Nature Insight: Regenerative Medicine to keep you updated!

The 2006 Nature Insight: Stem Cells edited by Nature Report Stem Cells editor Natalie DeWitt is still a basic reading for me. The newest Nature is accompanied by a similar supplement called Nature Insight: Regenerative Medicine

BioBarCamp in the Valley before the SciFoo Camp!

It seems that my favorite ever unconference, the SciFoo Camp will be aroundunconferenced by a BioBarCamp this year. The whole idea of the BioBarCamp is based upon the SciFoo Camp, so it is by no means a competitive but a complimentary event.

From the BarCamp wiki: “The BioBarCamp is an idea (fed by the tweets of the BioTwitterer community) to organize a life sciences - biotechnology - personalized genomics & medicine - bioinformatics unconference at the Bay Area around the 3rd SciFoo Camp time, which is 8-10th August. The SciFooCamp generates a lot of enthusiasm & activity but not just for those who are invited (only 200). On the other hand, it would be nice to organize a bio-related BarCamp, just like the Cambridge BarCamb, in which the bio-related SciFoo Campers and all the other biogeeks could gather together.”

The main activity is happening right now at the public BioBarCamp Google Group. If interested please join there or just follow the discussions. We are right now in the process of finding a proper venue and sponsors and any help would be most welcome. Right now 6 or 7 August seems to be the consensus day and we have a very generous offer from The Institute for the Future via Alex Soojung-Kim Pang in Palo Alto (no response from 23andMe so far, see below).

It’s against a classic Twitter story, just like this before. You can reconstruct the whole conversation with Twitter Search Engine Tweet Scan by searching for terms SciFoo, BioBarCamp, SciBarCamp but here are my selected tweets:

Scene One, 04/10/08 How the idea was born on that day in reverse chronological order:

Scene Two 04/22/08 How the biospecificity and name was born alongside with a possible venue idea:

Human proteome project: 21000 genes/1 protein, 10 years, $1 billion?

In order to have the slightest change to design a robust, systemic life extension technology, we need to accumulate every systemic macromolecular, cellular, tissue- and organ level data of the normal, physiological human body, connect the trillions of nodes with scalable software algorithms and suck out the draft of the proper sequence of consecutive treatment/regeneration steps later. Fortunately not only life extension technology needs systems biology projects (this is not enough for getting grants), but more importantly the effective design of new drug targets and the discovery of disease biomarkers are clearly crying for the systemic level. The urgent diagnostic and therapeutic demands are sufficient to launch international, many-lab projects.

Finally a complete ‘Human Proteome Project’ is in the pipeline (illustration via BioMed Search). It aims the tissue-level complete knowledge of the human proteome revealing “which proteins are present in each tissue, where in the cell each of those proteins is located and which other proteins each is interacting with”. Keep in mind also that around 21′000 human genes encode 1 million different proteins and that the effort cannot localize exactly which cell types in a given tissue is producing which protein. According to Nature’s Helen Pearson: Biologists initiate plan to map human proteome

“Those involved in the draft plan say that a human proteome project is now feasible partly because estimates of the number of protein-coding genes have shrunk. It was once thought that there might be around 50,000 or 100,000, but now, just 21,000 or so are thought to exist, making the scale of human proteomics more manageable. And the group plans to focus on only a single protein produced from each gene, rather than its many forms.

The plan is to tackle this with three different experimental approaches. One would use mass spectrometry to identify proteins and their quantities in tissue samples; another would generate antibodies to each protein and use these to show its location in tissues and cells; and the third would systematically identify, for each protein, which others it interacts with in protein complexes. The project would also involve a massive bioinformatics effort to ensure that the data could be pooled and accessed, and the production of shared reagents.”

The idea is to analyze and list all the proteins manufactured by chromosome 21 within 3 years as a pilot study and then finish the whole project within 10 years. Chromosome 21 is the smallest child in the family and likely contains between 200 and 400 genes, so the pilot study can yield us a couple hundreds proteins. Another powerful idea (actually I prefer this) is to start with the human mitochondrial proteome which is around 1000-1500 proteins as far as I know, that is at least 3 times as many as encoded by chromosome 21.

Thesis live: 1.2 Liver, regeneration and stem/progenitor cells

In the live thesis building blogxperiment I edit (digest, compile, write, rewrite, delete) my ongoing doctoral thesis in blog posts and put the parts together on thesis live. The title: The physiologic role of stem cells in tissues with different regenerative potential.

1.2. Tissues, organs with different turnover and regenerative potential

/bioenergetics data missing/

Liver

During organogenesis the hepatic endoderm epithelium invades the surrounding mesenchyme to form the liver bud and continued epithelial/mesenchymal interactions stimulate cell proliferation and morphogenesis. Consequently, the liver is largely of endodermal origin - including cells with a mesodermal origin and - and contains many different cell types: two epithelial liver cell types, the hepatocytes and bile duct cells, stellate cells (formerly called Ito cells), Kupffer cells, vascular endothelium, fibroblasts, and leukocytes (Desmet 1994). Hepatocytes are the main funtional liver cells accounting for ~70% of the cells in the liver and form the bulk of the liver weight (90%), yet only ~60% of total liver DNA is hepatocyte-derived (many of them with 2n, 4n, 8n DNA content). An adult human liver contains about 80 x10(9), hepatocytes. Hepatocytes are in a quiescent state and the turnover rate is low, 1-2 times/year[]. The remarkable regenerative potential of liver is well-known, in humans the liver almost completely regenerates in about 1 month after two-thirds (up to 75%) partial hepatectomy and this process can occur repeatedly in contrast to most other parenchymal organs, such as kidney or pancreas. In the literature the term liver or hepatic stem cells is used for precursors of the hepatocytes and the bile duct epithelial cells. On the other hand liver stem/progenitor cells can be define in different ways.

Thesis live 1.1 The stem cell niche

In the live thesis building blogxperiment I edit (digest, compile, write, rewrite, delete) my ongoing doctoral thesis in blog posts and put the parts together on thesis live. The title: The physiologic role of stem cells in tissues with different regenerative potential.

1.1 Stem cells and regenerative medicine

The concept of the stem cell niche was first proposed theoretically by Schofield exactly 30 years ago in the context of hematopoietic stem cells: “a hypothesis is proposed in which the stem cell is seen in association with other cells which determine its behaviour. It becomes essentially a fixed tissue cell. Its maturation is prevented and, as a result, its continued proliferation as a stem cell is assured. Its progeny, unless they can occupy a similar stem cell ‘niche’, are first generation colony-forming cells, which proliferate and mature to acquire a high probability of differentiation, i.e., they have an age-structure.”

Niches are restricted and specialized tissue microenvironments that integrate local and systemic signals for the regulation and maintenance for resident stem cells. The elements of the stem cell niche include the constraints of the architectural space, cellular components like stromal supporting and descendent/progenitor cells and acellular elements, like soluble and membrane bound molecules, paracrine and endocrine signals from local or distant sources and neural input [Figure by Jonas].

Niches are dynamic entities, could be redistributed and ideally “a candidate niche

Thesis live: 1.1 Turnover or Every cell has a lifespan

In the live thesis building blogxperiment I edit (digest, compile, write, rewrite, delete) my ongoing doctoral thesis in blog posts and put the parts together on thesis live. The title: The physiologic role of stem cells in tissues with different regenerative potential.

1.1 Stem cells and regenerative medicine: basic concepts

/turnover: cellular turnover/

The concept of biological turnover (rate) can be interpreted on many levels: molecules, molecular pathways (signaling), organelles, cells, tissues, organs. The turnover rate by which a biological entity is replaced can be quantified by measuring its half-life. /In abstract form “the half-life of a quantity whose value decreases with time is the interval required for the quantity to decay to half of its initial value” (Wikipedia) I have to check whether it is problematic to explicitly use a Wikipedia entry - I am sure it is used implicitly - in a PhD thesis/ The concept of half-life refers to the time required for an initial quantity of entity E to decay half of its initial value. According to Caplan [reference]: “Every cell in the body has a specific half-life; every cell comes to maturation and will, predictably, drop dead in due course.” For instance erythrocytes have half-lives of 60-90 days and the turnover rate of hepatocytes is 1-2 times/year. On Figure 1 from Caplan the lineage development of a differentiated cell and its replacement cell is delineated. The relative position of these two curves to one another defines growth, steady-state, or atrophy depending on when the first cell dies and when its replacement, the second cell, comes online. /I am not sure here how to solve the problem of legends in the case of figures coming from the literature but I figure it out, here is/

Thesis live: 1.2 tissue/stem cell introduction scheme

In the live thesis building blogxperiment I edit (digest, compile, write, rewrite, delete) my ongoing doctoral thesis in blog posts and put the parts together on thesis live. The title: The physiologic role of stem cells in tissues with different regenerative potential.

When producing a text, a post my building strategy is not linear, but heavily non-linear (I wouldn’t say it’s circular): I’d like to jump to the part of the story where there is something instantly to write/edit; be it the beginning, middle or end. In case of scientific articles frequently the first part to be build are figures/methods, which forms the bulk, the middle of the story after introduction, before discussion.

1.2. Tissues, organs with different turnover and regenerative potential

In order to discuss the different adult tissues in a unified manner, from a systemic point of view, I use the following tissue/stem cell introduction scheme where data are available: development of particular tissue, number of cell types, bioenergetics (high/intermediate/low energy demand), turnover (high/intermediate/low), regenerative potential (high/intermediate/low), resident stem cells, niche, markers, cell sources from other tissues that can contribute to the particular tissue during normal turnover or chronic/acute injury.

Thesis live: 1.1 Basic concepts: Let’s roll!

In the live thesis building blogxperiment I edit (digest, compile, write, rewrite, delete) my ongoing doctoral thesis in blog posts and put the parts together on thesis live. The title: The physiologic role of stem cells in tissues with different regenerative potential.

After the Introduction draft it’s time to actually start to fill in the text and that’s really the hard part. In the text I mix complete sentences, paragraphs (source code, object language) with fragmented metacomments (labeled as /draft, comments are here/) as a GTD technique. Used literature, links come after the text in a reference form like: Rando TA. Stem cells, ageing and the quest for immortality. Nature 2006;441:1080-1086. or Rando TA. (2006) Stem cells, ageing and the quest for immortality. Nature 441:1080-1086. (maybe I should check the official rules here)

Figures, diagrams will be included and I don’t promise to figure out brand new ones (but promise to find good ones), but that’s not a necessary job for thesis writers.

Expect me to start with a low quality (including older texts of mine) material and progress toward something more valuable.That is a trend people usually would like to follow throughout their professional careers.

1.1 Stem cells and regenerative medicine: basic concepts

Looking for the exact definition of stem cell is sometimes the source of endless semantical debates, but at least we do know two generally accepted criteria: stem cells are able to renew themselves and could differentiate into other type of cells. First, they are unspecialized, mitotic cells that renew themselves for any (i.e. long) periods through series of cell divisions, which result in similar unspecialized stem cells. This is the so called and overstated “immortality” characteristics.

Oxygen control of stem cell niches and cell fates

Did you know that physiological normoxia generally falls in the 2-9% O₂ (14.4-64.8 mm Hg) range for most adult cells in vivo? 3 remarkable exceptions are thymus, kidney medulla and most importantly bone marrow which can exist at 1% O2 (7.2 mm Hg). On the other hand, stem and progenitor cells are frequent residents of hypoxic niches and low O₂ regulates their differentiation. Conclusion?

Although most cells are maintained in culture conditions at 21% O₂, this is unlikely to be optimal for maintaining their normal proliferative or developmental state. The derivation of novel stem and undifferentiated cell populations should therefore be enhanced by culture in the range of 3–5% O₂.

More on this very important and usually neglected oxyphsiological angle on stem cells, development and culture in the very uptodate review: The role of oxygen availability in embryonic development and stem cell function by Simon@Keith in Nat Rev Mol Cell Biol. 2008 Apr;9(4):285-96.

Some stem cells (such as those in the endosteal bone marrow compartment) occupy extremely low O2 microenvironments (<0.5% O2)

Ward Cunningham - What If Bacteria Designed Computers?

There is a pattern of successful technological innovations I can summarize the following way: there is a nerd engineer who actually invents something and builds the first functional prototype, and there is a geeky enough yo who recognizes the value of the prototype and makes the bigger money/fame/other beneficiaries out of it by turning it into a commercial product: the archetypal nerd/geek pair in this respect is Wozniak/Jobs. In case of the wiki software the programmer/inventor was Ward Cunningham, while Jimmy Wales became the official Mr. Wiki due to Wikipedia.

Recently I discovered Cunningham on Twitter and I learnt that for coding he takes inspiration from life’s processes ranging from cell signaling to cultural evolution. His coming speech:

Friday Gumbo Journal Club: hESC line differences and a killer MSC review

It’s Friday, that is a lunch heaven for a Gumbo loving biogeek at Tulane:

Stem Cell Express: Copy Number Variant Analysis of Human Embryonic Stem Cells from the Teitell Lab (It’s good to see that CIRM funded results and papers are coming out):

Mitowheel now helps you design PCR primers for mitochondrial DNA!

Gábor Zsurka, scientist and developer made another upgrade on our favorite human mitochondrial DNA visualization tool, MitoWheel: this time allele frequencies at polymorphic positions are included in the sequence bar in the form of a gray bar above or below a nucleotide representing the number of individuals carrying the SNP.

This is really cool as it is a definite step to turn MitoWheel into a tinkering, engineering, mtDNA hacking tool besides its core science mission:

“This can help you to design reliable PCR primers for the human mitochondrial genome. After all, you don’t want your primer’s 3′-end sitting right on a very frequent polymorphism (risking that under certain conditions you will not be able to amplify a PCR fragment from a subset of individuals).” Source: MitoWheel Blog.

Blow your Brain Explorer out with the Human Allen Brain Atlas!

At the SciFoo Camp last year at the Googleplex I suggested a little unconference session (ok, there were some slides ready on my MacBook) and one participant was Chinh Dang (another was this inventor) Technology Director of the Allen Institute for Brain Science who made a little intro to the work of the Institute to the 9-10 attendees after this slide of mine:

Paul Allen is the likable, Steven Wozniak-type co-founder of Microsoft, but I guess a bit richer (once we estimated with a friend of mine that he could buy all the Budapest condos circa 180 times or sg like that).

But instead of doing that he provided $100M - amongst others - in seed money to fund the Allen Brain Atlas.