It is actually not like we thought before – ISSCR 2008 annual meeting report

by Alexey Bersenev on June 20, 2008 · 6 comments

in events, under discussion

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We don’t know the cause of death in these mice. In order to translate this technology to the clinic, we really have to understand the cause of this higher mortality… (Shinya Yamanaka)

It is actually not like we thought before – for me, this was the slogan of the conference of the year – the International Society for Stem Cell Research (ISSCR) in Philadelphia. Many previous hypotheses and journal reports were challenged. It’s understandable, because on the one hand, the field is new and dynamic, but on the other hand, a lot of publications come from many researchers’ desire to publish first and win the scientific competition. The cost of this race is too expansive: provocation in mass media and false expectations from desperate patients. Ok, let me tell you some of my thoughts about conference.

Organization:
was ok – not too bad but not so great either. There were some acoustic problems at the begining, and the absence of real food at the “final social mixer” turned me off. My main disappointment was about poster sessions – too short! 1.5-2h a day, 7pm security started to clear the hall of the scientific crowd. Nobody wanted to leave the posters. Secondly, I checked posters in the book (that summarized all the posters, presenters and locations) that i wanted to see and discuss about, ran there – and there was no presenter! Same with me – people can’t spend too much time near their own poster, because there are too many other posters to see (more then 1000) and too many people to speak with. This is a disadvantage and I have a solution – create an online database where I can search for any name or any topic and poster location easily instead of having to study this thick book. It’s so simple, why can’t the society do that on the web-site? And of course – another thing to do- extend poster session. Positive moment – free alcohol (which is definitely promote networking)!!! I was drunk every poster session.

Philadelphia near the Convention Center (I took this picture actually last year)

General trends:
1. iPS, iPS and iPS! It is a fetish!

If you’re not doing iPS or not interested – you’re not a cool scientist! So go and do it! And of course – one of winners of the best poster awards was: “creation of iPS by 2 factors”. Just add water… So, seems like a good thing about iPS is that the technique very reproducible and really works! Now everybody can make them.
Expert’s panel discussion about iPS was so crowed, but there were no questions about future therapy – too early and unsafe. Efficiency still low and reprogramming events are stochastic, tumors in 50% of chimeras created by injecting iPS in blastocyts, promoted by aged donor cells and using c-myc and (!) surprisingly high mortality rate of chimeric mice caused by unknown reasons. Panelists suggested that we need to come up with more or less standard protocol, which everybody can use to test iPS in preclinical models. It will allow to minimize differences in iPS lines heterogeneity and make results between labs around the world comparable, that overall will advance this technology.

2. OK, if not iPS, cancer stem cell then. Isolation from any organ and targeting them for therapy – very modern and fashionable.
One of my favorite talks was given by Irving Weissman. He summarized our knowledge about leukemic stem cells and reminded that some leukemias (chronic myelogenous, for instance) can be initiated not only by stem cells (in relapse) but also hematopoietic progenitors (in blast crisis of CML). Also he named new potential therapeutic targets for eradication of leukemia-initiating cells, such as CD47 and CD96. CD47 is upregulated during the migratory phase of hematopoietic stem cells (HSC) and leukemic cells and gives the command “don’t eat me!” to macrophages. CD96 is highly express on acute myelogeneus leukemia (AML) cells and in the same time it’s an activating receptor for NK cells. So, modulation of innate immunity (playing with macrophages, NK cells and their receptors) could be a new useful tool for eradicate leukemia-initiating cells, pointed out Dr. Weissman.
Many other potential targets for eradiacation of leukemic stem cells (LSC) were named in Craig Jordan report. Along with a new approach – modulation of innate immunity, he indicated antibody-ligand-based approach (CD33, CD44,CXCR4, CD123, CD38) and small molecules & compounds (MG132, ABT737, DMART, TDZD-8…). Jordan pointed out how we can keep track of anti-LSC therapy efficiency and also said that some of the molecules are moving to the clinic soon, for example clinical trial of TDZD-8.

3. Stem cell niche – very controversial and still unclear. Our japanise friends – Toshio Suda and Hiromitsu Nakauchi added more signals in the map, regulating hematopoietic stem cell (HSC) niche, such as HIF (endostel region is hypoxic – they need very low oxygen!) and TGF-beta. Speakers were asked about vascularization of endosteal region and role of mesenchymal stromal cells. Olaia Naveiras reported about negative regulation of HSC niche by bone marrow adipocytes. Seems like dividing HSC niche for endosteal and vascular is too simplistic, since so many signals and cell types surrounding HSC play a role. Maybe multiply niches exist? Or maybe it’s just one but we should look at it in 3D? Or maybe HSC don’t really care what type of cells surround them (osteoblasts, endothelium, mesenchymal progenitors or adipocytes), maybe they are really care only about singnaling, transcription factors and epigenetic regulation?

It is actually not like we thought before:
General concept of cancer stem cells was challenged by Sean Morrison (incredible guy gave unscheduled talk!). He reported about higher rate of human melanoma-initiating cells than we thought before. Using more advanced immunocompromise xeno-model – NOG mice, he concluded that frequency of tumorogenic human melanoma cells at least 1 in 330 in NOG mice compared with 100-fold less in NOD/SCID control and 3000-fold less then was reported before (used NOD/SCID model also). So, the general conclusion is cancer stem cell concept could not be applied to all of tumors and more accurate assays could change our view of previously published results.
The same xeno-model – NOG mice made Dominique Bonnet reconsider the leukemic stem cell concept, which was described for the first time in 1994-1997 by John Dick’s group on NOD/SCID mice. 10 years ago it was postulated that only human CD34+/CD38- cells from acute myelogenous leukemia (AML) samples initiate leukemia in immunocompromise mice, but not CD34+/CD38+. Now, using NOG model, Bonnet got leukemia either from CD34+/CD38- and CD34+/CD38+ cells and even in some cases AML was initiated only by CD34+/CD38+.
Using new technique called ‘chromosome orientation FISH’ or CO-FISH Peter Lansdorp was able to look at functional differences between sister chromatin in asymmetric cell division. He showed that asymmetric cell division also occured in the intestinal epithelial crypt but not only with stem cells within the niche how we thought before.

These examples can show us how new and more advanced models can change a concept or maybe even a whole research field.

Crowd:
was amazing! Very very good speakers, non-stop discussions, job searching and just hanging out with like-minded friends. George Daley – president of ISSCR looked like real leader to me. I’d like to notice that a lot of young people attended; it shows high interest in the field. I’d say that the scientific crowd made this meeting spectacular!

——————
This is my view of this remarkable event. Of course i didn’t write here everything that i was excited about during the meeting – it’s too much, but all of last week I was trying to collect all of the news and blogs reaction to the ISSCR meeting in Philadelphia. So, read more posts by other authors below, enjoy and

see you in Barcelona?

by Gregory Block (Oracy blog):
Some of My Highlights from the ISSCR
More on ISSCR – Junior Investigator Events
Senescence and MSC differentiation

by Andrea Gawrylewski and Alla Katsnelson (the Scientist NewsBlog):
Reprogramming ups mortality?
Stem cell guidelines on the way
Compounds target cancer stem cells
Embryonic stem cells still gold standard
(registration required to read)

by Monya Baker (the Niche blog):
ISSCR in Philadelphia
Stem-cell society condemns undocumented human treatments without oversight
Panel: how do you know an iPS cell is an iPS cell?

by Nature news:
Stem-cell society condemns medical tourism

{ 6 comments… read them below or add one }

Alex De Los Angeles June 22, 2008 at 6:26 am

Hi,

I was wondering, you mentioned that someone had a poster that claimed generating iPS by two factors — which factors were they? Do you remember which lab the poster came from?

All the best,

Alex

Reply

Oracy June 23, 2008 at 4:44 am

The fact that the iPS cells don’t form viable animals with high efficiency shouldn’t really be a surprise . . . I mean, the complete resetting of the genome is daunting task. One obvious possibility is incomplete reprogramming of methylated chromatin, especially within imprinted regions vital for embryo survival. Perhaps, there should be a later stage readout of differentiation potential, like the reconstitution of adult bone marrow after a tranplantation of chimeric fetal liver cells or something like that, like these guys did: Genes Dev. 2007 Feb 15;21(4):409-19.

Reply

JWS June 27, 2008 at 6:06 pm

I think Jaenisch group did bone marrow transplantation with iPS cells in mouse to correct a gene defect of sickle cell anemia. I don’t think they reported long-term survival of mice, however, or looked at in terms of epigenetic signatures. Maybe DNA methylase inhibitor or more specifically, knockout mice of methylase enzymes (that are not lethal such as MBD2) can be used as a proof of principle to see if iPS cell-derived embryos survive better.

Reply

Alex June 30, 2008 at 1:40 am

to Alex De Los Angeles –

Poster title: Pluripotent stem cell induced from adult neural stem cells by reprogramming with 2 factors.
Kim Jeong Beom et al… Scholer Hans (lab); Germany

Oct4 and klf4 are sufficient to generate iPS cells from mouse neural stem cell without drug selection.

Conclusion: in inducing pluripotency, the number of reprogramming factors can be reduced when using somatic cells that endogenously express appropriate levels of complementing factors.

Reply

Kenny November 8, 2008 at 9:23 am

Does anyone know about experiments to potentially “reprogram” a cancer cell either by putting in the key transcription factors(iPS) or nuclear transfer into ES? I just wonder how epigenetic status in the first place could predispose the DNA to mutation to begin with, but if the epigenetic state could be reset. Basically I am just wondering if a nucleus from a cancer cell could be reprogrammed to a pluripotent state…would it produce a variety of different cancers?

Reply

Alex November 9, 2008 at 3:46 am

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