Squinting at a Regenerated Finger

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Rereading this CNN.com article on the apparent regeneration of a woman’s severed fingertip, I can’t decide which bothers me more: the frustratingly incomplete presentation of the science, the possibility that the science behind the story may actually be incomplete, or the editorial choice to turn the story into an encouragement for patients to badger their doctors for unorthodox treatments. Let’s call it a draw.

CNN.com screenshot of its story about the "empowered patient" who regenerated her fingertip

First, some background on the case. As the CNN story relates, last January, Deepa Kulkarni of Davis, Calif., lost the tip of her right pinky to a slammed door. Surgeons refused to try to reattach it, and in fact suggested removing a bit more of the finger to improve its healing, but Kulkarni was resolute about wanting her intact pinky back. Eventually, after considerable investigation, she found Michael Peterson, a nearby orthopedic surgeon who agreed to help her try an experimental regenerative therapy. Seemingly, it worked: Kulkarni proudly shows off her regrown-and-maybe-even manicured digit for CNN. It’s a happy outcome.

Nevertheless, the presentation of the science in the story is spotty, and I’m left wondering just how remarkable this minor medical miracle really is.

Spotted salamander

Spotted salamander (credit: Scott Camazine)

If one can say in the light of current technology that there’s a right way to go about regenerating fingers, Kulkarni and her physician were doing it. As Ken Muneoka, Manjong Han and David M. Gardiner describe in their April 2008 Scientific American article “Regrowing Human Limbs” (alas, behind the paywall), we humans and almost all other vertebrates lack the ability to regenerate lost digits and limbs throughout our lives because after an amputation, fibroblast cells invade the wound and form a scar over the stump as part of healing. Salamanders are the exception: in them, the fibroblasts instead develop into a structure called a blastema that resembles an embryonic limb bud. Whereas the scar chokes off the entry of additional fibroblasts and muscle cells into the wound, the blastema supports cell migration and redifferentiation so that new tissues and structures can take shape. Amazingly, the cells in the blastema then not only reenact the embryonic development of the member but, through a phenomenon called “catch-up,” grow the missing part to fully adult size faster than it did originally.

Regeneration researchers have started to have some success in mice by removing scar tissue and treating the wounds with factors that might promote blastema formation. Earlier this year in the February issue of Development, for example, Muneoka, Han and their colleagues at Tulane reported that applications of bone morphogenetic protein seemed to trigger reprogramming of the tissues in the stump of a mouse’s toe and to initiate the growth of a new digit.

So it’s tempting to think that Kulkarni and Peterson succeeded by doing essentially the same thing. But here’s where there’s room for uncertainty.

First, as far as I can tell, no formal medical paper yet documents their success. One may exist and I’ve missed it, but my quick searches through PubMed came up empty. (If anyone can point to one, please let me know.) Indeed, everything I can find on this story seems to owe to the CNN story.

The photos documenting the regeneration on CNN.com

And that seems particularly bad because CNN doesn’t seem to have documented the case particularly well. How much did the finger regrow, for example? The CNN story shows a photo of the finger after the accident, measuring almost exactly two inches long. It also shows the finger today, but without a ruler beside it.

We can also see in closeup what the finger looks like today and the amputated tip. As best I can judge, about a quarter inch of finger was chopped off in mid-fingernail. The regenerated tip does seem very nicely formed, but in the story, Kulkarni acknowledges the finger is shorter than it used to be. But how much shorter? And how much elongation might one normally expect to see even as a result of scar tissue? CNN says that Kulkarni scrupulously photographed the finger throughout its recovery but neglected to include the details.

Better documentation for a regenerated fingertip seems available in the well-publicized case of Lee Spievack, a man who accidentally cut about an inch off his right middle finger while working on a model airplane. His brother Alan, a tissue engineering researcher (handy to have one of those in the family!), applied a powder of extracellular matrix material derived from pig bladders to the wound, and within a month Lee’s finger had regrown fairly normally. Esquire seems to have dubbed this the “medical breakthrough” of 2007. Skeptical journalist Ben Goldacre, however, on his Bad Science blog, took a much dimmer view of it.

Alan Spievack went on to found ACell, Inc., the company that made the MatriStem wound powder that Kulkarni applied to her pinky’s stump. (Sad to say, he died in 2008.) According to ACell, its MatriStem materials generally promote wound healing with reduced scar formation and can be used in reconstructive procedures. Among the growth factors claimed to be in the complex collagenous mixture are bone morphogenetic proteins. The company does offer a “Finger Amputation Brochure” that discusses two cases of MatriStem wound powder having been used to help regenerate missing parts of fingers but, quite correctly, no one seems to be making ambitious claims about the treatment’s success.

Yet, even if Kulkarni’s fingertip (or Spievack’s, for that matter) did truly regenerate, it’s not at all certain how much the applied material can be credited. To quote the Muneoka et al. SciAm article (emphasis added):

One of the most encouraging signs that human limb regeneration is a feasible goal is the fact that our fingertips already have an intrinsic ability to regenerate. This observation was made first in young children more than 30 years ago, but since then similar findings have been reported in teenagers and even adults. Fostering regeneration in a fingertip amputation injury is apparently as simple as cleaning the wound and covering it with a simple dressing. If allowed to heal naturally, the fingertip restores its contour, fingerprint and sensation and undergoes a varying degree of lengthening. The success of this conservative treatment of fingertip amputation injuries has been documented in medical journals thousands of times. Interestingly, the alternative protocol for such injuries typically included operating to suture a skin flap over the amputation wound, a “treatment” that we now know will inhibit regeneration even in the salamander because it interferes with formation of the wound epidermis. The profound message in these reports is that human beings have inherent regenerative capabilities that, sadly, have been suppressed by some of our own traditional medical practices.

In short, the possibility that Kulkarni and Spievack regrew their fingertips as a result of a rare but purely natural process can’t be ruled out, and if their treatments did have something to do with it, the regrowth might have owed more to leaving the wounds open than to any applied factors.

(Also, at the risk of stating the obvious, let me emphasize that in all these cases of successful digit regeneration, what regrew were fingertips, not fingers. The regenerated tissues may have contained some structured tissues but they didn’t contain joints, which are much more complex. Regeneration of whole fingers with working joints has never been observed in humans.)

All of the preceding therefore leaves me additionally uncomfortable that CNN decided to pitch this story as a tale of a medical patient’s empowerment. It encourages its audience to “E-mail doctors you don’t know” and “Don’t be afraid to be a ‘bad’ patient.”

Yes, patients should aggressively advocate for their own health and seek out experimental trials if they might offer hope than established medicine can’t. But news stories encouraging them to second-guess their physicians and seek unorthodox therapies in the context of recoveries that may sound miraculous could send people with afflictions far worse than a missing fingertip into the arms of snake-oil salesmen. (No, I’m not implying that either Dr. Peterson or ACell have done anything wrong or unscrupulous; as far as I can tell, they have only been helpful to Kulkarni. But the world is full of quacks selling shark cartilage and laetrile who live off of the medically desperate.)

Update (added 12:55 pm): Reader Juan Jose passes along links to this announcement by the Wistar Institute and this related BBC news story, concerning the discovery that knock-out mutant mice lacking the p21 gene seem to have exceptional regenerative powers—though not complete abilities to regrow lost limbs or digits.

Noted readings:

BMP signaling induces digit regeneration in neonatal mice. Yu L, Han M, Yan M, Lee EC, Lee J, Muneoka K. Development, 2010 Feb; 137(4): 551-9.
Regrowing Human Limbs. Ken Muneoka, Manjong Han and David M. Gardiner. Scientific American, 2008 Apr; 56-63.
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