BETATROPHIN FACES SCRUTINY

     

Islets of Langerhans are made of four different cell types.
The majority are insulin-producing beta cells (shown in green)

A study published in Cell last year offered evidence that a hormone called betatrophin, or Angiopoietin-like protein 8 (ANGPTL8), could ramp up pancreatic β cell proliferation in a mouse model of insulin resistance. [1] The results made quite a splash; the study’s authors—led by Doug Melton at Harvard University—even wrote that betatrophin treatment “could augment or replace insulin injections by increasing the number of endogenous insulin-producing cells in diabetics.” [2]

Early this month, Melton and his colleagues report a complex recipe that can transform either human ES cells or iPS cells directly into functional β cells. The breakthrough is based on more than a decade of tenacious work in Melton’s lab. He and his colleagues have painstakingly studied the signals that guide pancreas development, applying what they and others have found to develop a method that turns stem cells into mature β cells. “There’s no magic to this,” Melton says. “It’s not a discovery so much as applied developmental biology.” The protocol “is reproducible, but it is tedious,” Melton adds. The stem cells are grown in flasks and require five different growth media and 11 molecular factors, from proteins to sugars, added in precise combinations over 35 days to turn them into β cells. On the bright side, Melton says, the technique can produce 200 million β cells in a single 500 ml flask—enough, in theory, to treat a patient. Melton says the protocol seems to work equally well with ES and iPS cell lines. [3]

But a follow-up study by an independent group of researchers found that the hormone is not required for β cell function or growth. “The lack of expansion of the beta cell area could theoretically be due to simultaneous increases in replication and apoptosis frequencies. However, even if this were the case, it would not change our observation that Angptl8 overexpression did not increase beta cell area, contrary to what was reported by Yi et al. (2013),” Viktoria Gusarova of Regeneron Pharmaceuticals and her colleagues wrote in a Cell paper published October 23. [2]

 Melton’s group redid its experiments to see what might have caused the discrepancy, finding the same result as Gusarova’s team. The problem appears to have been variability in how the mice responded to betatrophin. “Some mice respond strongly to ANGPTL8/betatrophin expression but many do not” Melton and his colleagues wrote in a response article accompanying Gusarova’s study [2]____________________________________________________________________________________________________________

References

1 P. Yi  et al: Betatrophin: A hormone that controls pancreatic B cell proliferation,
Cell 153, 747-758 (5) (2013)  | doi: 10.1016/j.cell.2013.04.008

2 Diabetes 'Breakthrough' breaks up | The Scientist |27 October 2014 | ArticleTS

3 For diabetes, stem cell recipe offers new hope |Science | 9 October 2014 | ArticleSci

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A new evolutionary theory 

could explain the origins of eukaryotic cells

Scientists have long pondered the question of how simple "prokaryotic" cells, like bacteria, which are little more than a membrane-bound sack, evolved into more complex eukaryotic cells, which contain numerous internal membrane compartments. These compartments include the nucleus, which holds genetic information in the form of DNA; the endoplasmic reticulum, which shunts proteins and lipids around the cell; and mitochondria which act as the cell's powerhouse. The mitochondria also contain their own distinct DNA, which is one good indicator of their once having been separate organisms. The trouble is that no one has identified eukaryotic cells that are intermediate in complexity, making it much harder to know how they evolved. [1]

At present, the most widely accepted theory is that mitochondria derive from a bacterium that was engulfed by an archaeon (plural = archaea), a kind of prokaryote that looks similar to a bacterium but has many molecular differences. The eukaryotic membrane systems, including the nuclear envelope, then formed within the boundaries of this archaeal cell through the invagination of the outer membrane. This fits with much current data, but a few problems remain. Most significantly, no archaeal cells are known that invaginate membranes [1]

In his paper published in BMC biology, David Baum from the University of Wisconsin explains:

'' we invert the traditional interpretation of eukaryotic cell evolution. We propose that an ancestral prokaryotic cell, homologous to the modern-day nucleus, extruded membrane-bound blebs beyond its cell wall. These blebs functioned to facilitate material exchange with ectosymbiotic proto-mitochondria. The cytoplasm was then formed through the expansion of blebs around proto-mitochondria, with continuous spaces between the blebs giving rise to the endoplasmic reticulum, which later evolved into the eukaryotic secretory system. Further bleb-fusion steps yielded a continuous plasma membrane, which served to isolate the endoplasmic reticulum from the environment '' [2]

David Baum explains the differences between the outside-in and inside-out theories using a metaphor: "A prokaryotic cell can be thought of as a factory composed of one large, open building in which managers, machinists, mail clerks, janitors, etc. all work side by side. In contrast, a eukaryotic cell is like a factory complex, composed of a several connected work spaces: a single control room and specialize rooms for receiving, manufacturing, shipping, waste disposal, etc. The traditional theories propose that the factory complex arose when partitions were built within a single hangar-like building. The inside-out theory, in contrast, imagines that a series of extensions were added around an original core building -- now the control room -- while others functions moved out into new, specialized quarters. [1]

The inside-out theory provides an alternative framework by which to explore and understand the dynamic organization of modern eukaryotic cells. 

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References

1 How did complex life evolve? The answer could be inside out | Science Daily | October 2014 | http://bit.ly/1wLN1En

2 David Baum, Buzz Baum: An inside-out origin for the eukaryotic cell, BMC biology, 12:76 (2014)

 |doi:10.1186/s12915-014-0076-2

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