One factor is enough for neural stem cells to become pluripotent. They can then be differentiated into smooth muscular cells that are found, for example, in blood and lymph vessels. The muscle cells are marked with red dye, and the cell nuclei fluoresce blue. 56 MaxPlanckForschung 3 | 09 BIOLOGY & MEDICINE_Stem Cells Potency Boost for Cells It is one of the dogmas of biology that no specialized cell could ever change its nature and become something different. However, the researchers working with Hans Schöler at the Max Planck Institute for Molecular Biomedicine in Münster have succeeded in using a single factor from adult brain stem cells to generate the cellular jacks-of-all-trades on which regenerative medicine is pinning its hopes. TEXT KLAUS WILHELM een from a purely optical per- emergence of Parkinson’s disease with ent’s immune system. There is, howev- spective through a microscope, a view to developing suitable drugs er, one catch: from today’s perspective, the test tube revolution doesn’t more easily and effectively. In this cut- this kind of individual form of regener- appear all that spectacular. ting-edge branch of research involving ative medicine entails enormous effort However, something extraordi- induced pluripotent stem cells, known and expense – and is conceivable only S nary recently occurred in the cells – as iPS cells for short, or “ipses” in labo- with the help of automation. which are identifiable as small dots – in ratory jargon, “we are without doubt As recently as 2005, Hans Schöler the laboratory of the Max Planck Insti- one of the world’s leading research would not have bet a single cent that tute for Molecular Biomedicine. Just groups,” says Hans Schöler. Very few the impossible would become possible two weeks ago these were skin cells teams have succeeded in reprogram- within the space of just one year, that from a patient with Parkinson’s disease – ming “diseased” human cells up to the skin cell of a mouse would be differentiated somatic cells that carry a now; in these cases, differentiation into transformed into a pluripotent stem genetic defect – and were harvested disease-specific nerve cells was success- cell by genetic manipulation alone. from a patient by doctors at the Dres- fully achieved for two rare brain and What this does, in effect, is turn the bi- den University of Technology. The cells muscle disorders. ological clock back. It is one of the were then handed over to the scientists dogmas of almost a century of modern working with Hans Schöler in Münster. FRESH REPLACEMENT CELLS biology that no specialized cell could This group provided the cells with a FOR DISEASED TISSUE ever change its nature and become mixture of nutrients and growth fac- something different. Once a cell has tors, and also infected them with virus Up to now, visionaries could conceive differentiated, it deactivates all of the particles loaded with four genes bear- of removing cells from patients suffer- genes in its genetic program that allow ing the cryptic abbreviations Oct4, ing from cardiac infarction, diabetes, it to divide without restraint. At the Sox2, c-Myc and Klf4. Parkinson’s and many other diseases, same time, it switches on the genes Over the course of about one reprogramming them into iPS cells and that specialize it, making a skin cell month, these four genes transformed replacing the diseased or injured tissue into a skin cell. some of the skin cells into “human in- with the fresh and vital cells. This Cells basically manufacture proteins duced pluripotent stem cells,” embry- would be the ideal solution and, from and other molecules that they need on onic stem cells without the embryos, so a purely technical perspective at least, the instruction of the genes. In hu- to speak. Stem cells are the cells from one that no longer seems utopian. mans, only a portion of the 25,000 or which all 200 cell types found in the Moreover, it would also eliminate one so genes are switched on in every cell. human organism develop – cells in the of the main problems faced by regener- Cells control the activity of their genes skin, bones, kidneys, stomach, and so ative medicine: the cells used in the via complicated signaling pathways in- on. Moreover, scientists hope that these treatment originate from the patient volving large numbers of proteins. This Photo: MPI for Molecular Biomedicine – Jeong Beom Kim cells will make it possible to trace the and are thus not rejected by the recipi- requires, above all, the services of tran- 4 | 09 MaxPlanckResearch 57 The pioneers of stem cell research: Shinya Yamanaka from the University of Kyoto (left) succeeded for the first time in transforming mouse skin cells into cells that are very similar to embryonic stem cells. Hans Schöler from the Max Planck Institute for Molecular Biomedicine (right) managed to propagate these pluripotent jacks-of-all-trades from mouse brain cells using a single factor (Oct4). scription factors – usually proteins that carried out successfully with 24 genes thereafter. The pluripotent stem cells switch genes on or off. But even the was amazing in itself. I would have supply the growing and increasingly transcription factors are coded by genes thought it was very unlikely to work,” complex embryo with all of the differ- and are controlled, in turn, by a com- says Schöler. ent cell types it needs to grow muscles, plex information network. In a series of follow-up experiments, internal organs, the brain, arms, legs, Yamanaka reduced the number of genes and so forth. KICK-START FROM JAPAN to just four: the quartet Oct4, Sox2, Back in 1998, it took enormous c-Myc and Klf4, all of which are normal- skill and ingenuity to propagate the Shinya Yamanaka from the University ly switched off in skin cells. In the end, extremely sensitive embryonic stem of Kyoto experimented with the genes he succeeded in harvesting pluripotent cells – as the pluripotent stem cells are for some transcription factors in 2006. stem cells. Although the process is not known when harvested from the em- When Hans Schöler describes the pio- exactly efficient – only one in every bryo – in the laboratory in a way that neering achievements and the persist- thousand to one in every ten thousand ensured they would remain unspecial- ence of his Japanese colleague, respect skin cells is reprogrammed – it works! ized and genetically intact. Today, shines through his every word, despite A new chapter in stem cell research be- there are over 500 human embryonic the intense competition in the field of gan with the unlimited self-renewing stem cell lines and the trend is rising. international stem cell research. “The iPS cells and continues to develop at an However, these cellular jacks-of-all- program of the somatic cells appeared ever-increasing pace. trades also raise ethical issues, as their to be so definite,” explains the Max As far back as 1998, US scientist harvesting results in the destruction of Planck scientist, “that most researchers James Thomson succeeded in repro- the embryo. This was among the rea- believed this could never work.” How- ducing human embryonic stem cells sons why, in the early years of this cen- ever, the unwavering Yamanaka provid- (ES cells) in the laboratory, which tury, German scientists in particular ed the kick-start for what has since been marked the very first milestone. concentrated on adult stem cells, unfolding “at breakneck speed” in the Pluripotent stem cells usually grow which can be harvested from various world’s stem cell laboratories. only at a very early stage in embryon- sources within the mature adult body. With the help of viruses that acted ic development: they collect in the in- However, these cells are not pluripo- as gene ferries of sorts, the Japanese terior of blastocysts, spherical struc- tent and can therefore differentiate to scientist transported 24 genes for tran- tures that comprise between 150 and form only a few specific cell types. scription factors in all conceivable 200 cells and that form just under one Yamanaka’s feat was a timely one. combinations into skin cells. “The fact week after the fertilization of an ovum Not only are his iPS cells pluripotent, that this kind of experiment could be and in the first eight or so cell divisions they have also succeeded in defusing Photo: dpa Picture-Alliance (left); MPI for Molecular Biomedicine – Sarah Eick 58 MaxPlanckResearch 4 | 09 BIOLOGY & MEDICINE_Stem Cells » Oct4 appears to command the reprogramming of cells like the captain of a ship. The other genes are the sailors. the stem cell debate, as they can be grown mice that develop into different Münster-based scientists even succeed- harvested without the use of embryos. cell types of the central nervous sys- ed in applying these results to stem However, one major problem re- tem. The Sox2 and c-Myc genes are al- cells from the human brain. mained: if these iPS cells are injected ready switched on in these cells. The It is clear from this “that Oct4 ap- into mice, many of the animals devel- two cell biologists quickly demonstrat- pears to command the reprogramming op tumors. The reasons for this are ed that a virus cocktail containing just of cells like the captain of a ship,” ex- clear. First, the viruses with the four in- Oct4 and Klf4 can reprogram these plains Hans Schöler. “The other genes, tegrated genes Oct4, Sox2, c-Myc and cells into iPS cells. such as Sox2, c-Myc and Klf4, are the Klf4 slot randomly into the genotype sailors.” Despite the fact that he has of the mice. As a result, things like can- TRANSFORMATION REQUIRES been working on this molecule and its cer genes can be activated or anti-can- PATIENCE functions for a good two decades, cer genes destroyed.