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Pro-Test: standing up for science
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Archives for: February 2009

25/02/09

Permalink 11:02:11 pm, by Tom, 799 words, 2252 views   English (UK)
Categories: Information

A passive defence against the flu?

Influenza is a disease that kills hundreds of thousands of people every year, and periodically causes global pandemics that kill many millions. There are three major types, A, B and C that can infect humans, although the A is responsible for the most cases and deaths. Within influenza A virus there are two major groups, 1 and 2, each of which includes several subtypes, and finally within each subtype there are many strains. Currently available vaccines can only protect against a narrow range of strains, sometimes only one, and as a consequence every year the World Health Organization (WHO) has to try to predict which strains will cause problems over the following year and make vaccines to protect vulnerable people from them, and naturally they can't always get the prediction right. More worryingly it takes several months to develop each vaccine so in the event that a new pandemic strain arises a vaccine to protect against it may not become available before it has spread widely. For this reason scientists are working to develop vaccines that will protect against a broad range of influenza strains and subtypes, as we have discussed in a post last year, while at the same time others are developing improved treatments for those who do become infected.

In an exciting paper published online in Nature Structural & Molecular Biology (1) a team led by Wayne Marasco of the Dana-Farber Cancer Institute, Robert Liddington of the Burnham Institute for Medical Research, and Ruben Donis of the Centers for Disease Control and Prevention (CDC) have used an in vitro screening method to identify human antibodies that bind to a protein called hemagglutinin (the "H" in H5N1) that is found on the surface of the virus and is required for the virus to enter a cell once it has bound to it. As described in in Nature news the antibodies they identified using an in vitro phage display screening method bind to a portion of hemagglutinin known as the stem that varies little between different subtypes of group 1 influenza A virus and stop the virus entering the cell. Having proved that the antibodies could block virus entry into cells in vitro the scientists then tested if clinically realistic doses of antibody could protect animals from an otherwise lethal influenza A infection. They found that when these antibodies were given to mice that had previously been infected with highly pathogenic strains of the H5N1 and H1N1 virus subtypes the mice remained healthy and the spread of the virus through their organs greatly reduced, while mice that were not given the antibodies died. While H5N1 and H1N1 are both group 1 subtypes of influenza A currently available vaccines against one do not protect against the other, so this result taken with the in vitro data demonstrated that the antibodies provide broad protection against group 1 influenza A viruses. This protection was even observed when the antibodies were given 3 days after infection, indicating that these antibodies are suitable for a passive immunization approach to the treatment of influenza following infection, which would be a very valuable addition to the limited range of treatments currently available. Their research also indicated that their screening technique can be used to identify antibodies that can be used to protect against other groups of influenza virus.

But what of "classic" vaccines that stop people acquiring the flu in the first place? Well, the authors of this study suggests that by designing vaccines that direct the immune system to target the conserved stem region of hemagglutinin, rather than the more variable portions of hemagglutinin as is now the case, it may be possible to have vaccines that confer protection against a broad range of influenza subtypes. A combination of only a few such vaccines could yield a "universal" flu vaccine, which is certainly an exciting prospect, though since flu is also found in many wild and domesticated animal populations which can transmit it to us we will probably never be possible to control it as thoroughly we have controlled polio.

Regards

Paul Browne
1) Sui J. et al "Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses" Nat. Struct. Mol. Biol. Advanced Online Publication , 22 February 2009, doi:10.1038/nsmb.1566

p.s. Just in case you are wondering how the proposed hemagglutinin stem targeting vaccine would differ from the influenza A vaccine developed by Acambis that we reported on earlier, the difference lies in the protein targeted. The Acambis vaccine targets a virus membrane protein called the M2 ion channel that is required for full virulence and is also highly conserved among influenza A subtypes. If both strategies are successful (and at this stage that is by no means a given) they could be combined in a future flu vaccination schedule for even better coverage.

16/02/09

Permalink 10:23:01 am, by Tom, 565 words, 2416 views   English (UK)
Categories: Information

Shedding some light on the dark side of stem cells

In recent weeks we have discussed the potential of stem cells in developing new therapies and powerful new research methods, but stem cells also have a more sinister side. Over the past decade scientists have become increasingly interested in the possibility that in many, perhaps most, cancers there is a small population of cells that are the only tumour cells with the capacity for limitless self-renewal, and that to completely cancer from a patient treatments must target these cancer stem cells (CSCs). Until now it has not been clear how the gene disruptions seen in cancer cells relate to their potential to become cancer stem cells (CSCs), and how the disrupted gene alters cellular signaling pathways to turn the cells into CSCs.

The BBC reports an exciting development at Stanford University where scientists have discovered that CSCs in acute myeloid leukemia (AML), known as leukemia stem cells (LSCs) bear a striking similarity to embryonic stem cells. To make this discovery the scientists led by Dr Tim Somervaille (1) used a mouse model of AML where the mice are injected hematopoietic stem cells which had been modified by using a retroviral vector to add a mixed-lineage leukemia (MLL) gene whose activity had been altered by fusion with another gene. MLL is an important regulator of gene function in normal development but when it acts abnormally, for example after a mutation fuses it to another gene, it is associated with leukemia, including some cases of human AML. Dr Somervaille found that the number of LSCs found in the spleen and bone marrow of mice that were injected with cells that had been transformed using the MLL-ENL and MLL-AF9 fusion genes was greater than that found in mice that were injected with cells that had been transformed with other MLL fusion genes. Microarray analysis showed that the LSCs produced by MLL-ENL and MLL-AF9 strongly expressed genes that were characteristic of embryonic stem cells and a poor prognosis in the clinic, whereas these genes were not expressed strongly in cells transformed by MLL fusion genes that did not give rise to high numbers of LSCs. They obtained further evidence to support the role of genes of the embryonic stem cell program by demonstrating that when the action of these genes was blocked the number of LSCs that MLL-ENL cells could produce was greatly reduced.

This work indicates that the prognosis for AML patients may depend on the number of LSCs and on the extent to which a gene disruption such as the MLL fusion genes subverts the normal self-renewal program in hematopoietic so that it resembles that of embryonic stem cells. This is exciting since it was previously believed that the LSCs were thought to be similar to normal hematopoietic stem cells, the adult stem cells that are needed to produce blood cells, and the observation that they are in fact more similar to embryonic stem cells may allow the development of chemotherapy that targets the LSCs while sparing the blood cell producing cells. This is a piece of basic research that helps to explain previous clinical observations and may well influence the design of new cancer therapies for years to come.

Regards

Paul Browne

1) Somervaille T.C.P. et al. "Hierarchical Maintenance of MLL Myeloid Leukemia Stem Cells Employs a Transcriptional Program Shared with Embryonic Rather Than Adult Stem Cells" Cell Stem Cell, Volume 4, Pages 129-140 (2009) doi:10.1016/j.stem.2008.11.015

08/02/09

Permalink 11:30:04 am, by Tom, 987 words, 3276 views   English (UK)
Categories: Information

The Year of the Rat ends on a high note

Transgenic animal technology allows scientists to study the molecular basis of disease, and since the first transgenic mice were produced in the 1980’s it has become a mainstay of biomedical research. Early efforts focused on silencing an existing gene (knockout models), but subsequently methods were developed to introduce a new gene (knockin models), and to express the new gene in a specific tissue and/or at a specific time (conditional transgenic models). In mice transgenic techniques rely on the manipulation of embryonic stem (ES) cells, which have three main properties: i) ability to renew themselves and develop into any cell in the body (pluripotency); ii) ability to be incorporated into an organism; and iii) ability to develop into germ cells to be passed onto offspring. These cells can be modified genetically very easily, and can be reintroduced into the embryo and will develop into many of the body’s cells. Transgenic mouse models are proving to be very useful, especially for genetic disorders such as Duchenne muscular dystrophy and cystic fibrosis. Indeed, in an evaluation of the efficacy of mouse knockout models of genes that are the targets for the 100 best-selling drugs, Zambrowics & Sands (1) note that “A retrospective evaluation….indicates that these phenotypes correlate well with known drug efficacy, illuminating a productive path forward for discovering future drug targets”. It is perhaps not surprising that the Nobel Prize in Physiology or Medicine for 2007 went to Sir Martin Evans, Professor Mario Capecchi and Professor Oliver Smithies for "their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells".

Whilst transgenic mice offer much to the scientific community, scientists have long desired to create transgenic rat models of disease. Behaviorally, rats are much more similar to humans in their ability to learn to accomplish different experimental tasks, and because of their larger size it is much easier to perform surgical procedures and monitor physiological states (2). However, attempts to produce transgenic rats have been severely hampered by the inability to isolate rat ES cells and grow them in vitro. This problem was overcome in some animals such as sheep and pigs by cloning, but again, when applied to the rat, this approach proved exceptionally difficult to perform. This is not to say that transgenic rats have never been used in experimentation, but it has meant that other techniques have had to be employed, all with fundamental drawbacks, meaning they are not ideal for experimental purposes. One of the more popular approaches, for example, takes a gene of interest, and incorporates it into the nucleus of a single-celled embryo by direct injection (3), or by using a lentivirus to infect the cell with the gene (4). This methods suffers from the fact that it is limited to genetic material of about 10kb in length, too small to accommodate most genes, and it is subject to “position effects”, in other words it will affect, and be affected by, the genetic material around it when it is introduced to the genome, because it will be inserted at a random position in the genome. For these reasons the impact of transgenic rats on biomedical research has been very limited.

At the end of 2008, though, two groups independently developed a very similar method to isolate and maintain pluripotent embryonic stem cells in rats: Professor Austin Smith’s lab at Cambridge, UK (5) and Professor Qi-Long Ying’s lab at the University of Southern California (6). Serum, which is used in the protocol for isolating mice ES cells, contains substances that drive rat ES cells towards commitment to a particular cell lineage. Removal of serum alone from the medium is not sufficient to maintain stem cells because the rat ES cells themselves secrete a protein known as fibroblast growth factor 4 (FGF4) that also drives them to commitment, through a cell signaling system known as the MEK/ERK pathway. Earlier research in mice had already shown that inhibiting this pathway maintains self-renewal in stem cells, so both groups of scientists used a 3 inhibitory (3i) strategy, which used i) an inhibitor of FGF4, ii) an inhibitor of the MEK pathway, and iii) and an inhibitor of glycogen synthase kinase 3 (GSK3) - an enzyme that inhibits the biosynthetic capacity of the cells and therefore their ability to proliferate. Excitingly, both studies found that rat ES cells could be kept in a pluripotent state indefinitely, displaying the 3 main characteristics of stem cells, and express certain protein such as Oct4 and nanog that are characteristic markers of stem cells. Whilst one of the studies (5) initially encountered problems, bias in the sex ratio of the offspring and in some cases trisomy on chromosome 9, a minor modification to the procedure made it robust and reliable.

The impact of this work on medical research is predicted to be enormous, as now for the first time ES cells can be used as a method to create transgenic rat models where the modified gene directly replaces the normal gene, overcoming the problems associated with rat transgenics up until now. Using this method, rat transgenics should become as precise, robust and powerful as is currently the case in mice, whilst yielding better models of human disease. The year of the rat may be over, but a new era for rats in research is only just beginning.

Matthew Evans

References

1. Zambrowics, B. P. & Sands, A. T. (2003) Knockouts model the 100 best-selling drugs – will they model the next 100? Nat. Rev. Drug Disc., 2(1), 38-51.

2. Jacob, H.J. & Kwitek, A.E. (2002) Multifactorial genetics: Rat genics: attaching physiology and pharmacology to the genome, Nat. Rev. Gen., 3(1), 33-42.

3. Wall, R.J. (2001) Pronuclear microinjection, Cloning & Stem Cells, 3(4), 209-220.

4. Lois, C. et al. (2002) Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors, Science, 295(5556), 868-872

5. Buher, M. et al., (2008) Capture of authentic embryonic stem cells from rat blastocysts, Cell, 135,1287-1298.

6. Li, P. et al., (2008) Germline competent embryonic stem cells derived from rat blastocysts, Cell, 135(7), 1299-1310. doi:10.1016/j.cell.2008.12.006

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