Monthly Archives: May 2010

A shield against the nightmare: Ebola virus vaccine success

There must be few diseases that can conjure up images of horror the way Ebola virus can. Since it was first identified in Zaire (now the Democratic Republic of the Congo) in the mid-1970’s there have been several outbreaks that have left hundreds of people dead, but it is the potential for far worse outbreaks that has epidemiologists worried. Ebola infection causes a viral hemorrhagic fever characterised by rapid onset of fever, followed within days by vomiting and diarrhea, and eventually bleeding from bodily orifices and injection sites; mortality varies between 50 and 90% depending on the strain of Ebola. There is no specific treatment or cure available for Ebola virus, although through research on mice and guinea pigs scientists at the U.S. Army Medical Research Institute of Infectious Diseases developed a morpholino based treatment that protected 75% of rhesus monkeys exposed to Ebola virus. Subsequent studies showed that these morpholino based therapies – AVI-6002 and AVI-6003 – could confer protection against Ebola and Marburg viruses respectively when administered within an hour of infection, and further studies are under way to determine if they can offer protection when administered later.

Transmission electron micrograph of Ebola virus. Courtesy of the Centers for Disease Control and Prevention

While efforts to improve the efficiency of this treatment are ongoing other scientists have turned to developing a vaccine against Ebola virus.  So far we have been quite lucky with Ebola, most outbreaks have occurred in remote areas and due to the rapid progression of the disease – and the fact that no strains have been capable of airborne infection – the outbreaks have tended to burn themselves out quite quickly once travel restrictions and containment protocols were implemented, but we can’t rely on being lucky forever.

A difficulty with designing vaccines against Ebola is that the antibody-producing B-cells of the immune system that many vaccines stimulate can only recognize one strain at a time, so for each new strain of Ebola that emerges you would need a new vaccine.  This would obviously result in a significant delay between reporting of an outbreak and getting the vaccine into the areas where it’s needed, so scientists have been studying another vaccination strategy that stimulates the cellular arm of the immune system that is capable of recognizing a wider range of virus strains. The two part “Prime-Boost” strategy they developed involves first administering a “prime”, a DNA vaccine that codes for part of the surface proteins of the “Zaire” and “Sudan” strains of Ebola, followed several months later by administration of a “boost” vaccine based on a weakened adenovirus (cold virus) that also produces fragments of the Ebola surface proteins that are then recognized as foreign by the immune system. This strategy successfully protected cynomolgus macaques from the Zaire strain of Ebola virus (1) and has since been shown to be safe to stimulate an immune response in small scale human trials (2).

The question remained as to whether this vaccine strategy would be able to protect against Ebola strains other than “Zaire” and “Sudan”, and the opportunity to test this came in 2007 when a new strain of Ebola was identified in the Bundibugyo region of Uganda. The outbreak burnt itself out before any program of vaccination could be implemented, but the new strain did offer the opportunity to re-evaluate the prime-boost vaccination strategy.  In a report, published yesterday in the open access journal PloS Pathogens, Dr Nancy J. Sullivan and colleagues at the National Institute of Allergy and Infectious Diseases report that the prime-boost strategy can protect cynomolgus macaques from the otherwise fatal Bundibugyo Ebola virus, demonstrating that it can protect against several different strains of the disease.

This is great news and brings us a lot closer to the goal of a vaccine that can protect us against Ebola virus, in particular it is possible that this vaccine could be used to immunize people living in areas where Ebola is a threat even before an outbreak is detected.  It is not just humans who may benefit from this vaccine research, in the past decade tens of thousands of chimpanzees and gorillas have died from Ebola, and the disease now poses a significant threat to the their very survival.  A vaccine against Ebola would help reduce death toll among these endangered apes, though even with an effective vaccine developing and implementing a successful immunization program will be neither cheap nor easy.

Paul Browne

1)      Sullivan N. J. et al. (2000) Development of a preventive vaccine for Ebola virus infection in primates. Nature 408: 605–609. DOI:10.1038/35046108

2)      Martin J.E., et al. (2006) A DNA vaccine for Ebola virus is safe and immunogenic in a phase I clinical trial. Clin Vaccine Immunol 13: 1267–1277. DOI:10.1128/CVI.00162-06

3)      LE Hensley et al. Demonstration of cross-protective vaccine immunity against an emerging pathogenic Ebolavirus species. PLoS Pathogens Online open-access publication (2010) DOI: 10.1371/journal.ppat.1000904

We Need You – Debunk AR myths

We’ve been a little slower on our postings lately – a busy time for most of our regular contributors. So we’re calling for help on one of our latest projects.

We aim to expand our “Bad Science” section by scientifically challenging some of the false “facts” produced by animal rights groups. Many of these myths can be found on the Vivisection Absurd website, which produces a list of 50 “disasters of animal experimentation”. To debunk these myths we suggest you go to the source (see the endnotes on the page), many myths are created after activists misrepresent or misunderstand what is being said in peer reviewed scientific literature.

Debunkings should be full, but (preferably) not too long (see Bad Science section for guidance). Please email them to contact@speakingofresearch.com . We aim to run a small series of blog posts on some of these debunkings (with full credit given to the astute scientists responsible).

Not all myths are as beautiful as this one

Cheers

Tom Holder

Symposium Explores Animal Rights Tactics, Responses

On Saturday April 24, 2010, the American Physiological Society sponsored a symposium on Trends in Animal Rights Activism and Extremism. This event, attended by about 100 people,  was part of the Experimental Biology 2010 meeting, which was recently held in Anaheim, California. In introducing the symposium, session chair Bill Yates noted the importance of animal welfare, and the obligation of human beings to provide for the well-being, humane care, and judicious use of animals in research. However, some individuals reject the notion that research with animal models plays a critical role in advancing our understanding of biological processes and is essential to the search for cures. Some with this belief use tactics such as violence and intimidation to prevent researchers from conducting studies using animals. The intent of the symposium was to inform researchers about the tactics of animal rights extremists and what researchers and their institutions can do to protect themselves and their work.

Bill Yates opens the discussion

UCLA Senior Campus Counsel Amy Blum opened the symposium by explaining what kinds of protected information may be subject to the federal Freedom of Information Act (FOIA) or state open records laws. Animal rights extremists have used information obtained under FOIA to target investigators for intimidation and harassment. While FOIA is a mandatory disclosure statute, certain kinds of information may be exempted from disclosure, such as privileged communications between attorneys and clients; trade secrets or confidential commercial or financial information; personnel and medical files; or information that might endanger a person’s life or safety. Researchers should exercise care in how documents and communications are written to avoid unnecessary disclosure of personal information or intellectual property. This effort may be “difficult in the short run” but will “make your life easier in the long run,” Blum said.

University of Iowa (UI) Attending Veterinarian and Office of Animal Resources Director Paul Cooper reviewed the 2004 Animal Liberation Front (ALF) break-in during which some 400 rats and mice were removed from the facility. Four individuals were involved in that break-in, and they made a video. It shows them dumping animals into plastic storage bins, destroying laboratory equipment; trashing researchers’ offices, and pouring acid over research records. Cooper noted that the animals in the storage bins were clearly having trouble getting enough air and probably died of suffocation. Based upon the ALF video and images captured by UI security cameras before and after the break-in, it was evident that the intruders included someone who was familiar with the facility. ALF break-ins have been rare occurrences, but Cooper’s message was clear: Every research institution has to take its security seriously because while if an ALF break-in can happen in Iowa City, it can happen anywhere.

David Jentsch discusses events at UCLA with symposium participants

David Jentsch, a UCLA professor of psychology and psychiatry and bio-behavioral sciences, reviewed the history of animal rights extremism at UCLA. From 2001 to 2003, there were annual demonstrations where animal rights demonstrators criticized the university, researchers, and their work. “When they do that and you make no response, you are contributing to the decline in public confidence,” Jentsch noted. Starting around 2003, extremists began sending threatening emails and vandalizing researchers’ homes during late-night visits, which led to a climate of increasing fear. Extremists left a Molotov cocktail on the doorstep of one UCLA researcher—except that they actually left it at the home of the researcher’s elderly neighbor (Fortunately, the device failed to detonate). Another faculty member and his family were subjected to repeated home demonstrations and threats. The university’s only public comment during this period was a statement denouncing terrorism. This was consistent with views widely held across many institutions that they should not respond to accusations against researchers because that would add to the critics’ credibility. It was the university’s pursuit of this strategy of silence in the face of increasingly hostile and violent attacks that ultimately precipitated a crisis: In the fall of 2006, a researcher who was studying how the brain processes visual information announced that he would terminate his research program. He asked in return that animal rights activists leave him and his family alone. He delivered his plea in an email message to the North American Animal Liberation Press Office with the subject line “You win.”

Over the next couple of years, the University’s responses improved, however the activists’ attacks did not abate. In 2007, there was an unsuccessful attempt to firebomb one faculty member’s car, the home of another faculty member was deliberately flooded. In 2008, the door to the same individual’s home was set on fire; a commuter van belonging to the university was burned; and cars were vandalized in the driveway of a post doc’s home and at the home of a researcher’s neighbor. Finally, in early 2009, Jentsch’s car was firebombed in the driveway of his home. This “intensification to a climax of violence” demonstrated to Jentsch that the “strategy that the university was using wasn’t working and wasn’t going to work.” His response was to found Pro-Test for Science, an organization that subsequently staged the first major public demonstration in support of animal research in the United States.

The first Pro-Test for Science Rally was held April 22, 2009. The goal of the rally was to let the public know that “animal research is contributing to basic science understanding of physiology and helping us to solve an array of problems in biomedicine.” Although counter-protesters showed up to take pictures, Jentsch said that not only did this fail to intimidate the participants, it was “fair to say that everyone who came left feeling that there was something they can do” to support research. It should further be noted that since the 2009 Pro-Test rally, there have been no further violent attacks against UCLA researchers.

“Get ahead of the issue,” Jentsch urged. “Don’t wait.” He recommended that every individual scientist get into the habit of engaging the public about science: “Tell them what you do—be your own advocate.”

Hayre fellow Megan Wyeth emphasizes the importance of public outreach

Americans for Medical Progress Hayre Fellow Megan Wyeth spoke about public outreach for the early career scientist. Public outreach can take many forms, she noted, recommending that everyone work within his or her own comfort levels. She urged those who teach to cite the basic animal research that led to the breakthroughs in order to raise their students’ awareness of what animal research has contributed. “Tell people what you do,” Wyeth said. She suggested emphasizing that animal research is necessary for medical progress, that is irreplaceable for the foreseeable future, and that it is a humane and highly regulated activity.  This was a point that was appreciated by many attendees, including session chair Bill Yates who had earlier stressed the importance of developing good relationships with local journalists and conveying this positive message before a crisis occurs.

Alice Ra’anan

Director of Government Relations and Science policy

The American Physiological Society

Bill J. Yates

Chair, Animal Care and Experimentation Committee

The American Physiological Society

Public outreach is an important duty for all involved with medical research, though as Megan said it takes many forms. Allyson Bennett has discussed how scientists can become involved in debates and web-based advocacy , and organize community outreach programs, while Paul Browne has stressed the need for scientists and physicians to explain how animal research has contributed to the latest advances in medicine. There are many ways to improve public understanding of the importance of animal research to medical progress, but they can all be summed up by David Jentsch’s call to “Tell them what you do—be your own advocate”.

Finding animal research in medical news

One of the things that often strikes me when reading about medical advances or clinical trials is how variable the reporting of basic and applied research, including animal research, that underpins the clinical research is.  In some cases it is discussed in some depth, but far too often it is either skimmed over or not mentioned at all.  This is a shame since it makes it more difficult for readers to make the connection between what is happening in the clinic and animal research that may have begun years earlier. A few stories in the news this week illustrate this variability very nicely.

I’ll start with an excellent report by Miriam Falco on CNN entitled “Stem cell treatment goes from lab to operating room” which describes a clinical trial of fetal stem cells in the treatment of Amylotrophic Lateral Sclerosis (Lou Gehrig’s disease), a progressive neurodegenerative disease affecting the motor neurons that leads to severe muscle weakness and eventually death as the muscles that control breathing fail.  As the CNN report points out research on rats was vital to the identification of the correct type of cells for this transplant, and Dr. Eva Feldman demonstrated that injecting fetal stem cells into rats with ALS preserved the large motor neurons and muscle strength.

Lead researcher Dr. Eva Feldman, a neurologist at the University of Michigan, designed the trial just four years ago. After a lot of animal testing, her team determined that using fetal nerve stems rather than human embryonic or adult stem cells (such as bone marrow stem cells) was most effective, she says.

Stem cells have the ability to turn into different cells in the body. However, human embryonic stem cells, which come from 4- or 5-day-old embryos, also been found to sometimes turn into cancer cells. Fetal stem cells, such as those used in this trial, are a few weeks older and have already taken on a specific identity — in this case nerve cells.

Feldman says the fetal stem cells used in this trial did not become any of the unwanted cell types. “That’s very, very important,” she says.

Basic animal research showed the potential of this therapy, but applied research also played an important part in making this clinical trial possible. Through studies on pigs Dr. Nicholas Boulis developed an apparatus that allows the stem cells to be injected at precise locations in the spine, and then practice the technique before attempting to use it on a human patient.

Animal testing also proved very useful when it came to figuring out how to actually inject the stem cells. Emory University’s neurosurgeon Dr. Nicholas Boulis invented the device that holds the needle that injects the stem cells. The goal is to inject the cells without injuring the spine and causing even more paralysis. He practiced on 100 pigs before attempting the procedure on a human.

Our second report is from the LA Times, and in an article entitled “A personal fight against a lethal childhood illness reports on the work being done at the Centre for Duchenne Muscular Dystrophy at UCLA. It’s a nice report which shows how passionate scientists like Stan Nelson and Carrie Miceli are about finding effective treatments and cures for serious diseases.  While the report does refer to  experimental therapies such as exon-skipping and gene therapy it unfortunately does not discuss them or the research that led to their development in any depth.

Exon skipping is a particularly innovative approach to treating some cases of Duchenne Muscular Dystrophy (DMD) where the disease is due to a mutation in the dystrophin  gene that stops translation from messenger RNA prematurely and prevents the production of the protein  dystrophin. In exon-skippping a molecule known as an antisense oligonucleotide or morpholino acts to remove the portion of mRNA that contains the mutation and allows the translational machinery of the cell to read through and produce a working dystrophin protein.  As I discussed in an article last year research in mice and dogs has been crucial to the development and refinement of exon-skipping and early versions of this therapy have already had promising results in clinical trials undertaken at  Great Ormond Street Hospital in London and Royal Victoria Infirmary in Newcastle.  Gene therapy, where the faulty dystrophin gene is replaced by a working version, is also being developed, though it has not yet entered human clinical trials. A recent review (1) available to read for free at PubMed Central discusses the progress that has been made in recent years, the challenges that remain before DMD can be cured, and the vital role played by animal models  in overcoming these challenges. The review also covers stem cell therapy for DMD, another exciting approach to treating the disease that we have discussed previously.

The final news item is a BBC report on a successful clinical trial of stem cells to treat Multiple Sclerosis, this time using stem cells isolated from a patient’s own bone marrow. Multiple Sclerosis (MS) is an autoimmune disorder where the patient’s immune system turns on the myelin sheath that insulates the axons of nerve cells, leading to a range of often serious neurological problems.  At present few effective treatments have been approved for MS, and several are currently being evaluated in clinical trials.  While the improvements seen in the clinical trial were modest they do hold promise for longer and lager trials that are now being planned, and I suspect that as with other therapies the key might be to start treatment early to prevent damage as well as allowing damage to be repaired.

The symptoms of Multiple Sclerosis. Image courtesy of Mikael Häggström

The trial at Frenchay Hospital in Bristol built on years of careful animal research, including research conducted by Professor Neil Scolding who lead this clinical trial.  Interestingly the research, conducted in mice with experimental allergic encephalomyelitis that reproduces many of the features seen in autoimmune diseases that attack the myelin sheath, showed that rather than replacing the damaged cells that produce the myelin sheath or nerve cells the injected stem cells protected the myelin sheath and nerve cells by turning down the pathogenic immune response responsible for damaging the myelin sheath (2,3). This was important since it meant that it was not necessary to inject the stem cells directly into the site of the MS lesion, rather the cells could be as (if not more) effective if injected into the bloodstream so that migrate to tissues such as the lymph nodes where they can interact with cells of the immune system.  This discovery paved the way for the clinical trial reported by the BBC.

There’s a lot of stories in the news that are relevant to animal research, the trouble is that it’s not always easy to see the connection. At Speaking of Research we believe that the onus is on scientists to make sure that when they talk to reporters they give the full picture of what their research involves, and what earlier studies it depended on. Only then can the public really begin to appreciate just how important animal research is to continued medical progress.

Paul Browne

1)      Wang Z. et al. “Gene Therapy in Large Animal Models of Muscular Dystrophy” ILAR J. Volume 50(2), Pages 187-198 (2009). PMCID: PMC2765825

2)      Matysiak M. et al “Stem cells ameliorate EAE via an indoleamine 2,3-dioxygenase (IDO) mechanism” J Neuroimmunol. Volume 193(1-2), Pages 12-23 (2008) DOI:10.1016/j.jneuroim.2007.07.025

3)      Gordon D . et al “Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration.” Neurosci Lett. Volume 448(1), Pages 71-73 (2008) DOI:10.1016/j.neulet.2008.10.040

Make a Difference – The Hayre Fellowship

Do you want to make a difference in the movement to protect biomedical research from animal rights militants?  Do have an idea to build public support for lifesaving research?  If so, you are very much needed and here’s a way to get involved.  Once again, Americans for Medical Progress are accepting applications for the Michael D. Hayre Fellowship in Public Outreach.  The deadline is coming up soon – May 15 – but you can apply online.

I was the first Hayre Fellow, and during my time in the program I founded Speaking of Research and built this website.  The three Fellows who followed me developed their own projects – two Fellows created a program for private practice veterinarians, their employees and clients that includes a website and other educational materials about the importance of animal research to human and animal health, and the third Fellow helped to galvanize support on the UCLA campus for scientists facing intimidation and violence by animal rights militants. These projects are designed to continue on even though the Fellowship term has ended.

The program is for those in the 18-30 age group who believe that they can help improve the public’s understanding of animal research. Successful applicants will receive a $5,000 stipend and a $2,000 program budget, as well as the full support of both Americans for Medical Progress and Speaking of Research. Click the image below for more details (or here).

You may use the Fellowship award to create a local or national campaign, and I hope your plans include using and developing the Speaking of Research network.  The other Fellows and I will work closely with you to help you develop your project should you receive a Fellowship award.

I have been asked by AMP to be on the committee that determines who will be the new Hayre Fellows for the 2010-2011 academic year, and I look forward to seeing your proposals.

Whether or not you choose to apply for the Hayre Fellowship, you can get involved right now by contributing to the news section of the Speaking of Research website. We need people to help write articles about new medical breakthroughs, pro-research advocacy, and the misguided activities & illegal acts of animal rights activists.

For those of you seeking to financially contribute to research advocacy, you may donate online to support the Hayre Fellowships.

The action or inaction of scientists, researchers and students will determine the future of animal research, and with it the future of medical progress – are you prepared to make a difference?

Cheers

Tom Holder