When identical genes just aren’t enough

This image of neurons that were derived from induced stem cells comes from a Nature paper itself--but I found it on a cool blog that features both beautiful biological images and pithy explanations!

For the last decade, everyone has been excited about the medical possibilities of stem cells.

Need a new liver?   What if we could grow one for you in essentially the same way that you grew your first liver when you were in your mother’s womb?

That’s the promise of stem cells, that scientists could take an undifferentiated cell, just like the cells that made you up before you were even you, insert your own DNA into it, and direct it to differentiate into a new liver or kidney or heart. Even better, because the new liver has your own DNA, your body’s immune system will welcome it as one of its own. In a traditional transplant, your immune system must be suppressed, or it will recognize the new liver as an outsider and “reject” it (that’s a euphemism for killing the new organ).

One problem. Those embryonic cells, known as embryonic stem cells, come from only one place: embryos. This fact has made a lot of people uneasy or worse, especially because human embryonic stem cells are derived from aborted embryos. So you can imagine everyone’s excitement a few years ago, when scientists were able to take adult cells and turn them into stem cells. These are called induced pluripotent stem cells—“induced” because they didn’t start out as stem cells, and “pluripotent,” because they have the potential to become many (think “plural”) different types of cells.

This achievement eliminated the ethical problems of using aborted embryos.  Even better, it could still produce cells that were genetically identical to the person receiving them, thereby avoiding that pesky immune system problem.

So scientists assumed. But sometimes identical genes just aren’t enough, as it turns out.  Thus transpires another opportunity for us all to learn that genes aren’t everything!

“Epigenetic effects” are biological changes in cells that are outside or beyond (that’s “epi”) of the genes. Throughout my life, my genetic sequence remains the same in every cell of my body. Clearly, however, in different cells and at different ages, those genes are “expressed” differently, meaning that different proteins are produced from the same genes under different conditions. My poor old cells know that I am heading into my mid-30s, despite the fact that their DNA is identical to the DNA of the fresh young cells that I rocked in my 20s.

Sadly, some adult cells induced into becoming stem cells may not be able to forget their real age either. A group in San Diego just published a paper in Nature showing that some types of induced pluripotent stem cells overproduce certain proteins, which allow the immune systems of the animals (mice, in this case) receiving the implanted cells to recognize them as intruders and kill them.

There are other ways of inducing pluripotency, so it’s really not the end of this kind of research. But hopefully it’s the end of assuming that it’s enough to be genetically identical. It’s also one more reason to reconsider the use of embryonic stem cells. Even on the cellular level, youth is one thing you just can’t fake.

For further reading on this research, see the link to the Nature paper above and check out the New York Times coverage.

For further reading on how scientists became fixated on DNA as a “master molecule,” check out the work of some fantastic females from my field and enjoy Evelyn Fox Keller‘s The Century of the Gene and Lily Kay‘s Who Wrote the Book of Life? A History of the Genetic Code.

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5 Responses to “When identical genes just aren’t enough”

  1. Sarah says:

    Ethics and genetics aside, there’s a whole host of issues involved in both organ-generating models you mentioned. Cost wise, embyonic will be infinitely less expensive per patient, but even then it is not something likely to be incorporated into socialised healthcare. Also, even if the scientific principle exists, realistically it will be 10-20 years in pre clinical and clinical development costing over a billion dollars (for just one indication) before this type of therapy can be commercially available.
    iPS cells are most valuable right now as a research tool.

    • Thanks so much for commenting, Sarah! It’s funny, isn’t it, that the public is generally only presented information about stem cells in the context of their potential as a medical therapy. And of course, it’s the best way for researchers to garner public funds for their research. Do you think it’s irresponsible of scientists to emphasize the possible medical application when it’s probably still decades out?

  2. Casey Katerndahl says:

    I had no idea about the 2011 Nature paper that showed that iPS cells are immunogenic. Thanks for sharing! I am not completely surprised that overexpressing or underexpressing a few genes does not turn fibroblasts into stem cells that truly match embryonic stem cells. It seems that the more differentiated a cell is the more permanent the histone modifications are. Maybe if less differentiated cells (such hematopoetic stem cells) were used as a cell source, then the histone code would be more reversible and the cells wouldn’t be as immunogenic. Also I was wondering if you knew anything about the proliferative capacity of iPS cells. I would guess that these cells would not have as high of a proliferative capacity as embryonic stem cells. Sounds like the iPS field still has some kinks to work out. Love your blog by the way!

    • Thank you, Casey. You make an interesting point, that the type of adult cell induced into pluripotency could really make a difference. I have to admit that I do not know enough about this research as a whole to know whether hematopoietic cells are commonly used or if they are used more successfully than other cell types—but it’s an intuitively appealing idea. Ditto on the proliferative capacity of iPS cells vs. embryonic stem cells. Sorry I can’t be more informative, but I really appreciate your comments!

  3. Casey Katerndahl says:

    Rachel have you read the recent publications by Carl June’s group?

    Kalos, M., et al. “T cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Extablish Memory in Patients with Advanced Leukemia.” 2011. Science Translational Medicine. 3: 95ra73.

    Porter, D., et al. “Chimeric Antigen Receptor-Modified T Cells in Chrionic Lymphoid Leukemia.” N Engl J Med. 365: 725-33.

    They were able to induce a complete response in two patients and a partial response in another patient who had chemotherapy-resistant chronic lymphocytic leukemia. These patients had no other hope and could not receive bone marrow transplants. They used a novel approach – harvested the patients’ own T cells, transduced them with lentiviral vectors that encoded tumor-specific antigen receptors and then put those cells back into the tumor-ridden patients. And within 28 days two of the patients no longer had any detectable leukemia – even by PCR. The third patient that had a partial response had the largest tumor burden and was the oldest of the patients (77 yrs old). This patient had to be put on steroids as a result of cardiac dysfunction and this could have been why he did not have a complete response. Let me clarify one other thing – the antigen receptor that they transduced into the T cells was a fusion protein composed of:

    extracellular domain: a portion of a B-cell receptor (antibody/scFv) that recognizes CD19 (which is on all B cells, including the tumor and normal B cells)

    intracellular domain: contains the signaling domain (4-1BB and CD3zeta) that activates the T cell to kill the tumor cell upon recognition of the tumor cell by the T cell.

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