Dreams of a Pill to Enable Regeneration

Eight years ago, I assumed erroneously that the chute of my food processor was longer than my fingers.  I lost a quarter inch from the tip of my right middle finger.  Today, my finger has grown back, right down to the pattern of the fingerprint.  I am fortunate to be a good healer.  This is the extent of regeneration that adult humans can normally expect.

Many “lower” animals can regenerate large parts of their bodies when damaged.  This includes not just the legendary cases of starfish and planaria worms, but also zebrafish and salamanders.  Porpoises that have suffered deep and severe lacerations in encounters with sharks regenerate their skin quickly, without scarring.  So why can’t we?

It has long been assumed that mammals have “lost” the capacity for large-scale regeneration, and the cellular machinery is no longer present.  But 20 years ago, Ellen Heber-Katz (then at Wistar Institute in Philadelphia) noticed that a strain of mice in her lab routinely erased the ear punches that her lab used to identify them.  There was no scar or mark where the hole had been punched a few weeks earlier.  She was curious enough to investigate what was different about these mice, and traced the ability to a defective gene–a defect in a gene that shuts off regeneration.  She turned on a dime, put aside her research on immunity, and set about to breed this mouse, to study the biochemistry of this defect, and the latent power of the mouse to heal itself cleanly.  The defective gene was p21.  (read more from my blog from last year)

p21 plays a role in apoptosis, the elimination of cells that self-detect that they are damaged or dangerous or cancerous.  We might suspect that eliminating p21 would increase cancer, but that seems not to be true.  Apparently, p21 has both pro- and anti-cancer effects, and in fact, inhibitors of p21 have been studied as a strategy for treating cancer.  Mice lacking p21 can heal more effectively, and there seems to be no downside.

 

Prostaglandin inhibition

A headline in Science Daily this week announces identification of a drug that can dramatically increase healing capacity by blocking the enzyme that degrades prostaglandins.  Prostaglandins are eicosanoids, fats and oils that serve as signal molecules.  (Usually we think of signal molecules as proteins, or less commonly RNAs.)  Hormones circulate through the bloodstream and reach the whole body, but eicosanoids circulate locally, which is the definition paracrine signals.

If the word “prostaglandin” is familiar to you, it may have an association with headaches.  E2 is the most famous prostaglandin (PGE2), and PGE2 is associated with pain and fever.  NSAIDs including aspirin inhibit the COX enzymes (cyclo-oxygenase) which have a primary role in creation of prostaglandins.  This is not a side-effect but an important mode of action of aspirin.  Prostaglandins are pro-inflammatory.

We think of inflammation as destruction of tissue, and regeneration as renewing or re-building tissue.  So it seems surprising that prostaglandins should be involved so deeply in both processes.  But PGE2 is known to be associated both with inflammation and with anabolism, stem cell activity, and tissue formation.

Prostaglandins are constantly being created and degraded, signaling on a short time frame.  The amount of prostaglandin in the system is determined by a balance between production and destruction.  The new drug has already been promoted with the catchy name SW033291, and it is an inhibitor of 15-PGDH, which is the enzyme that degrades prostaglandin.

A team of scientists at Case Western (Cleveland) and U of Texas (Dallas) were searching for ways to enhance PGE2, based on preliminary evidence that it could promote healing.

Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. To date, therapeutic interventions have largely focused on targeting two PGE2 biosynthetic enzymes, cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), with the aim of reducing PGE2 production. In this study, we take the converse approach: We examine the role of a prostaglandin-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), as a negative regulator of tissue repair, and we explore whether inhibition of this enzyme can potentiate tissue regeneration in mouse models. [ref]

They noted that mice lacking the gene for 15-PGDH had twice as much PGE2, and these mice recovered more rapidly after exposure to radiation, or surgical removal of part of the liver.  They also had stronger immune systems, with more white blood cells.

 

Preliminary Findings from Heber-Katz Lab

Also new last week was a paper from the Heber-Katz lab, recently moved to the Lankenau Medical Center.  They have identified the protein HIF-1α as a target for therapy, and have preliminary, positive results for an injectible drug that enhances healing power to the level of the p21-null mice by promoting HIF-1α. “Increased expression of the HIF-1α protein may provide a starting point for future studies on regeneration in mammals.”  The chemical name of the drug is in the article, but it is not enlightening.

In a press release, Heber-Katz reports indications that the drug she is applying de-differentiates some “end-user” cells and restores their ability to act as stem cells.

“Our experiment shows the possibility of taking mature cells and, with addition of HIF-1a, causing dedifferentiation to a highly immature state where the cells can proliferate, followed by redifferentiation upon withdrawal of HIF-1a,” says Heber-Katz. “Many researchers in the field see tissue regeneration as a very complex set of events, but some of us look at it more as a process that needs to be turned on and allowed to go to completion. This is what is so exciting about what we saw with drug-induced stabilization of HIF-1a.”

 

So, What’s the Prognosis, Doc?

NSAIDs including aspirin have well-estalished benefits that lead to substantially lower mortality from heart disease, stroke and cancer.  NSAIDs work in two ways:  (1) reducing blood clotting, which is the proximate cause of most heart attacks and strokes, and (2) reducing inflammation, which is a deep cause of cancer, damage to arteries, and other ailments associated with age.  All these benefits are associated with reduced PGE2.

The new drug increases PGE2, and demonstrates some promising benefits that also have potential benefits against aging.  My guess is that this is a hint of something important, but that SW033291 itself is unlikely to have a net benefit for longevity, because its action is opposite to aspirin.  (Garret FitzGerald expresses this caution in a Perspective piece accompanying this week’s Science article.)

The benefit will come when next-stage science learns to tease apart the benefits of enhanced regeneration from the liability of increased systemic inflammation.  There is every reason to believe this is possible, but the intervention will have to come at the next level down from PGE2.

As for the HIF-1α stabilizers, the challenge at this point is that this approach requires repeated injections of time-release capsules of the drug, which has a short lifetime in the body.

Where are the p21 inhibitors?  I can find no literature on p21 drugs being studied for regeneration.