Gene therapy: is IL2RG oncogenic in T-cell development?

The gene IL2RG encodes the gamma-chain of the interleukin-2 receptor and is mutated in patients with X-linked severe combined immune deficiency (X-SCID). Woods et al. report the development of thymus tumours in a mouse model of X-SCID after correction by lentiviral overexpression of IL2RG and claim that these were caused by IL2RG itself. Here we find that retroviral overexpression of IL2RG in human CD34+ cells has no effect on T-cell development, whereas overexpression of the T-cell acute lymphoblastic leukaemia (T-ALL) oncogene LMO2 leads to severe abnormalities. Retroviral expression of IL2RG may therefore not be directly oncogenic--rather, the restoration of normal signalling by the interleukin-7 receptor to X-SCID precursor cells allows progression of T-cell development to stages that are permissive for the pro-leukaemic effects of ectopic LMO2.     

Comparison of the cell cycle and cell migration in the intestinal epithelium of suckling and adult mice

Zusammenfassung Die Zellwanderung sowie die Zellvermehrung in den Krypten und auf den Zotten der Dünndarmwandung werden bei säugenden Mäusen mit dem Adulttier verglichen. Die scheinbar herabgesetzte Zellmigration ist auf das bei jungen Mäusen stattfindende Wachstum der Krypten und Zotten zurückzuführen, ist also nicht geringer als bei adulten Tieren.     

The cell cycle and turnover times of the small intestinal epithelia of the pouchless opossum,Marmosa mitis

Zusammenfassung Es wird erstmals der in vivo Zellzyklus von intestinalen Zellen des MarsupialiersMarmosa mitis beschrieben. Die bei diesem beutellosen Opossum beobachteten längeren Generationszeiten gehen gleichzeitig mit längeren Erneuerungszeiten der Epithelzellen in oberen Darmabschnitten überein.     

Gene therapy: X-SCID transgene leukaemogenicity

Gene therapy has been remarkably effective for the immunological reconstitution of patients with severe combined immune deficiency, but the occurrence of leukaemia in a few patients has stimulated debate about the safety of the procedure and the mechanisms of leukaemogenesis. Woods et al. forced high expression of the corrective therapeutic gene IL2RG, which encodes the gamma-chain of the interleukin-2 receptor, in a mouse model of the disease and found that tumours appeared in a proportion of cases. Here we show that transgenic IL2RG does not necessarily have potent intrinsic oncogenic properties, and argue that the interpretation of this observation with respect to human trials is overstated.     

The relationship between cell division and cell specialization in the mouse intestinal epithelium

Zusammenfassung Der Zusammenhang zwischen der Teilung von Ursprungszellen und der Differenzierung ihrer Tochterzellen wurde anhand von Epithelzellen des Duodenums weisser Mäuser untersucht. Um den Zustand des «steady state» zu erhalten, finden die folgenden Arten von Teilung der Ursprungszellen statt: 1) zwei neue Ursprungszellen; 2) zwei differenzierte Tochterzellen; oder 3) eine neue Ursprungszelle und eine differenzierte Tochterzelle.

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I wish to particularly thank Mrs. Z.Trirogoff for her skilled technical assistance. This work was supported in part by Research Grant No. GM 14749-01, National Institutes of Health and General Research Support Funds, UCLA School of Medicine. Portions of this work were presented before the American Association of Anatomists, Anat. Rec.157, 333 (1967).     

Electrostatic trapping of ammonia molecules

The ability to cool and slow atoms with light for subsequent trapping allows investigations of the properties and interactions of the trapped atoms in unprecedented detail. By contrast, the complex structure of molecules prohibits this type of manipulation, but magnetic trapping of calcium hydride molecules thermalized in ultra-cold buffer gas and optical trapping of caesium dimers generated from ultra-cold caesium atoms have been reported. However, these methods depend on the target molecules being paramagnetic or able to form through the association of atoms amenable to laser cooling, respectively, thus restricting the range of species that can be studied. Here we describe the slowing of an adiabatically cooled beam of deuterated ammonia molecules by time-varying inhomogeneous electric fields and subsequent loading into an electrostatic trap. We are able to trap state-selected ammonia molecules with a density of 10(6) cm(-3) in a volume of 0.25 cm3 at temperatures below 0.35 K. We observe pronounced density oscillations caused by the rapid switching of the electric fields during loading of the trap. Our findings illustrate that polar molecules can be efficiently cooled and trapped, thus providing an opportunity to study collisions and collective quantum effects in a wide range of ultra-cold molecular systems.     

Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy

The gene Prph2 encodes a photoreceptor-specific membrane glycoprotein, peripherin-2 (also known as peripherin/rds), which is inserted into the rims of photoreceptor outer segment discs in a complex with rom-1 (ref. 2). The complex is necessary for the stabilization of the discs, which are renewed constantly throughout life, and which contain the visual pigments necessary for photon capture. Mutations in Prph2 have been shown to result in a variety of photoreceptor dystrophies, including autosomal dominant retinitis pigmentosa and macular dystrophy. A common feature of these diseases is the loss of photoreceptor function, also seen in the retinal degeneration slow (rds or Prph2 Rd2/Rd2) mouse, which is homozygous for a null mutation in Prph2. It is characterized by a complete failure to develop photoreceptor discs and outer segments, downregulation of rhodopsin and apoptotic loss of photoreceptor cells. The electroretinograms (ERGs) of Prph2Rd2/Rd2 mice have greatly diminished a-wave and b-wave amplitudes, which decline to virtually undetectable concentrations by two months. Subretinal injection of recombinant adeno-associated virus (AAV) encoding a Prph2 transgene results in stable generation of outer segment structures and formation of new stacks of discs containing both perpherin-2 and rhodopsin, which in many cases are morphologically similar to normal outer segments. Moreover, the re-establishment of the structural integrity of the photoreceptor layer also results in electrophysiological correction. These studies demonstrate for the first time that a complex ultrastructural cell defect can be corrected both morphologically and functionally by in vivo gene transfer.