Back to the Future


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(l-r) Drs. Jacob Hanna and Noa Novershtern, Ohad Gafni and Dr. Abed Mansour



Time travel is still science fiction. But several years ago, Japanese scientists managed to send human cells back in time, to a very early stage of development. They took adult cells that were differentiated – at the end of their developmental road – and turned them into stem cells. These stem cells were nearly identical to embryonic stem cells – cells that have not yet “specialized,” and thus have the potential to become any type of cell in the body. The technique for creating these so-called induced pluripotent stem cells (iPSCs) consisted of reprogramming them by inserting just four genes into the cell. Ideally, iPSCs could be used to treat a range of diseases, while bypassing the ethical and technical issues involved in using embryonic stem cells from fertilized eggs. But that promise is unmet, at this point, in part because the success rate of the reprogramming is still too low.

“The reprogramming process is basically a black box,” says Dr. Jacob (Yaqub) Hanna of the Molecular Genetics Department. “We insert four genes into the cell, wait two weeks, and if all goes well we get stem cells. But we still don’t know exactly what is happening inside those cells.” A study recently conducted by Hanna and his research team has shed some light on that black box. Their findings, which appeared in Nature, reveal the function of a key enzyme that helps activate the iPSC genetic program.

To understand how adult cells can become stem cells, one must understand what makes one cell different from another: Certain combinations of genes in each cell are expressed while others are silenced. Patterns of gene expression and silencing, in turn, depend on the way that the genetic material is packaged: Exposed genes can be expressed while those that are tightly packed away don’t get used in that particular cell. The effect of the reprogramming is to change that packaging. Some of the genes that were previously exposed get packed away, while others are removed from their packaging so they can be expressed.

How do those packaging changes occur? To find out, the research team, including Drs. Noa Novershtern and Abed Mansour, and Ohad Gafni, created cells with random mutations and inserted the four reprogramming genes into them. They then looked for those cells in which the reprogramming process did not succeed, on the assumption that the mutations would tell them which genes in the cell are essential for reprogramming. In this way, they discovered an enzyme whose activities are crucial for genetic repackaging. Utx, as the enzyme is called, is activated by the reprogramming genes, and it works together with them to expose hundreds of genes that get expressed in the embryonic cell program. In adult cells, these genes are normally so well packaged that they are completely and totally silenced.
Embryonic stem cells (marked in green fluorescent protein) that should become sex cells, in which the gene encoding Utx is not present. Each column shows a gene needed for sex cell development (top row – marked in red, purple and orange). After 12 days (bottom row) the expression of the four genes has stopped and, rather than develop into sperm or ova, the stem cells die


Of course, Utx is not just waiting around the cell for a scientist to come along and produce iPSCs. To reveal its natural function, the scientists created genetically engineered mice that do not produce the enzyme. They were surprised to find that these mice were sterile. Probing further, they discovered the reason: Utx appears to be necessary for producing sex cells – sperm or eggs – in the developing embryo. On second thought, says Hanna, the finding is not all that surprising, because this process also involves a sort of developmental turning back of the clock: “To become sex cells, certain embryonic cells at a certain stage of development – after they have already begun to differentiate – need to ‘regress’ and go back to a stem cell state. The genetic program of such sex cells is very similar to that of the reprogrammed stem cells: In both cases, it is the Utx enzyme that paves the way for this regression. For this reason, our findings may have relevance for research on fertility and the search for infertility treatments.”

Understanding the details of cell reprogramming and identifying where things can go wrong may enable researchers to improve the reprogramming success rate – thus advancing the use of iPSC technology for biomedical and research applications. As an added bonus, it should advance our understanding of developmental processes. Hanna: “We succeeded in locating an important crossroads in embryonic development – that in which sex cells are created. Changes in the embryo – especially in the early stages of development – are quite difficult to investigate as they are rapid and dramatic, leaving researchers a very small window of opportunity for observation. We hope to use the insight we have gained to open more of those windows.”
Dr. Jacob Hanna’s research is supported by the Leona M. and Harry B. Helmsley Charitable Trust; Pascal and Ilana Mantoux, France/Israel; the Sir Charles Clore Research Prize; Erica A. Drake and Robert Drake; and the European Research Council.