Commentary Gatekeepers of organ growth (1997)

As morphologically complex animals approach adulthood,how is it that each organ knows how to arrive at its appropriatesize? This question has prompted relatively limited experi-mental inquiry during the molecular age of biological research.It did, however, spark considerable interest 30–40 years ago.Perhaps the most intriguing and controversial research on thistopic came from scientists studying organ regeneration inrodents and putative substances claimed to be capable ofselective control of organ growth.When a significant part of the liver of a rat is removed, theremaining tissue is quickly triggered to regenerate via mitoticcell growth. The same process can happen with the kidney andcertain other organs. Hepatectomized rats somehow know thattheir liver-to-body ratio is abnormally low and respond by theselective regeneration of just the right organ. Research carriedout in the 1950s and 1960s, championed by W. S. Bullough (1,2), sought to explore the phenomenon of balanced organgrowth from an experimental perspective. Rat liver tissue wasdissected, homogenized, and fractionated to separate solublecomponents from tissue debris. When injected into hepatec-tomized rats, this liver solute was observed to impede regen-eration. Similar experiments carried out with kidney homog-enates were reported to impede kidney regeneration. Remark-ably, however, liver homogenates failed to block kidneyregeneration and kidney homogenates could not block liverregeneration.Based upon these findings Bullough hypothesized the exis-tence of soluble factors whose job it was to control organ size.Such factors were dubbed ‘‘chalones’’ (Greek, to make slack),owing to the proposal by Shafer (3) that this term waspreferable to ‘‘hormone’’ for the description of chemicalmessengers that function by a depressant mode of action. Theidea was that a mature organ should produce, at its growthapex, a substance whose job it is to specifically limit furthergrowth of its cognate tissue.The assays required for biochemical purification of thesehypothetical substances were obviously difficult. Research onchalones failed to progress, was maligned, and eventuallyforgotten by modern biologists. However, to the rescue, lastspring tabloids hit the press describing ‘‘supermice,’’ labora-tory mice that display twice the normal amount of musclemass. These animals were the outcome of studies by AlexandraMcPherron and Se-Jin Lee of Johns Hopkins UniversityMedical School, two of the last keepers of the chalone talis-man.Although all previous work on chalones may have beenbogus, the concept provided McPherron and Lee with invalu-able perspective. Using modern methods of gene cloning, Leeand colleagues identified a large family of genes encodingproteins designated growth and differentiation factors(GDFs). These proteins resemble transforming growth factorb (TGF-b) in primary amino acid sequence and encodesecreted, disulfide-bonded polypeptides. Because TGF-b isknown to display growth inhibitory properties (4), it wasreasonable to hypothesize that the related GDFs might sharethis biological activity. Unlike TGF-b, however, certain ofLee’s GDFs are expressed in a highly tissue-restricted manner.For example, the first to be studied by targeted gene disrup-tion, GDF8, was known to be expressed selectively in skeletalmuscle. Lo and behold, GDF8-deficient mice are endowedwith musculature admirable even to Hollywood’s most notable(5). The product of GDF8, now termed myostatin, can therebybe interpreted to function as a selectively governor of skeletalmuscle mass in adult mice. In its absence, skeletal muscle massexpands far beyond its normal bounds.Before returning to the chalone–myostatin connection, an-other flash of the Paparazzi cameras warrants summarization.Published in this issue of the