A new patent has been awarded to James Sherley for a very unusual method claimed for making induced pluripotent stem (iPS) cells.
The patent, No. 8,759,098, claims that a single non-genetic chemical agent, xanthine, can by itself reprogram adult stem cells (ASC) into iPS cells (aka iPSCs; see image they released at left).
Surprising patent, huh?
Another notable element to this patent story is the identity of the patentee: Dr. James L. Sherley.
Sherley fought a court battle (Sherley v Sebelius) with the Obama administration seeking to ban all federal funding for embryonic stem cell (ESC) research. Sherley, now leading the Adult Stem Cell Technology Center, LLC (ASCTC), lost that case so federal funding of ES cell research continues. The resolution of that case was a victory for science and patients.
The ASCTC claim of reprogramming cells by xanthine treatment alone seems striking and to me immediately brought to mind the STAP cell case. ASCTC must have realized that its claimed method would provoke some skepticism because it right away sought to distinguish its now patented iPS cell technology from STAP cells (aka acid bath stem cells):
“Unlike the recently discredited reports of acidic conditions as a single non-genetic agent for producing iPSCs, the ASCTC’s technology has a well-established historical record and biological rationale. The method was originally proposed in the National Institutes of Health (NIH) Director’s Pioneer Award research of ASCTC Director Sherley, when he was a research professor at the Massachusetts Institute of Technology.”
How would xanthine all by itself cause cellular reprogramming?
Sherley is an incredibly smart scientist so I pondered if this could indeed work, but I have to admit that after a bit of thought I’m still very skeptical that it would work. Any possible reasonable concrete mechanism escapes me. Unfortunately, ASCTC does not detail a proposed mechanism in the released material and only vaguely invokes something having to do with p53, but they say their method works really well:
“For the ASCTC technology, xanthine-expanded adult tissue stem cells are placed in commonly used iPSC culture medium supplemented with xanthine as the only additive. The usual introduction of specific genes or their experimental manipulation is not required. The new single-agent technology yields iPSCs at efficiencies similar to methods that require direct genetic manipulation.”
In my opinion this claim of high efficiency seems too good to be true.
Is there actual data to support this claim? ASCTC cites a paper by Sherley and co-author Jean-François Paré published in Journal of Biomedicine and Biotechnology.
The paper kind of proposes a mechanism for xanthine-based reprogramming:
“We find that adult mouse pancreatic tissue stem cells derived by the method of suppression of asymmetric cell kinetics (SACK) acquire increased potency simply by culture under conditions for the production and maintenance of pluripotent stem cells. Moreover, supplementation with the SACK agent xanthine, which promotes symmetric self-renewal, significantly increases the efficiency and degree of acquisition of pluripotency properties.”
This makes little sense to me and more broadly the paper’s data are pretty much entirely unconvincing.
The bottom line is that to me xanthine-based reprogramming seems too good to be true just like STAP cells did a few months ago. I don’t see the biological rationale for xanthine reprogramming cells all by itself. I could be wrong. Maybe I’m missing something and if I am, please someone provide more info/perspective in the comments. Let’s see if anyone else thinks or reports that xanthine can reprogram cells to pluripotency.
Dear Paul,
the study used “expanded adult mouse pancreatic stem cell strains derived from transgenic mice expressing the xanthine phosphoribosyl transferase
(XPRT) gene [26]. The XPRT gene is absent in mammalians.”
So, I do not think that the method can be applied to what ever adult cells. The cells should bear a construct containing XPRT gene expressing system to make this method work, and it still should be proven. .
Paul;
Can you tie in Bridgette Gomperts recent publication on the role of ROS in mediating SC-renewal with your own observations on Xanthine?
Good for him. Feds should be funding research of methods to produce and use iPSCs, instead of ethically questionable ES cells.
Here’s an interesting connection for you, Paul. Taken from your PLoS One pub in 2012.. “Thirdly, purine metabolism was found to be significantly changed in iPSCs with a decrease of the nucleotide adenosine-5-phosphate and its deamination product inosine-5-phosphate which led to an increase in xanthine, a metabolite in the purine salvage pathway [35].”
It’s not a direct connection, but an interesting circumstantial connection. Perhaps the increase in xanthine can support or maintain these populations of iPSC. More interestingly, maybe the processes by which induce stem cells rely on this metabolite for complete conversion…
Yeah, I remembered that when I read the xanthine reprogramming story. I’m not sure what to make of it though.
Congrats Sir!
Its a big win against “Obama administration Ban” With respect you are getting again federal funding. Its like over the moon for any scientist who is committed for science & their nation.
Best
Prateek
There is a genetic disorder called xanthinuria (http://en.wikipedia.org/wiki/Xanthinuria) in which the body cannot metabolize xanthine, leading to elevated levels.
Yet people with this condition are not an amorphous mass of stem cells.