Tag Archives: mouse

A new drug to treat type II diabetes: Thank the…Gila monster?

Posted on May 2, 2013 by | Leave a comment
Earlier this week Lyxumia (generic name Lixisenatide), a new drug that helps to control type II diabetes, was launched in the UK. In addition to being an effective and saft therapy for type II diabeted, including in some patients that do not respond to current first-line therapies, Lyxumia is relatively inexpensive when compared to current therapies for type II diabetes, which will help to save the health services money that can be invested in other therapies.

Lyxumia belongs to a new class of drugs known as the glucagon-like peptide 1 receptor agonists that work by increasing the secretion of insulin in response to consumption of food, and is administered by a once daily injection.That animal research played a key role in the development of the glucagon-like peptide 1 (GLP-1) receptor agonists for treating diabetes should not be a surprise, but when I took a quick look at the paper (1) reporting the preclinical development of Lyxumia (them called ZP10A)  I got a surprise.

The low half-life of native GLP-1 (90-120 s) (Deacon et al., 1995; Egan et al., 2003) has led to extensive research to find new compounds with pharmakokinetic properties suitable for development of a drug candidate. Exendin-4 was first isolated from the salivary gland of the Gila monster (Heloderma suspectum), and characterization showed that the peptide was structurally related to, but distinct from GLP-1 with a sequence homology of only 52%. Further characterization of exendin-4 showed that the peptide is a potent agonist for the mammalian GLP-1 receptor  with a longer in vivo half-life and prolonged duration of action compared with GLP-1 (Raufman et al., 1992; Young et al., 1999). Recent studies have shown that administration of exendin-4 induces pancreatic endocrine differentiation, islet proliferation and an increase in β-cell mass (Edvell and Lindström, 1999; Xu et al., 1999), indicating that exendin-4 may exert insulinotropic effects on the β-cells (Greig et al., 1999; Parkes et al., 2001).

Yes, you read it correctly, the development of effective GLP-1 receptor agonists started with a discovery made by a scientist studying venom peptides found in the the saliva of a large lizard!

The Gila monster - an unlikely ally in the fight against diabetes. Image courtesy of Jeff Servoss

The Gila monster – an unlikely ally in the fight against diabetes. Image courtesy of Jeff Servoss

This should actually not come as so much of a surprise, venom is an incredibly rich source of bioactive molecules, and scientists around the world are studying the venom of a bewildering array of animals in order to identify everything from better painkillers to therapies for Parkinson’s disease. Recently EU recognized the value of such research by setting up the VENOMICS project to provide tools and resources to the scientists engaged in it.

Lyxumia itself was created as a synthetic analogue of exendin-4, and following   in the db/db mouse model of diabetes the team at Zealand Pharma concluded that:

[T]hese studies demonstrate that ZP10A is an effective antidiabetic compound that effectively improves FBG and glucose tolerance, resulting in a long-term improvement of total glucose control. Furthermore, the sustained effect on glucose metabolism, and pancreatic expression of insulin even after discontinuation of ZP10A treatment indicates that ZP10A preserves β-cell function in diabetic db/db mice. Therefore, it is concluded that ZP10A is not only a promising candidate for the treatment of human type 2 diabetes but also it has the potential to prevent the progression of the disease.

On the basis of these very promising results ZP10A underwent further preclinical evaluation in collaboration with Sanofi-Aventis before entering into successful clinical trials.

The availability of a new and cost effective therapy to help people to manage type-2 diabetes is very welcome, but the story of the development of the Glucagon-like peptide 1 receptor agonists reminds us that new therapies can lurk in the most unlikely – and indeed most unpleasant – places!

Paul Browne

1) Thorkildsen C, Neve S, Larsen BD, Meier E, Petersen JS. “Glucagon-like peptide 1 receptor agonist ZP10A increases insulin mRNA expression and prevents diabetic progression in db/db mice.” J Pharmacol Exp Ther. 2003 Nov;307(2):490-6. Epub 2003 Sep 15.

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Treating Progeria; How GM mice give hope to some very special children

Posted on April 11, 2013 by | Leave a comment

Something big is going on right now in the world of research.

Something very specific for some very special children with a very rare disease. It may not be widely known by name but I am sure you have seen these children. The disease is called Progeria. From the Progeria Research Foundation’s website, we learn:

Hutchinson-Gilford Progeria Syndrome “Progeria” or “HGPS” is a rare, fatal genetic condition characterized by an appearance of accelerated aging in children*.  Its name is derived from Greek and means “prematurely old.”  While there are different forms of Progeria, the classic type is Hutchinson-Gilford Progeria Syndrome, which was named after the doctors who first described it in England: in 1886 by Dr. Jonathan Hutchinson, and in 1897 by Dr. Hastings Gilford.

Progeria affects approximately 1 in 4 – 8 million newborns.  There are an estimated 200-250 children living with Progeria worldwide at any one time.  It affects both sexes equally and all races.  Since The Progeria Research Foundation was created in 1999, we have discovered children with Progeria living in over 40 countries.”

Most of us will have come across a picture of one of these children in the papers, on TV, or on the internet. We remember them because they look different from other kids their age. If you ever get the privilege to chat with them, you will find that are some of the wisest people you will ever meet. To speak with them is truly inspiring because of their personalities and outlook on life. It is also heart wrenching because we know most will never reach their twenties.

About eight years ago I was working as a veterinary technician in a research facility. During that time a new investigator moved his lab into our facility, and we received his colony of mice a few weeks before he arrived. After we had cared for the mice for a few days, we started to see some very strange things. The weanlings were sometimes very small, and occasionally they were also thin. It was strange to see mice that were so young but  looked like such old men. The reason was simple, these mice had been genetically modified to carry the same defective Lamin A gene that is responsible for Hutchinson-Gilford progeria syndrome in children. The ‘sick’ mice we saw were actually mice with Progeria!”

GM mice aided the development of a therapy for Progeria

GM mice aided the development of a therapy for Progeria

Several years later Dr. Stephen G. Young and colleagues at UCLA  published a study that detailed what they found within this small population of mice (1). Once a GM model of mice had been developed, cells from these mice were studied (2). When a farnesyltransferase inhibitor  was used in vitro on these cells, it showed this drug was a possible treatment for this terrible disease. Once this was learned, they went on to the next step which was to test farnesyltransferase inhibitor in vitro on cells from actual Progeria patients (3). When these studies looked very promising, confirming that the process occurring in the mouse and human cells were very similar, the GM mice were once again indispensable for the first in vivo study to determine if farnesyltransferase inhibitors could improve the health of mice with Progeria (1). This is the part that cannot be replicated by any calculations, test tube chemicals or computer programs. Without in vivo studies, it is impossible to know what a treatment will do in a living creature. The mice that were born with Progeria were given a farnesyltransferase inhibitor. Would they get better or would they stay the same? Once the study was complete, all results were compared and this therapy looked very promising indeed!

Professor Young gave a talk on his progeria research to the Congressional Medical Research Caucus in 2009, in which he discusses his group’s GM mouse studies in much more detail, and you can watch the video here.

From there, a drug needed to be developed that could be evaluated in children with Progeria. This is a process that can often take many years, but fortunately some farnesyltransferase inhibitors designed as cancer treatments looked promising (see more about it here). lonafarnib was selected for clinical trials in progeria because it had already been assessed in pediatric cancer clinical trials where it had a demonstrated an acceptable safety profile. This is how decades of drug development happened in less than 10 years.

Researchers were able to move many steps ahead, much closer to the Progeria clinical trials that were needed. Remember, the one thing these children do not have is time. They grow old and die, sometimes as young as seven, and very rarely live past twenty. Most die in their teens. If a completely new drug had been needed, nearly every child alive with the disease that day would have passed away by the time it was ready for a clinical trial.

I think it is very important to explain briefly genetic disease and the role GM play in finding treatments and cures. Francis Collins is a well known and oft cited geneticist and physician, and currently Director of the National Institutes of Health, who gave a TED talk in April 2012 about this very topic.  Dr. Collins has long been interested in Progeria, he led the team that first identified defects in the Lamin A gene as a cause of Hutchinson-Gilford progeria syndrome in 2003, and later in 2008 published a study that examine the effect of farnesyltransferase inhibitors on cardiac defects in a mouse model of Progeria (cardiac defects are the most common cause of death in children with Progeria).


At the most basic, a genetic disease is caused when there is a faulty gene somewhere in the genetic code. While the *reason* the gene is broken may be a mystery, there are roughly 4,000 genetic diseases that scientists at least know what gene is causing the problem, which is the case for Progeria. Scientists know what is causing the problem, but how do you fix it? Dr. Collins has a vision of accelerating the transition from the bench to the bedside, and the example of progeria shows that one of best tools for finding the treatments and cures is Genetically Modified mice. Our GM mice.

In the case with Progeria, researchers were able to create the same disease in mice that was found in humans, effectively mirroring the disease. By doing this, they are able to study not just the disease itself, but study treatments on a live organism with the disease. With GM mice, researchers are able to find treatments and cures at an unprecedented pace. As Dr. Mark Kieran, who led the first clinical trial of  lonafarnib to treat progeria (4), said:

PRF (Progeria Research Foundation)provides a model for disease research organizations, and is a good example of successful translational research, moving from gene discovery to clinical treatment at an unprecedented pace,”

There are over 4,000 genetic diseases known to us right now, yet only 250 of them have treatments. If we can find help for these people so quickly, why are there so few cures? One reason is that in many cases there are still no mouse model available to study. In our case of Progeria, a mouse model of the disease was developed which sped up research by years or even decades. Without GM mice, this treatment would not be available now. Progeria clinical trials moved very quickly compared to most treatments and it was announced in September of 2012. Finally, these children had a treatment! While this is not a cure, it is a huge step forward. With early diagnosis and treatment, these children have a much better chance at a normal life!

Because of the extremely rare occurrence of this disease, these children can be hard to find, especially in less developed countries where they may have never seen this disease before. In 2009, the Progeria Research Foundation  (PRF)launched the “Find the Other 150” campaign. As of September 2012, they were aware of 96 of the estimated 200-250 children living with Progeria. If you are aware of any of these children, please visit www.FindTheOther150.org to find information on how to participate in future studies.

I have spent nearly a decade in this field now. I will always remember those mice and those children. To see a treatment developed and to even have played a small part it helping it happen is humbling. Will I make headlines? No. Will my name ever be in a published paper? Probably not. Will I make millions off any of the discoveries I participate it? Never. I went into this field knowing full well I will never get rich or retire early and wealthy. That is not why I am here.  I choose to do what I do because of people out there like these Progeria kids. I do this for them, and all the millions of cancer patients out there like my late husband. I do this so we can find a cure.

And to know I had even a tiny part in making that cure happen, that, is priceless.

Pamela Bass

1)  Yang SH, Meta M, Qiao X, Frost D, Bauch J, Coffinier C, Majumdar S, Bergo MO, Young SG, Fong LG.”A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation.” J Clin Invest. 2006 Aug;116(8):2115-21

2)  Yang SH, Bergo MO, Toth JI, Qiao X, Hu Y, Sandoval S, Meta M, Bendale P, Gelb MH, Young SG, Fong LG.”Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation.” Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10291-6. Epub 2005 Jul 12.

3) Toth JI, Yang SH, Qiao X, Beigneux AP, Gelb MH, Moulson CL, Miner JH, Young SG, Fong LG. “Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes.” Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12873-8. Epub 2005 Aug 29.

4) Gordon LB, Kleinman ME, Miller DT, Neuberg DS, Giobbie-Hurder A, Gerhard-Herman M, Smoot LB, Gordon CM, Cleveland R, Snyder BD, Fligor B, Bishop WR, Statkevich P, Regen A, Sonis A, Riley S, Ploski C, Correia A, Quinn N, Ullrich NJ, Nazarian A, Liang MG, Huh SY, Schwartzman A, Kieran MW. “Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome.” Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16666-71. doi: 10.1073/pnas.1202529109. Epub 2012 Sep 24.

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From Macaques to Humans: UK regulator gives cautious thumbs up to advanced IVF techniques to prevent mitochondrial disease

Posted on March 21, 2013 by | Leave a comment

Yesterday the UK’s Human Fertilisation and Embryology Authority (HFEA) advised the government that there is no evidence the two advanced forms of IVF developed to prevent mitochondrial diseases are unsafe, recommending that research using human embryos should continue, with close monitoring of the  health of children born through these two techniques, which are known as maternal spindle transfer and pronuclear transfer. At the same time the HFEA announced that a public consultation undertake last year had found broad support for the techniques.

The UK parliament will need to make the final decision on whether these techniques – somewhat misleadingly dubbed “three person embryos” - should be allowed, and it’s important to note that even if they give their approval the HFEA stressed in its assessment that further studies of human embryos in the lab will need to take place over the next 3 to 5 years before they can move into the clinic. These further studies will help to minimize any risks associated with the procedures, though Professor Robin Lovell Badge, a member of the HFEA panel that undertook a thorough scientific review of the science underpinning the techniques, did stress in a statement to the BBC that the ultimate test of the techniques would only cone then they were tried in the clinic.

Safety is absolutely not a black and white issue. In reproductive medicine in particular it is not possible to be absolutely certain about the consequences of any new treatment until children are born.

“Someone at some point is going to have to take the brave decision to go ahead with it.”

This announcement demonstrates that 35 years after the birth of the first IVF baby, the UK still leads the way in pioneering reproductive medicine. The UK did not get here alone though, as scientists in other countries – particularly the USA – have played a vital role in the development of these techniques.

In particular just a few months ago we discussed how Professor Shoukhrat Mitalipov of the Oregon National Primate Research Center  had developed the technique of spindle–chromosomal complex transfer – a.k.a. maternal spindle transfer, and one of the two techniques that the HFEA assessed  – through studies of Rhesus macaque monkeys. These studies included one where the health of four monkeys created using these techniques was followed closely for three years, with no ill effects observed.

Mitochondrial Gene Therapy. Source Mitalipov Lab/OSHU

Mitochondrial Gene Therapy. Source Mitalipov Lab/OSHU

The development of offspring born through the technique of pronuclear transfer, which was originally developed through research in mice, has not yet been studied in primates. Professor Douglass Turnbull of Newcastle University , who has demonstrated the technique is viable in human embryos in vitro, has cited the Rhesus macaque studies undertaken by Professor Mitalipov as evidence for the safety of the approach.

It is good to see the positive but cautious approach being adopted by the HFEA  as these techniques developed through a synergy of in vivo research on mice and monkeys and in vitro research on human embryonic cells in vitro move closer to becoming a clinical reality for the many parents who are waiting for them.

Speaking of Research

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Universal Meningitis B vaccine nears approval by European regulators – thank the mice (and the scientists)!

Posted on November 22, 2012 by | 2 Comments

Bacterial meningitis is an infection of the fluid that is found in the spinal cord and surrounding the brain that affects thousands of people – usually children or young people – every year and can result in brain damage, hearing loss, or learning disability. In about 10% of cases the infection is fatal. One of the most common causes of bacterial meningitis is infection by Neisseria meningitides, and while vaccines have been developed against some serotypes of N. meningitides, but so far no vaccine has been produced that can provide broad protection against N. meningitides serotype B (Meningitis B), which is responsible for most cases of bacterial meningitis in Europe. A major problem has been that there are many different strains of Meningitis B, and until now vaccines made against it have only protected against single specific strains, so that their usefulness has been very limited.

Last weekend we learned that a new “Universal” vaccine that protects against a  broad range of Meningitis B strains  the has been given a ‘positive opinion’ by the European Medical Agency’s Committee for Medical Products and is now expected to be granted a license within 2-3 months. The Bexsero vaccine – called 4CMenB during its development – was developed by Novartis and has been hailed as the “biggest leap forward in the field” in 30 years by the charity Meningitis UK, and if added to the vaccination schedule will for first time enable babies and young people to be vaccinated so that they are protected against Meningitis B strains for many years to come.

Studies in mice played a crucial role in the development of the new Meningitis B vaccine. Image courtesy of Understanding Animal Research.

At this point some of our readers may be wondering why this all sounds a little familiar. Never fear, there is a good reason for this.

Bexsero was made by adding to an experimental recombinant antigen vaccine named rMenB – a vaccine that had already provided a high degree of protection against a wide range of Meningitis B strains in earlier trials – the outer membrane protein that had been used in a vaccine against a specific strain of Meningitis B that was responsible for an outbreak in New Zealand.  The resulting multicomponent vaccine provided an even higher degree of protection against multiple Meningitis B strains, particularly in infants, making it more suitable for use in large-scale preventative vaccination programs (1).

But where did rMenB come from? For that we have to take a look back at a post I wrote for this blog in 2008 entitled “A vaccine against Meningitis B”, which describes the key role played by experiments in mice and rats during the development of this innovative vaccine:

The development of the new vaccine is also noteworthy because of how it was done. Vaccine development relies on identifying parts of the bacterium known as antigens that can act as targets for the immune system. Rather than using the usual method of attempting to isolate bacterial protein that might act as antigens the Novartis team led by Dr. Mariagrazia Pizza adopted a “reverse vaccinology” approach where they searched the Neisseria meningitidis genome for genes that encoded proteins that might be useful antigens. They identified over 300 potential antigens, and the next step was to screen these for their ability to stimulate the immune system to produce antibodies that kill bacteria in vitro. This required an intact functioning mammalian immune system, so the researchers used mice.

The mice were injected with candidate antigens and later antibodies were harvested from the mice and tested for their bactericidal activity against three distinct strains of Neisseria meningitidis, identifying twenty eight antigens that induced the production of bactericidal antibodies. However none of these 28 antigens were potent enough to be used alone in a universal vaccine, so the researchers next assessed various combinations of the most promising antigens. A vaccine containing 5 antigens was found to induce the production of antibodies that had excellent bactericidal activity against all three strains of Neisseria meningitidis. The multicomponent vaccine was then tested against a panel of 85 type B Neisseria meningitidis strains that represent the global diversity of the bacterium, and was found to be effective against almost all strains, especially the most lethal strains. To check that the bactericidal activity in vitro correlated to an ability to prevent disease rats which had been infected with Neisseria meningitidis were treated with serum containing antibodies from vaccinated mice. Rats that were treated with serum were fully protected, a result that provided good evidence that the multicomponent vaccine works.”

It’s great to see how this work has resulted in an effective vaccine that will soon protect thousands of people from disability and death, as Meningitis Trust Chief Executive Sue Davie noted in a statement earlier this week:

Vaccines are the only way to protect against bacterial meningitis and given the successes of the other meningitis vaccines already in use here in the UK, it’s hard not to be really excited at the news. We realise there is still a way to go before it is available, but this is a major step forward in protecting against MenB.”

It is worth noting that the successful meningitis vaccines already in use in the UK include the Hib polysaccharide-protein conjugate vaccine, which has almost eliminated meningitis due to infection with the Haemophilus influenzae type B bacteria, once the major cause of meningitis in babies and young children.  Needless to say animal research played a crucial role in the development of this vaccine against Haemophilus influenzae type B (2,3). Soon Bexsero may have an equally dramatic impact on Meningitis B, and mark another success against this devastating illness.

Paul Browne

1)      Toneatto D, Ismaili S, Ypma E, Vienken K, Oster P, Dull P. “The first use of an investigational multicomponent meningococcal serogroup B vaccine (4CMenB) in humans.” Hum Vaccin. 2011 Jun;7(6):646-53. PubMed: 19622040

2)      Kelly DF, Moxon ER, Pollard AJ. ”Haemophilus influenzae type b conjugate vaccines.” Immunology. 2004 Oct;113(2):163-74. PubMed: 15379976

3)      Schneerson R, Barrera O, Sutton A, Robbins JB “Preparation, characterization, and immunogenicity of Haemophilus influenzae type b polysaccharide-protein conjugates.” J Exp Med. 1980 Aug 1;152(2):361-76. PubMed: 6967514

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ScienceWhiskers tells the story of the mighty mouse

Posted on October 17, 2012 by | 3 Comments

ScienceWhiskers is a blog dedicated to the “scientific contributions of the mouse.” The blogger, highlights a wide range of topics. Recent examples include how the brain controls eating behavior to a study that may point the way to a male contraceptive pill.

It’s a relatively new blog. An entry dated August 10, 2012 welcomes readers to learn about “everything mouse related in the world of science.” The blogger’s aims are:

 . . . to keep you updated with new research using mice and its impact on science

And

. . . to try and educate you on the use of mice in scientific research and how much this wonderful small creature has helped contribute to science and what we know today.

The blogger also explores ethical implications of research, such as the study in which scientists created mouse eggs from stem cells. He/she also highlights resources such as Shared Ageing Research Models (ShARM), which keeps a database of current research on aging in mice in the U.K., as well as tissue bank of samples. This, as the writer points out, can help to reduce unnecessary duplication of the research.

The blogger is also to be commended for the tone of the essays, which is conversational and informative. This looks to be a helpful resource. Keep up the good work.

Alice

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Reprogrammed frog and mouse cells win the 2012 Nobel Prize

Posted on October 8, 2012 by | 2 Comments

This morning the Nobel Assembly announced that the 2012 Nobel Prize in Physiology or Medicine will be shared by John B. Gurdon and Shinya Yamanaka for their “discovery that mature cells can be reprogrammed to become pluripotent”.  Animal research played a key role in the research honoured by the prize, specifically the studies of frogs undertaken by Professor Gurdon and studies of mice performed by Professor Yamanaka.

Sir John Gurdon. Image: Nobel foundation.

Professor Gurdon’s key work showed in a series of studies undertaken at the University of Oxford in the late 1950’s and 1960’s that if the nucleus of a specialised cell from a frog of the species Xenopus laevis - initially from late embryonic cells and subsequently adult intestinal and skin cells – was transferred into an egg whose nucleus had been removed, it could give rise to normal frog that could themselves produce offspring. This demonstrated for the first time that the nucleus of an adult cell is totipotent, and that in under certain conditions it could give rise to all cell types, including eggs and sperm, that are required in a healthy adult.

The very first Xenopus frog produced by somatic nuclear transfer to reach sexual maturity. Image: J.B. Gurdon

In 2009 Sir John wrote an account of his research on nuclear transfer in Xenopus for Nature Medicine, which can be read online without subscription, after he and Professor Yamanaka were presented with the  Albert Lasker Basic Medical Research Award in 2009.

Professor Shinya Yamanaka. Image: Nobel foundation

Almost 4 decades later Professor Yamanaka, then at the Kyoto University Institute for Frontier Medical Sciences, made another great step forward by proving that it was possible to transform adult mouse cells into a pluripotent stem cells without nuclear transfer. By inserting 4 genes whose expression is associated with the embryonic state into the adult cell, his team were able to create the first induced pluripotent stem (iPS) cells, cells that could give rise to any tissue in the body.

Earlier this year in a post congratulating Professor Yamanaka’s on winning the 2012 Millenium Technology Prize I noted that:

The work briefly described above was a technological tour-de-force where Prof. Yamanaka and his colleagues selected 24 genes which had previously been identified as having key roles in mouse embryonic stem cells, and developed a screening method using skin fibroblast cells derived from mice that had be genetically modified with an antibiotic resistance gene that was only expressed in embryonic cells, so that only cells that were in an embryonic state would survive in a culture containing the antibiotic. Different combinations of these 24 genes were screened for their ability to induce to the production of colonies of embryonic -like cells from adult fibroblasts.  They eventually identified just 4 genes – Oct3/, Sox2, Klf4 and c-Myc – that together could reprogram adult mouse fibroblast cells to a pluripotent embryonic-like state (1), and subsequently demonstrated that these iPS cells could give rise to a wide variety of  tissue types when incorporated into mice, either by subcutaneous injection into adult mice or incorporation into early mouse embryos. By modifying their method slightly to also include expression of an important developmental gene named Nanog  they were then able to generate chimeric mice (mice whose tissues are made up of a mixture of cells derived from their own embryonic stem cells, and cells derived from iPS cells) which were capable of transmitting the iPS cells to the next generation of mice (2).

Soon after this Prof. Yamanaka succeeded in generating iPS cells from human fibroblasts, using the same techniques used for the mouse cells, and a whole new and exciting field of biomedical research was born.

1)      Takahashi K, Yamanaka S. “Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.” Cell 2006 Vol. 126(4):663-76. PubMed: 16904174

2)      Okita K., Ichisaka T., Yamanaka S. “Generation of germline-competent induced pluripotent stem cells.” Nature Vol. 448:313-317 (2007). PubMed:17554338””

It’s worth remembering that this breakthrough did not come out of thin air, and built on years of research that followed the pioneering work of Martin Evans and Gail Martin who demonstrated that cells derived from mouse embryos could be cultured and give rise to all tissue types…the first embryonic stem cells.

The field of iPS cell research has progressed swiftly since the first mouse iPS cells were produced just 6 years ago, and the techniques used to produce the cells have been refined to address early concerns that the inserted genes might give rise to tumors, but as Prof Yamanaka outlined in a recent review of progress in the field there is still a lot of scope for improvement.  Nevertheless iPS cells are already showing promise in a variety of medical research applications – for example to create nerve cell lines from Parkinson’s disease patients in order to study the processes that trigger the degeneration, or  to evaluate the toxicity of new drugs – and are expected to join  human embryonic stem cells as key components of regenerative medicine.

This year’s Nobel Prize in Physiology or Medicine highlights once again the key role played by animal research in making groundbreaking discoveries that give rise to new fields of medicine, and we offer our heart-felt congratulations to John Gurdon and Shinya Yamanaka.

 

Addendum: In a statement to Reuters on the problem of the unproven stem cell therapies being offered for a myriad of disorders by private health clinics around the world - and widely touted on the internet -Professor Yamanaka highlighted the key role played by animal research in ensuring that real stem cell therapies are safe and effective:

Yamanaka, who shared the Nobel Prize for Medicine on Monday with John Gurdon of the Gurdon Institute in Cambridge, Britain, called for caution [on stem cell therapies - PB].

“This type of practice is an enormous problem, it is a threat. Many so-called stem cell therapies are being conducted without any data using animals, preclinical safety checks,” said Yamanaka of Kyoto University in Japan.

“Patients should understand that if there are no preclinical data in the efficiency and safety of the procedure that he or she is undergoing … it could be very dangerous,” he told Reuters in a telephone interview.

Yamanaka and Gurdon shared the Nobel Prize for the discovery that adult cells can be transformed back into embryo-like stem cells that may one day regrow tissue in damaged brains, hearts or other organs.

“I hope patients and lay people can understand there are two kinds of stem cell therapies. One is what we are trying to establish. It is solely based on scientific data. We have been conducting preclinical work, experiments with animals, like rats and monkeys,” Yamanaka said.”

 

Paul Browne

 

 

 

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ERV blogs on GMO Herpes vs severe cancer pain

Posted on September 18, 2012 by | 3 Comments

As gene therapy emerges as one of the hottest areas of medical research, one thing that is striking is how it employs viruses – sometimes very nasty viruses - to deliver the gene to where it is needed in the human body.

Yesterday virologist Abbie Smith discussed another excellent example of this on the ERV blog in a post entitled “GMO Herpes vs. severs cancer pain”, describing how scientists at the Universities of Michigen and Pittsburgh have used a genetically modified herpes virus to deliver the preproenkephalin gene – which produced a precursor to pain-killing opiates – to the nerve cells of terminal cancer patients who were suffering from severe pain.

Abbie remarks that “This was one of the most depressing, yet hopeful, papers I have ever read.”. It’s difficult to disagree, after all most of the patients participating in the trial died within 3 months of it starting. But to focus on this sobering statistic would miss the reason for this study, namely that the pain-relief available to patients with severe chronic pain is often inadequate, as the drugs are not specific enough and cause unacceptable side effects when used at the high doses often required for prolonged periods of time. By targeting the opiate molecules to the nerve ccells themselves these side effects can be avoided, and more effective pain relief provided.

The paper “Gene Therapy for Pain: Results of a Phase I Clinical Trial” is available for anyone to read in PubMed Central and makes it very clear that this is a therapy that was discovered, evaluated and refined in animal models of different types of pain before entering this first clinical trial. The first two paragraphs of the introduction noting that:

A significant limitation to the development of analgesic drugs is that off-target effects at doses below the maximal analgesic threshold restrict the ability to selectively interrupt nociceptive neurotransmission1. To address this limitation, we developed a series of replication defective HSV-based vectors to deliver gene expression cassettes directly to DRG neurons from skin inoculation 2, 3. The anatomically defined projection of DRG axons allows targeting of specific ganglia by injection into selected dermatomes. In preclinical studies, the release of anti-nociceptive peptides or inhibitory neurotransmitters in spinal dorsal horn from the central terminals of transduced DRG neurons effectively reduced pain-related behaviors in rodent models of inflammatory pain, neuropathic pain, and pain caused by cancer4-9.

The human PENK gene encodes for preproenkephalin, a precursor protein proteolytically cleaved to produce the endogenous opioid peptides met- and leu-enkephalin. In the spinal cord, enkephalin peptides inhibit pain signaling through actions at presynaptic opioid receptors located on central terminals of primary afferent nociceptors and postsynaptic opioid receptors on second order neurons involved in nociceptive neurotransmission10. HSV vectors expressing opioid peptides appear to be particularly effective in animal models of inflammatory and cancer pain4, 5, 8.”

And in the conclusion:

In preclinical animal studies, skin inoculation of HSV vectors expressing PENK reduce acute hyperalgesic responses27, and reduce pain-related behaviors in models of arthritis28, formalin injection4, peripheral nerve damage6 and bone cancer5. Because this was the first human trial employing HSV vectors to achieve gene transfer, we elected to carry out the phase 1 clinical trial for safety and dose-finding in patients with pain caused by cancer…This Phase I clinical trial primarily addressed the question of whether intradermal delivery of NP2 to skin would prove to be safe and well tolerated by subjects. The small number of patients and the absence of placebo controls warrant circumspect interpretation of the secondary outcome measures. But the observation that subjects in the low dose cohort had little change in the NRS or SF-MPQ while subjects in the higher dose cohorts reported substantial reduction in NRS and improvement in SF-MPQ is encouraging.”

Encouraging is possibly an understatement, seeing clear evidence of therapeutic benefits in a Phase I trial like this is very promising, or as Abbie puts it “A trial turning out this successful is a great starting point for optimizing this kind of therapy.”.

Paul Browne

p.s. Those interested in a more detailed account of the research that led to this clinical trial can find it in this review published in 2008 and available to read online for free.

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Cancer Stem Cells: Mouse studies lead to paradigm shift in cancer research

Posted on August 2, 2012 by | Leave a comment

For the past 15 years one of the most intriguing ideas in cancer research has been that the growth and spread of most – if not all – cancers is driven by cancer stem cells. The hypothesis is that only a tiny proportion of cancer cells, cancer stem cells, have the stem cell-like ability to proliferate indefinitely to produce cells that can differentiate into other cancer cell types. It suggests that the reason why cancer often returns after apparently being eradicated is that while the therapy (surgery/radiation/chemotherapy) may remove the differentiated cancer cells it fails to remove all the cancer stem cells, whose subsequent proliferation results in the cancer’s return.

Multicolored intestine tissue in genetically modified mice allows scientists to track which cells give rise to tumors.
Credit: A. G. Schepers et al., Science (2012) DOI: 10.1126/science.1224676

Today 3 teams of scientists have announced important results that provide the strongest evidence to date that cancer stem cells are indeed at the heart of cancer proliferation.

The first evidence that only a small minority of cancer cells may have the ability to proliferate indefinitely came from a study of leukemia cells in 1997, when Dr Dominique Bonnet and Dr John Dick, then both working at the University of Toronto, observed that when they injected a variety of acute myeloid leukemia (AML) cell populations obtained from human biopsy into immunodeficient mice and analyzed which cells gave rise to leukemia cells in the mice, and found that regardless of the characteristics of injected AML cells the cells that initiated the leukemic cell populations in the mice always expressed the cell surface marker CD34 and lacked the cell surface marker CD38, a key characteristic of stem cells.

Since then similar observations have been made for a wide variety of cancer types, and scientists have discovered important new facts about cancer stem cells, for example in 2009 we discussed how scientists at Stanford University had used genetic modification of bone marrow stem cells to show that leukemia stem cells were very similar to embryonic stem cells.  However, these studies all involved the transplantation of cancer cells into mice, and there has always been some concern that the manipulation of these cells during their isolation from humans and sorting into specific populations before injection into mice may have affected their behavior.

Today, three independent studies of mouse models of brain, skin and intestinal tumours, led respectively by Dr Luis Parada at the University of Texas Southwestern Medical Center, Dr Benjamin Simmons of the Gurdon Institute and Dr Cédric Blanpain of the Free University of Brussels, and Dr Hans Clevers of the Hubrecht Institute, and published in the prestigious scientific journals Nature and Science,  provide the first evidence that cancer stem cells do arise during tumour formation in intact organs, and drive tumour formation.

What these studies all share is that they were able to do this because rather than injecting cancer cells into the mice they used genetically modified mice in which cancer develops spontaneously. Using additional genetic modification to label certain types of cells they were able to track the different cell types involved in the growth and spread of cancer, and even assess the differing effects of standard cancer therapies and therapies that included drugs that specifically target cancer stem cells.

There is an excellent discussion of the three projects and their implications for cancer research in Nature News, and Science Now also offers a informative prespective on the work.  From its very first paragraphthe Nature News article highlights how these studies provide crucial information that could not be obtained through other methods:

Cancer researchers can sequence tumour cells’ genomes, scan them for strange gene activity, profile their contents for telltale proteins and study their growth in laboratory dishes. What they have not been able to do is track errant cells doing what is more relevant to patients: forming tumours. Now three groups studying tumours in mice have done exactly that. Their results support the ideas that a small subset of cells drives tumour growth and that curing cancer may require those cells to be eliminated.”

Commenting in an article in the LA Times, Dr. Owen Witte of the UCLA Broad Stem Cell Center was clear about what these results mean for cancer research.

People can stop arguing…Now they can say, ‘OK, the cells are here. We now need to know how to treat them.’ ”

And “how to treat them” will not be an easy problem to solve, perhaps drugs that target the cancer stem cells or prevent their development may be the answer, but as the Nature News, Science Now and LA Times articles stress we don’t yet know enough about the origins of cancer stem cells to be sure which approach will work.

What is true is that thanks to advanced animal research methods a huge gap in our knowledge of how cancer develops and spreads – a gap that we only recently realised existed – has been filled. As research accelerates to turn this new knowledge into effective cancer therapies we can be certain of one thing; animal research will continue to provide key insights that turn hypothesis into cures.

Paul Browne

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