both treatment as well as research.  These studies illustrate that scientists can now study diseases of the blood in a petri dish, Cheng says. 

SEM image of normal circulating human blood. A scanning electron microscope (SEM) image of human blood cells. (Photo/Bruce Wetzel and Harry Schaefer).

The hope, says Cheng, is that scientists may eventually be able to take blood from a patient with a blood disorder, reprogram that cell into its embryonic state, correct the mutation outside the body so that the procedure poses no risk to the patient, and then generate enough corrected cells to transfuse back into the patient. As a point of comparison, for the past 40 years doctors who treat blood disorders have had to rely exclusively on the bone marrow transplant, a procedure in which a patient is transplanted with donor blood stem cells. Despite significant improvements to this procedure, including the ability to conduct transplants between half-matched patients, 14 percent of bone marrow recipients still die from graft-versus-host disease—a condition in which the new immune system fails to recognize the patient's body and attacks it. Transplants using cells from the patient's own body, however, would eliminate the risk of rejection altogether.

To be sure, says Cheng, doctors have been using autologous transplants—where a patient's own bone marrow is removed, frozen during treatment and then returned to the patient—for decades, but that option is limited to patients with blood disorders. It would be impossible, for instance, to remove a person's heart, freeze it and then retransplant it. But iPS cells are beginning to show promise in becoming other types of specialized cells.

Cheng cautions that it might be years or decades before any of this research moves to the clinical trial phase. But the progress with iPS technology thus far, he says, “has been nothing short of revolutionary."

--by Sujata Gupta