Interesting commentary. Chemists still the most popular hire in biotech. But multi-disicplinary training is increasingly viewed as key:
The introductory analysis highlights a
common theme addressed by all interviewees
and points to a clear shift in the industry’s
demand for talent away from the senior scientist
positions that tend to be more highly
specialized and narrowly focused, to a talent
pool consisting of individuals who have
interdisciplinary academic training with the
ability to work broadly across multiple areas
and in project teams where not everyone has
to be an expert in everything.
Interesting analysis from the Sorger lab of dose-response curves for various lethal compounds in different cell lines. Lots of variability for the same compound between cell lines. This information can be used as the basis for richer characterization of lethal mechanisms, etc. It will be a nice challenge to relate changes in the slope of the curve, Emax and other variables to specific biological mechanisms.
An important question is how different cell death pathways interact with one another. Caspase 3/7 can cleave PARP, for example, which might prevent PARP-mediated cell death (parthanatos). In this paper, the Bogyo lab identifies an activity-based small molecule probe for caspase-1 and uses this to show that when caspase 1 activity is blocked, immune cells will still die, except now instead of dying via caspase 1-dependent pyroptosis, they die via classic caspase 3/7-medaited apoptosis. Clearly there is much redundancy in the cell death networks of the cell, as might be expected for such an important process.
Late to the party here, but this excellent paper from 2010 identifies the E3 ubiquitin ligase CRBN as a target relevant to the teratogenic effects of thalidomide. Inhibition of CRBN (either genetically or using thalidomide) results in dysregulation of FGF expression crucial for limb outgrowth. A nice example of where a small molecule exactly mimics the effects of a gene disruption. Further, thalidomide can be used as a tool to study CRBN function.
I enjoy papers that combine insights from multiple experimental models and systems. In this paper Giorgini's group first screens for suppressors of mutant Huntington protein (Htt)-induced cell death in yeast using a genome-wide ORF library, then validate hits in mammalian cell culture and Drosophila neuronal models. They identify a conserved role for glutathione peroxidases (GPXs) - important antioxidant enzymes - as inhibitors of Htt-induced pathology. These results support the notion that ROS are important for Htt-induced neuronal pathology. Again, however, the issue of cell-type specificity in vivo remains mysterious. Why is mutant Htt expression only lethal to a subset of neurons?
HIV virus kills CD4+ T cells, ultimately impairing the function of the immune system. It now appears that the death of these cells results from the integration of the provirus into the genome and is mediated by a signaling pathway involving the ATM/ATR family kinase DNA-PK. Inhibition of DNA-PK prevent HIV-induced apoptotic death, but actually enhances DNA damage-induced death, showing that it plays opposing roles in the response to different forms of DNA damage stress.
Pyroptosis is a form of non-apoptotic death typically observed in immune cells. Hett & Hung show that the protein kinase PKR is required to induce pyroptosis in response to anthrax lethal toxin. They figured this out by first finding a new small molecule inhibitor of death (7DG) in a large-scale phenotypic screen and then showing that it binds to PKR in pull-down experiments. PKR kinase activity itself is dispensable for death, surprisingly. Cool approach and findings.
A few years ago Zach Schafer was lead author on a paper showing that detachment of mammary cells from the ECM resulted in oxidative cell death that could be prevented by antioxidants. Cell death here did not involve ferroptosis (as we thought it might for awhile). Rather, ROS inhibited fatty acid beta-oxidation in the mitochondria and this resulted in a lethal drop in ATP levels in the cell. Now, Zach's lab has shown that this mechanism is active in tumors formed in mice and that the expression of SOD and catalase is essential to prevent the death of these cells. Yet another rationale for targeting the redox networks of cancer cells.
Methods, important findings and future directions in a very interesting field.
The portion of the proteome that is in theory considered "druggable" (i.e. amenable to small molecule modulation) is thought to be small (~1% of the total). And yet....we keep finding new druggable proteins and classes, such as this new report of both covalent and allosteric inhibitors for VCP/p97, an interesting AAA ATPase implicated in cancer and other processes in humans.
Some exciting recent advances in understanding how the chromatin state can affect the response to DNA damage. With all the usual thoroughness and clever use of in vitro reconstituted systems, Dan Durocher's lab shows that 53BP1 recognizes and is recruited to dimethylated and ubiquitinated histones (marks present at the site of DNA damage). In a similar vein, Michael Yaffe's lab shows that the BET domain-containing protein Brd4 (isoform B, specifically) influences the number and size of DNA damage foci in the nucleus by modulating chromatin compaction. Less clear to me exactly what implications this may have in vivo, but a nice use of high-content RNAi screening and the small molecule Brd4 inhibitor JQ-1 to dissect the phenotype. I wonder if cancer cells, due to modifications in the chromatin state associated with mutation, etc, become more or less susceptible to specific forms of DNA damage?
A few years ago the Cantley lab published a beautiful study showing the oxidation (in response to ROS) of a key cysteine residue in PKM2 regulated cancer cell metabolism by promoting the accumulation of NADPH, via the pentose phosphate pathway, and GSH. A new probe report suggests that the small molecule ML285 protects PKM2 from oxidation, eliminating this feedback regulatory mechanism and resulting in enhanced cell death.
We all know that p53 is often mutated in cancer. But what about the other p53 family members? New results suggest that p73 is often overexpressed in cancer and that this promotes resistance to oxidative stress via up-regulation of the pentose phosphate pathway (PPP) enzyme G6PD. More PPP flux, more NADPH, more reduced glutathione, better cancer cell viability. What are the drawbacks here, I wonder? Why wouldn't a 'normal' cell also want better antioxidant defences?
Huge advance from Tony Pawson's lab in our understanding of signaling dynamics downstream of receptor tyrosine kinase activation. They use scheduled multiple reaction monitoring to define how the composition of a signaling complex nucleated by the Shc1 adapter protein changes over time, directing different outputs downstream of EGF receptor activation. Makes me nostalgic: my first graduate project concerned a related protein, FRS3. Also was very fortunate to have Tony as one of my thesis committee members back in Toronto.