Monthly Archives: October, 2014

What is Collaborative Cross Recombinant Inbred (CC-RI) mice?

I was nicely surprised to see that on October 30, 2014, journal Science published an online article, in advance of print, that described experimental results with Ebola virus using Collaborative Cross recombinant inbred (CC-RI) mice.

Just day before, on October 29, 2014, I suggested that the common laboratory mice strains, like B6 or Balb/c, may not represent an adequate experimental models to study viral-host interactions relevant for human health.

To overcome some of the limitations of common laboratory mice, the authors in this paper have used so-called Collaborative Cross recombinant inbred (CC-RI) mice.

Honestly, I have not heard about these mice until I read this paper. So I read a little bit about CC-RI mice to understand the advantage of using them in this study. It appears that these CC-R inbred mice are derived from eight founders (C57BL/6J, A/J, 129S1/SvImJ, NOD/ShiLtJ, NZO/H1LtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ) that capture around 90% of gene diversity in all mouse.

I would like to explain how CC-RI mice are useful. For example, take as an example Ebola virus and host susceptibility or resistance to it as in this paper.

How to study which genes confers resistance or susceptibility to Ebola? What will be your control? Any given laboratory mouse strain will have an unique response to Ebola virus. Trying to compare two laboratory mouse strains may provide information that one strain is more or less susceptible or resistance compared to other mouse strain [to Ebola virus], but it will not tell you what makes this difference. Why is that? Because gene difference between mouse strains is too huge and there is no way to pinpoint to any gene of gene loci.

Here is where having CC-RI mice are helpful. Starting from eight founder strains, CC-RI mice are derived by multiple, marker-assisted inter-crossing between founder strains and their F1 off-springs. In the end, one can get CC-RI mice that differs from other CC-RI mice with just small known loci in entire genome. This locus or loci may contain either just one gene or few genes. Of course, number of CC-RI mice strains will be in hundreds.

See Genetics. Feb 2012; 190(2): 389–401.

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Now, one can conduct experiment on these different CC-RI mice and determine what gene or gene loci are responsible for observed phenotype.

In this new science paper the authors have used 47 CC-RI mice strains, 4-5 mice per group or per time point. The authors found that endothelial tyrosine kinases Tek (Tie2), determines susceptibility to Ebola virus in CC-RI mice. TEK signaling promote activation of coagulation factors, such as thrombin, so it make sense if considering that Ebola virus affects blood coagulation timing.

This type of experiments require enormous resources (imagine conducting experiments on hundreds of different CC-RI mice strain with 5-8 mice in each strain).

I hope someone will come up with new idea how to do this type of screening easier way.

posted by David Usharauli

What can we learn from Ebola outbreak?

It appears that Ebola 2014 outbreak is the first large-scale outbreak of a lethal virus in living memory. No other viral outbreaks, such as SARS, H5 or H7 Flu, MERS can come close.

While Ebola 2014 brought suffering and fear, it also brings an opportunity to create a scientific breakthrough in understanding and management of highly virulent infections.

Death rate for Ebola 2014 is estimated to range from 50% to 75%, so far. It is highly lethal. Even Black death in 14th century had on average 30% death rate (1 out of 3). For comparison, during Flu pandemic of 1918 around 50 million people died that represented ~ 2% of total world population in 1918 (death rate ranged from 2.5% to 10%). So, it is obvious Ebola is more lethal.

In general very few pathogens are so lethal to the host. Sometimes it is not even clear whether high death rate has to do with the direct pathogen effect on the host or the host’s own over-reaction to the pathogen.

Laboratory animals are not always suitable to study deadly viruses and not just because mouse immune system is not the same as human’s immune system. One big problem with mouse models that limit their use for translational medicine has to do with history of laboratory mice. All laboratory mouse strains are basically inbred strains, each strain carrying specific and unique immune genes called class I and class II (MHC in mice and HLA in humans). Actually mouse strain development itself was only possible because of MHC genes (based on skin graft rejection or antibody response).

However, studies derived from such inbred laboratory mice prevents its usefulness for human research since humans are outbred species.

Natural viral outbreak, such as Ebola 2014 with 10,000 people infected so far, is an unique opportunity for scientists to use all the experimental advances at hand to dissect the viral biology and host-pathogen interaction. This is literally one in a century opportunity (1918 – 2014) but with so much more knowledge and tools available.

posted by David Usharauli

PhD bottleneck

This week journal Nature published a few short opinion articles related to current situation with PhDs programs.

Basically, the author argued that we do not need to restrict access to PhD programs because no one can predict who will be the next Isaac Newton (see Pros and cons of the PhD glut).

Reasoning is correct, but the whole discussion misses the point.

For me the question is what is PhD or Postdoctoral training for?

You may think the answer is to produce scientists. Maybe this was the goal in 70s-80s. But these days what I have seen, read or heard, it is primarily to improve Principal Investigators’ (PIs) publication record. These days PhD Students or Postdocs are doing the job that was previously done by permanent research staff, like staff scientists or research technicians. Academia is filling out or replacing permanent research staff positions with temporary “employees”  like PhD Students or Postdocs. It is as simple as that.

If you consider this argument then it is obvious such an attitude towards future generation of scientists would affect their quality. Since Academia has no real reason to invest in development of PhD Students or Postdocs as scientists, PhD  or Postdoctoral training programs became just names with no real values attached to them.

You may wonder why Academia does not want to invest in development of PhD Students or Postdocs as scientists? In my opinion, it has something to do with current employment law and economy. Retirement age in USA is 65. However, many PIs do not retire at that age, and current law prohibits discrimination based on age. Thus, if PIs are healthy and capable at 65, then there is no legitimate reason to replace them with new generation of PIs. This is why so many PhD Students or Postdocs end up as contractors, which are, of course, temporary positions and provide less of everything, especially benefits (thus economical aspect).

What is the solution? Only practical solution is to be open about it. People entering PhD studies or Postdoctoral training should be told that the vast majority of them will end up as contractors, doing scientific research on an as-needed basis or working for someone else (in someone’s lab or in someone’s company). Idea of permanent jobs has become outdated.

Of course, one can argue that we need to scrutinize PhD awards more, increase qualification standards as Flexner’s Report did for Medical Schools in early 1910s, but all these will go against the natural flow of events and will not work.  It is not Evolutionary Stable Strategy so to speak (see John Maynard Smith).

posted by David Usharauli

Fake it to Make it

I love science. I love to debate.

When I first started my science career in immunology in early 2004 at NIAID, my boss, Polly Matzinger said to me something like this “David, pretend that everything is OK”. I just smiled at her. I had no idea what she meant. I never asked her.

After more ten (10) years in science, I may now know the answer.

In this blog, niaIDEAlist’s Report, I am going to write about my experience in science, my opinions about current scientific research and data, as well as about notable science news.

posted by David Usharauli