another step toward regenerative medicine -- clonal precursor cells

A recently online paper from Regenerative Medicine (May 2008, Vol. 3, No. 3, Pages 281-302) entitled The ACTCellerate initiative: large-scale combinatorial cloning of novel human embryonic stem cell derivatives might offer something toward both basic research and clinical medicine.

Michael D. West (BioTime, Inc, Alameda, CA) et al. used a shotgun-like, or random induction/selection, approach to isolate 140 cell clones (hEP as they named them)from human embryonic stem (ES)cells. These cells are not ES cells anymore. They are differentiated toward various different lineages but not terminally differentiated either. What are they? Not sure yet as of now because further characterization and comparison to all known cell types in our body is required. Are they useful? Yes. 1) these cells are relibable sources because ES cells are extremely sensitive to all kinds of environment factors and too difficult to control in experiment. Therefore ES cells with the same name from different labs may actually be different things. These hEP clones, once properly characterized, could certainly provide a reliable source for research. 2) From these, further study may induce them into different cell types needed in medical research/practice. Currently, people can only induce ES cells into a limited number of final differentiated cells and they are not pure at all. These certainly limited the progress of research and regenerative medicine. They didn't say this --but I think it is very interesting and practical -- following the same shotgun approach, these hEP cells could be induced to further differentiate down the road to become more specified cell types (randomly). Certainly, some of them should be actual tissue cells and could be useful. These might actually bypass the difficult targeted induction approach.

Ethical problems? Of course. For example, what exactly are those hEP cells or the further differentiated cells as I proposed? New entity?? Questions like these certainly exist but the research should move on because humans will benefit eventually. A quote from a pioneer Sir John. Gurdon, "if something works well, ethical concerns will disappear."

MethodShare from Genome Technology

Genome Technology Online has launched another method/technology forum called MethodShare. (www.methodshare.com or http://www.genome-technology.com/forum/index.php)

There are a few articles and some discussion about various life science techniques. But so far, I don't see anything really interesting or different from other general forums such as protocol-online. It is also not necessarily good if you are particularly interested in something for example python in bioinformatics -- you'd better go to more focused places.

Anyway, it is certainly a good e-Marketing strategy. And keep an eye on it!

not necessarily new but useful tips

http://bitesizebio.com/2008/04/08/5-more-tips-for-dna-gel-extraction/

These tips might help you increase the yield and quality of your DNA sample from gel extraction.

Although the manufactures don't really put these in their manual, actual bench scientist always have good tips for improving the experiments. --Talk to them or visit these blogs. --Will help.

Blogging your thesis?!

This guy, a PhD candidate in microbiology and currently at Tulane University, is blogging his ongoing thesis writing online.
http://pimm.wordpress.com

With his advisor's approval and several journal editors' positive feedback, he's posting part of his thesis, namely the introduction (which is a kind of review), and probably material and methods. As for the unpublished result part, I doubt that his advisor will allow him to do this before publication. Open science has not reached that level yet. You still have to publish your research somewhere to get noticed and get cited. I doubt Nature or any other journals will accept a paper with a blog article as one of the references.

-- Well, keep an eye on this. Certainly a brillant idea!

--Should I also blog my thesis when I write it? Maybe --

smoking leads to lung cancer??

Have you been told or been thinking that smoking causes lung cancer? Well, this is not exactly clear from recent studies.

An association between a genetic variation on chromosome 15 (15q24/15q25.1) and risk of lung cancer was found by three independent studies. But the link to smoking, or more scientifically nicotine dependence, is not clear. Some of the studies are still preliminary. So it is still possible that people with 'abnormal' chromosome 15 tend to be affected by environment - smoking - more easily and therefore are more likely to develop cancer in the long run.

We'll see if further studies with more - up to millions of - people can make it clear.

The papers mentioned here are:

1. Hung, R. J. et al. Nature 452, 633–637 (2008).
2. Thorgeirsson, T. E. et al. Nature 452, 638–641 (2008).
3. Amos, C. I. et al. Nature Genet. doi:doi: 10.1038/ng.109 (2008).

Dynamic "cold" genetic material

Two recent papers changed the concept of "cold" DNA, the so called heterochromatin.

1. Proliferation-dependent and cell cycle–regulated transcription of mouse pericentric heterochromatin
The Journal of Cell Biology, 2007; Vol. 179, No. 3, 411-421

2. Cell cycle control of centromeric repeat transcription and heterochromatin assembly
Nature, 2008;451(7179):734-7

Genetic information resides in DNA in most organisms. DNA is packed into chromatin and stays in nucleus of a cell. There are two different package status: one loose and one tight. These are the original concepts of euchromatin and heterochromatin coined by German botanist Heitz 80 years ago. He proposed that heterochromatin reflects a functionally inactive state of the genome (all DNA information of an organism). Decades of research have generally been supportive to this idea. Heterochromatin is generally gene poor, highly packed, late replicating, and has a very low recombination rate. Modern molecular hallmarks of heterochromatin generally include heterochromatin protein 1 (HP1, swi6 in fission yeast) and methylation of histone H3 lysine 9 (H3K9) by histone methyltransferase (HMTase) (suv39, clr4). On the whole, Heitz’s original “inactive state” hypothesis still holds until recently.

The first paper demonstrated cell-cycle-specific transient disruption and transcription of mouse pericentric heterochromatin. It shows that mammalian pericentric heterochromatin is transcribed by RNA polymerase II twice during the cell cycle. A heterogeneous population of short RNAs (about 150 bp) is generated during mitosis, while a longer (mostly >1 kb) population is produced in late G1 and early S phase. Cell cycle regulation of pericentric transcription does not require Suv39h1,2-dependent chromatin modification, but it does require passage through "Start" in G1 phase. Future studies will determine whether these mammalian pericentric transcripts are important for heterochromatin formation as they are in fission yeast, as reported in the second paper. in this paper, at regions serving as RNAi-dependent heterochromatin nucleation centers in fission yeast (in the pericentric, mating-type, and telomere regions), heterochromatin is abundant during G2 but greatly reduced during M, G1 and S phases. Heterochromatin reduction in M, G1 and S is correlated with phosphorylation of histone H3 on serine 10 (H3S10) and with binding of condensins. Genetic analyses show that condensin binding (in M and G1) and methylations of H3K36 (in S) and H3K9 (in G2) all contribute toward proper heterochromatin formation in G2 and toward proper regulation of transcription of the RNAi-dependent nucleation centers during S phase.

Because centromere /heterochromatin defect is almost the most common feature of cancers, this transcription could be the most basic factor during cancer formation. It might be that this transcription leads centromere structure problem, which leads to chromosome segregation defect which cause gene mutation etc. and cancer eventually.

Combining Genomic and Clinical Data for Cancer Therapy

This just came out today. So check it out.
http://jama.ama-assn.org/cgi/content/short/299/13/1574

An article entitled " Gene Expression Signatures, Clinicopathological Features, and Individualized Therapy in Breast Cancer" in the Journal of the American Medical Association, retrospectively studied traditional diagnostic standards of breast cancer outcomes — such as patient age, tumor size, and so on — and information about gene expression by modern genomic technology in a thousand breast cancer tumors. The conclusion is appealing: Gene expression patterns can, indeed, define subgroups of women with different prognoses and treatment responses.

“The combination of these two methods, one of which uses the clinical description of a patient’s breast cancer and the other which looks at gene expression at the molecular level in a patient’s tumor, may allow us to [match drugs with patients] with unprecedented accuracy,” senior author Anil Potti, an investigator at Duke University, said in a statement.

Traditionally, breast cancer evaluation is based on factors the so called TNM classification system, such as the patient’s age, tumor size, the level of lymph node involvement, and the degree of metastasis. These clinicopathological features could be employed to make predictions about clinical outcomes and help doctor’s to determine whether adjuvant cancer therapies such as chemotherapy or radiation therapy are warranted or necessary for different patients. However the estimation simply based on these factors are not always meaningful, e.g. it tends to overestimate cancer recurrence in younger patients.

To determine whether genomic data can provide additional information, the researchers studied women with early-stage breast cancer who had been followed for on average 11 years after initial assessment.

Indeed, the researchers did find that "molecular traits of patients in the poor prognostic clusters were highly specific and distinct from those of the good prognostic carriers”.

As the authors pointed out, identifying these subgroups may not only refine predictions about patient outcomes, it also provides information about patients’ underlying biology and the tumor microenvironment. That’s because gene expression patterns reveal different genetic pathways that are activated or silenced in different tumors during the long tumor formation progress.

For instance, low expression of cancer risk genes, chromosomal instability, and so on predict good outcome. However, high expression of genes associated with oncogenic pathway activation and wound healing etc. tend to be associated with poor outcome. Some genetic signatures also might indicate different responses to chemotherapy.

As wrote in an accompanying editorial in the same issue of JAMA, by Northwestern University researchers Chiang-Ching Huang and Markus Bredel, “This is one of the largest studies in human cancer showing the ability of gene expression profiles to improve risk stratification beyond established risk assessment algorithms that take into account clinicopathological variables”. This study “demonstrates the potential value of using microarray-based gene signatures to refine outcome predictions.”