Monthly Archives: June 2010

The Vivisector’s Tale – An LA Magazine Story

LA Magazine July 2010

A rather ominous 6 page article can in found in LA Magazine (click left for .pdf). Despite an AR slanted headline (vivisecton is only one part of animal research, but is used by AR groups because of its sinister tone), this article was a breath of fresh air. The byline reads:

Planting firebombs and issuing death threats, activists are waging war to stop scientists at UCLA from experimenting on animals. One researcher has chosen to push back. By Steven Mikulan.

The article begins with the destruction of David Jentsch‘s car back in March, 2009; covers some of the atrocities committed by animal rights activists; then moves on to the founding and growth of Pro-Test for Science. Scientists around the country can learn from Jentsch’s interview techniques as he makes sure the science has its place in the article:

“Compared to 15 years ago,” he says, “the number of things we can see inside your brain without opening your skull are remarkable. But at present time there are no nonanimal alternatives to explore how the living brain works.”

The original Pro-Test movement in the UK and its spokesman / SR founder, Tom Holder, both get mentions throughout the article:

Tom Holder, a spokesman for Britain’s Oxford University-based Pro-Test, addressed reporters: “Today is going to be remembered as the day when scientists stood up and said, “No more!” … No more to the fear and harassment of researchers who do lifesaving research at UCLA and beyond.”

Little sympathy is given to animal rights extremists – and they seem to damn themselves with every comment, as Pamelyn Ferdin, wife of ALF spokesman Jerry Vlasak, shows:

“Wasn’t Jentsch’s car burned or something? … I don’t know how to put this – I only wish he were in it.”

And so the hypocrisy of the animal rights movement is revealed – on the one hand they condemn the death of every animal, and on the other they condone the death of human animals.

This article comes rather late from the activities of Pro-Test for Science, but was nonetheless welcome.

Regards

Tom

How to build a lung

Tissue engineering, a field that combines cell biology, engineering, and materials science to manufacture tissues – and more recently even whole organs – to replace those lost to injury or illness, must be one of the most exciting areas in modern medicine.  Since the earliest reports about a mouse with a human ear growing on its back over a decade ago progress has been rapid, and last year we reported on how animal research enabled scientists to use a patient’s own stem cells to successfully replaced a trachea that suffered irreparable damage from tuberculosis.

Now science writer Ed Yong has written an excellent article on his Not Exactly Rocket Science blog about how a team of scientists at led by Laura Niklason Yale University are moving on from the trachea to a far more complex part of the respiratory system – the lung – and successfully transplanted it into rats.  As Ed points out, this technology needs to be improved significantly before it can be attempted in humans, and further research in rats is underway to do just that.  This work will take time, and as it progresses will almost certainly require studies in larger animals such as pigs whose lungs are closer to ours in size and structure than those of rats. Human trials are not expected for perhaps a decade or more.

Ed Yong was not the only one to note the importance of this research, the journal Science, in which the study was published (1), have included an interview with Laura Niklason in their latest podcast.

How to build a lung. Courtesy of Laura Niklason and Thomas Petersen.

Laura Niklason’s past record certainly gives cause for optimism. In 1999 they published a paper describing how they engineered arteries in vitro that supported blood flow when transplanted into pigs, an animal whose cardiovascular system is a valuable model for our own, and determined that a culture technique that mimics the pulsating arterial blood flow produced stronger and safer engineered arteries. Following a decade of refinement through in vitro tissue culture and animal research the artery is expected to enter human clinical trials next year.

And Laura Niklason’s group is not the only one that is working hard to develop tissue engineered lungs for transplant, at the Harvard University Medical School in Boston Professor Harald Ott and his colleagues have also had promising results with transplanted lab grown lungs in rats.

Engineered rat lungs in a bioreactor at Dr. Harald Ott's lab in Boston. Credit: National Geographic Explorer.

This wasn’t the only exciting lung-related research to be published in Science this week.  Scientists at Harvard University have used microfluidics to re-create the interface between the alveoli and capillaries (2) in the lung where exchange of oxygen and other gasses takes place. The response of this “Lab-on-a-chip” model to bacterial infection and inflammatory signals was similar to that seen in previous animal studies.

This technology represents huge advance over existing in vitro models of the lung; which, in addition to being a very promising research tool in its own right, has the potential to reduce the number of animals used in testing the effect of new drugs or toxins on lung function.  Eventually an improved version, perhaps combined with chips that simulate other tissue types, might replace animal use in the evaluation of toxicity in the lung entirely, though that goal is still years of dedicated research away.  Lab-on-a–chip technologies such as this that can integrate several cell types into a system that mimics real tissues in vivo are a great example of the 3Rs in action.

How to build a lung on a chip. Image courtesy of Huh D. et al. Science Volume 328 (5986), pages 1662 - 166 (2010)

One area the Harvard scientists were particularly interested in is using this lab-on–a-chip to evaluate the potential toxicity of nanoparticles, since existing in-vitro cell and tissue culture technologies are not adequate for this task, and using rodents is slow and expensive. Since nanoparticles are becoming increasingly common in daily life there is an urgent need to develop ways to rapidly assess their safety before humans and animals are exposed to them. So they examined how their lab-on–a-chip responded to a variety of nanoparticles, and then compared the results to those of parallel studies performed on the lungs of mice.

A key question was whether inhaled nanoparticles can cross into the bloodstream, several animal studies indicate that they can while in vitro studies suggest otherwise, though as mentioned the relevance of these in vitro methods has been questioned. With the new technology the results were in close agreement, the nanoparticles can cross into the bloodstream. This demonstration indicates that the lab-on-a-chip may provide a suitable platform for future evaluation of aspects of nanoparticle toxicity, as part of new pathways for the evaluation of chemical safety that use as few animals as possible.

So, all in all it is a very great week for building lungs in Science, one to which animal research made a huge contribution.

Paul Browne

1)      Patersen T.H. et al. “Tissue-Engineered Lungs for in Vivo Implantation”   Science Published Online June 24, 2010 DOI: 10.1126/science.1189345

2)      Huh D. et al. “Reconstituting Organ-Level Lung Functions on a Chip”  Science Volume 328 (5986), pages 1662 – 1668 (2010) DOI: 10.1126/science.1188302

Addendum

In my rush to finish the above post I forgot to mention another advance in the use of decellularized scaffold and in vitro cell repopulation approach to tissue engineering, scientists at Harvard Medical School produced artificial livers that appeared to function almost as well as normal tissue when transplanted into rats and connected to their blood supply . In the research paper published online in Nature Medicine the authors stress that the artificial liver needs further development before human transplants can be contemplated, but this is further evidence of just how quickly progress is being made in the field of complex tissue engineering.

FASEB Excellence in Science Award for Stem Cell Pioneer

The Federation of American Societies for Experimental Biology (FASEB) is one of the world’s largest and most influential scientific organizations, representing 23 independent scientific societies and over 90,000 individual scientists. Regular readers of this blog will be aware that FASEB also takes a keen interest in educating and informing the public about the value and achievements of biomedical research. Every year FASEB presents the Excellence in Science Award to ‘recognize outstanding achievement by women in biological science’, and this year the award has been given to Professor Gail Martin of the University of California, San Fransisco, principally for discoveries she made in mice.

Professor Gail Martin, stem cell pioneer and winner of the FASEB Excellence in Science award. Image courtesy of UCSF.

Gail Martin was the first scientist to isolate embryonic stem cells, a term she coined, from the mouse embryo and culture them in vitro in 1981, and demonstrated that when injected into a mouse these cells formed a type of tumor known as a teratoma (1).  The production of a teratoma was very significant since these tumors contain normal cells from all three of the germ layers that give rise to every tissue in our bodies, so their presence confirmed that the cells were pluripotent. This seminal study, along with the nearly simultaneous discovery by Martin Evans and Matthew Kaufman that pluripotent stem cells derived from the mouse embryo could be grown in the  mouse uterus, paved the way for the whole field of embryonic stem cell research and more recently the development of induced pluripotent stem (iPS) cells.

Gail Martin’s research continues to focus on the mechanisms that control early embryonic development in mice, chickens and zebrafish, with a particular focus on the role of the Fibroblast Growth Factor (FGF) family of signaling molecules. Her work is an example of basic research at its best. Mutations in FGF receptors are associated with more than a dozen congenital bone disorders (2), and it is through understanding of the fundamental processes involved in controlling development that we will be able to design effective treatments for these disorders.

We congratulate Professor Martin on this award, an award that highlights a career that has contributed a great deal to our understanding of life.

Gail Martin was not the only one to be honored last week, on Sunday our own Professor David Jentsch received the Joseph Cochin Young Investigator award by the College on Problems of Drug Dependence (CPDD). The CPDD is the largest and oldest organization for the scientific study of drug dependence and addictions in the US, whose members have made great contributions to the treatment of drug dependence, and is a World Health Organization collaborating centre for research and training.  Every year the CPDD awards the Joseph Cochin Young Investigator award to an investigator under the age of 40 in recognition of their research contributions to the field of drug abuse, and this award emphasises the importance of the David’s work to future progress in treating drug addictions.

J. David Jentsch, Professor of Psychology and Psychiatry & Biobehavioral Sciences at UCLA.

Well done to David from all your friends at Speaking of Research!

Paul Browne

  1. Martin G.R. “Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.” Proc Natl Acad Sci U S A. Volume 78(12), Pages 7634-7638 (1981). PubMed Central: PMC349323
  2. Chen L. and Deng C.X. “Roles of FGF signaling in skeletal development and human genetic diseases” Front Biosci. Volume 1;10, Pages 1961-1976 (2005). PubMed: 15769677

Animal Research Benefits Mom and Baby Alike

The contributions of animal research to human health are many.

In response to blanket statement that animal research “does not work” I wanted to provide three examples of how animal research has directly benefited the health of women and their babies: in-vitro fertilization, oral contraceptives and neonatal intensive care.

Do you or any of your friends conceived with help of in-vitro fertilization?  Do you know how the method was developed?

It turns out that rabbits played a central role in the development of in-vitro fertilization.   As far abck as 1891 Walter Heape in England reported the first known case of embryo transplantation from one rabbit species to another, thereby showing that it was possible to transfer the embryos to a gestational carrier without adverse effects.  In 1934 Dr. Gregory Pincus at Harvard achieved in-vitro fertilization in rabbits for the first time, and he made very detailed studies in animals of the effects of hormones on ovulation and early embryonic development.  Being ahead of his time brought him much negative reputation and was described by the media a modern “Dr. Frankestein” (in fact, he was denied tenure due to these experiments.)   In 1958 Dr. Min Chueh Chang demonstrated conclusively that IVF was possible by implanting black rabbit embryos conceived in the lab into a white rabbit.  His studies in rabbits, rats, mice and hamsters during the 1950’s, 60’s, and 70’s, identified key conditions for IVF to be successful, such as the need for sperm capacitation.  These findings paved the way for the development of in-vitro fertilization in humans by Dr. Robert Edwards and Dr. Patrick Steptoe, which allows families to have a children overcoming many obstacles to pregnancy, both in cases of female and male infertility.  Approximately 60,000 infants are born with the help of IVF in the US every year…   Thank the rabbits.

Have you ever asked yourself where oral contraceptives come from?

The “pill” was first introduced in the 60s based on synthetic hormones that mimic the way progesterone works to prevent ovulation.  In 1919 Dr Ludwig Haberlandt and colleagues first demonstrated that transplantation of ovaries of pregnant rabbits into fertile female rabbits suppressed their ovulation.   Shortly before his death Haberlandt was able to prevent pregnancy in mice through the oral administration of an extract from the ovaries. It later was discovered that this was caused by the hormone progesteroneMargaret Sanger, the famous American birth control activist,  asked Dr. Gregory Pincus (the same one that developed IFV) to think of new methods of contraception and, building on these results, he showed that repeated injections of progesterone indeed could stop ovulation in rabbits.   This key finding, along with the development of a synthetic version of progesterone, led the first clinical trials of “the pill” in Puerto Rico.   Identifying effective synthetic progesterones was not an easy task, Dr. Pincus and Dr. Chang screened over 200 candidates before identifying three that prevented ovulation in laboratory animals.  The subsequent clinical trials of one of these synthetic progesterones were successful and Enovid was approved by the FDA in 1957.   Thank the rabbits again…

Dr Gregory Pincus and Dr Min Chueh Chang, pictured alongside artificial insemination pioneer Sir John Hammond. Courtesy of Mrs. F. Hammond.

Have you any of your friends had a premature baby in the intensive care unit?   Do you know why survival rates are now much higher than in the past?

The rate of premature birth has increased by 36% since the 80s (1).  Most babies born before 37 weeks of pregnancy are premature and are at risk of many complications.  In the USA alone, about 12.8% of babies are born prematurely and will spend their first few days of their lives in the neonatal intensive care unit.  Among babies born before the 34th week, 23,000 a year of them suffer from respiratory distress syndrome (RDS).  Such babies lack a protein in their lungs (called surfactants) that keep the air sacs in the lungs from collapsing.

Surfactants were discovered and their chemical composition analyzed using dogs in biomedical research and through research on rabbits and lambs surfactant therapy, initially using surfactant from cows and later synthetic surfactant, was developed.  The fruits of this research were translated into the treatments using surfactants in the 90s, which reduced the death of babies from RDS by about 50% (2).  In other words, slightly more than 10,000 babies are saved every year just in the US alone due to surfactant-replacement therapy.

That’s more than one baby per hour just in the US… Saved.  Thanks to animal research.

And this work goes on, for example in recent posts Paul has discussed the use of brain cooling and xenon gas to protect babies who have suffered oxygen starvation during birth from brain damage.

So when animal rights activists and the medical wing of their movement state that animal research “does not work”, what they really mean is that it does not work… for them.

Yet, they cannot deny these facts with books full of half-truths and out-of-context citations.

Anyone can walk into the nearest neonatal ICU and face the babies and their parents.  Face the facts.

Dario Ringach

References:

(1) Martin, J.A., et al. Births: Final Data for 2006. National Vital Statistics Reports, volume 57, number 7, January 7, 2008.

(2) Engle, W.A., and the Committee on Fetus and Newborn. Surfactant-Replacement Therapy for Respiratory Distress in the Preterm and Term Neonate. Pediatrics, volume 121, number 2, February 2008, pages 419-428

Septic shock: Mice show way to a new treatment

When we think of the immune system we usually think of the adaptive immune system – the B-cells and T-cells that recognize and destroy specific pathogens – which isn’t surprising since this is the arm of the immune system that vaccines are designed to stimulate.  However working alongside the adaptive immune system is the innate immune system which protects us form infection in a non-specific fashion. Key to this system are phagocytes, a diverse set of cells whose primary characteristic is their ability to consume and digest invading microorganisms and secrete a range of chemical messengers known as the proinflammatory cytokines which stimulate other components of the immune system. This usually a useful part of the immune response, but sometimes there is an excessive release of cytokines which causes the patient to enter a condition known as septic shock where the immune system over-reacts and causes serious tissue damage, eventually leading multiple organ failure.  As a consequence of the increase in complicated surgery, implantable medical devices, elderly patients and patients with weakened immune systems, there has been an increase in the incidence of septic shock in recent years, and with around half of septic shock cases proving fatal it is now the number one cause of death in intensive care units.

Overreaction by the immune system to a bacterial infection can cause septic shock

This week a multinational team of scientists based in Bern, Frankfurt, Glasgow and Singapore, and led by  University of Glasgow physician Professor Alirio Melendeza, have published a paper in Science (1) announcing an important development in the struggle to reduce the death toll from septic shock.

They had previously used in vitro cell culture techniques to identify an enzyme called sphingosine kinase 1 (SphK1) in human phagocytes and demonstrated using both RNAi and a specific inhibitor of SphK1 called 5c that SphK1 was involved in stimulating the cellular signaling pathways that promote release of proinflammatory cytokines.  In this study they began by examining phagocytes isolated from 30 septic shock patients, finding that SphK1 levels were higher in these patients than in a control group. They next found that treating the phagocytes from septic shock patients with the inhibitor 5c blocked the production of proinflammatory cytokines by these cells in response to exposure to bacterial lipopolysaccharide, a molecule found on the exterior of some bacteria that usually provokes a strong inflammatory response.

The ability of 5c to block SphK1 dependent inflammation in-vitro was impressive but would the same happen in a whole organism where other pathways might promote inflammation? The team led by Professor Melendez next examined if 5c or RNAi could protect mice which were injected with an otherwise lethal dose of lipopolysaccharide, and they found that both methods of blocking the action of SphK1 did indeed provide complete protection against septic shock.

This was a very exciting result but acute, one-off exposure to lipopolysaccharide in vitro or in vivo is not the same as bacterial infection, where bacteria are multiplying and constantly interacting with the immune system to induce inflammation. Of course it is also vital that when turning down the inflammatory response the treatment doesn’t also compromise the immune system’s ability to fight the infection.  The team therefore assessed whether pre-treatment with 5c or RNAi could prevent systemic inflammation and mortality from septic shock in a mouse model that simulates microbial infection in humans following surgery or injury. Both treatments prevented death from septic shock,  and not only was the immune system’s ability to combat the infection not compromised but the infection was actually cleared more quickly.

Pre-treatment is all very well but in the clinic treatment almost always starts after sepsis develops, so it was cheering to note that  the inhibitor 5c reduced mortality when given up to 12 hours after infection it reduced mortality from septic shock, though it was most effective when given within 6 hours. This was as effective as the broad-spectrum the antibiotic co-amoxiclav, a standard treatment for sepsis, and when co-amoxiclav was administered along with 5c the combination was observed to be considerably more effective than either treatment used alone.

Professor Melendeza and his colleagues have identified an exciting new approach to reducing the toll from septic shock, hopefully work is already underway to translate this promising study from the bench to the bedside.

In other news the 2010 Kavli Prize in Neuroscience has gone to three scientists, Richard H. Scheller, Thomas C. Südhof, and James E. Rothman, who haveused a creative multidisciplinary set of approaches to elucidate the key molecular events of neurotransmitter release”.  Their work, which involved the study of tissues from a variety of species including rats and marine rays and studies of knockout mice, has made a huge contribution to our understanding of how the release of the molecules that carry messages between the cells of the immune system work.  This research may sit squarely in the realm of basic science, but the understanding of nerve cell communication that these three scientists have provided is now informing the development of new therapies for a wide range of psychiatric and neurological disorders.

Both these news items may at first seem unrelated, but what they have in common is animal research at the heart of a multidisclipinary approach that is increasingly typical of how biomedical science is done in the 21st century.

Paul Browne

1)      Puneet P. et al. “SphK1 Regulates Proinflammatory Responses Associated with Endotoxin and Polymicrobial Sepsis” Science Volume 328(5983), pages 1290 – 1294 (2010) DOI: 10.1126/science.1188635

Gallup Poll Puts Majority Behind Animal Research

Mixed news last week with the results of the latest Gallup Poll on the moral acceptability of medical testing. 2% more Americans believe that animal research is morally acceptable than in 2009 (with 2% fewer believing it is morally wrong). This is the second consecutive annual rise in support for this lifesaving medical technique.

However when we graph these numbers we can see that, although relatively stable over time, there has been a slight dip in support over the past decade. However, we must bear in mind that throughout this those who believe it is morally acceptable have held a 25% point lead. Overall these results should indicate that we still have much work to do to ensure that the public remains behind medical research.

The final fact is that although 69% of men find animal research morally acceptable, only 49% of women do (although due to “no opinion/depends” this is still more than those women who believe it is unacceptable). To remedy this, proponents of research should make sure to mention the importance of animals in the development of the recent Breast Cancer drugs (Herceptin and Tamoxifen) and Cervical Cancer Vaccine (HPV Vaccine).

I also do wonder if the numbers would differ if the more accurate term “medical research” was used?

Cheers

Tom