Monthly Archives: September 2010

Lasker awards highlight the contribution of animal research to medical progress

Each September the Albert and Mary Lasker Foundation recognizes the contribution made by scientists and doctors to medicine by awarding prizes to those who have made outstanding contributions to our understanding of disease, and to its treatment and prevention. The list of past recipients of these awards reads as a veritable who’s who of the greatest minds in medical research over the past 65 years, so it’s not surprising that the Lasker prizes are often called the “American Nobels”, indeed many Lasker prize winners have gone on to pay a visit to Stockholm not long afterwards.

As one might expect the Lasker prizes have often been awarded for discoveries and medical advances that relied on animal research, and this year is no exception.

The Albert Lasker Basic Medical Research Award went to Douglas Coleman and Jeffrey M. Friedman for their work on the hormone leptin, work that has led to a revolution in our understanding of the regulation of appetite and metabolism.  The story of leptin is the story of how decades of careful research in mice led to an important discovery that is now helping to improve the lives of patients with rare genetic disorders, and more recently to help patients whose own leptin levels are too low as a result of HIV-related loss of fat tissue.

Napoleone Ferrara won the Lasker-DeBakey Clinical Medical Research Award for his discovery of the Vascular Endothelial Growth Factor (VEGF) and its role in regulating the growth of blood vessels.  The description of Dr. Ferrara’s  research on the Lasker website shows how Dr. Ferrara identified VEGF through research on cattle, and how his subsequent research using mice and rats ultimately resulted in the development of effective monoclonal antibody treatments for wet age related macular degeneration, a leading cause of blindness.

The third prize, the Lasker-Koshland Special Achievement Award in Medical Science, was awarded to Sir David Weatherall, a pioneer in the field of human genetics who has made invaluable contributions to our understanding of inherited blood disorders including α-or β-thalassemia and sickle cell anemia. His research laid the foundations for successful programs to reduce the incidence of these disorders, and of course to the development of treatments, some of which we discussed here just last week.  Sir David may not have performed any animal research in his own career, but he recently chaired the committee which wrote an influential report on the role of primates in medical research. The report concluded that primate research has made an important contribution to medical progress, and is still needed in several important areas of medical research including neuroscience and vaccine development.

The message from this year’s Lasker prizes is clear; for medicine to continue to advance many different approaches to research must be applied, and among the many techniques that are necessary to progress animal research has an honored place.

Addendum: Dario Ringach has written an excellent essay on the Opposing Views website of the process through which basic scientific discoveries about the function of VEGF were harnessed to yield new therapies for retinopathy.

Paul Browne

Mice Help Develop Molecular Imaging of Tumors

Can you follow the structural growth and metabolic activity of a developing tumor?   Such an advance would allow one to track how patients are responding to their therapies right away instead of having to wait weeks.  The video shows new research in the field of molecular imaging and yet another example of how the development of novel medical devices relies on the use of animals in research.

You can learn more here:

1: Mather SJ. Design of radiolabelled ligands for the imaging and treatment of cancer. Mol Biosyst. 2007 Jan;3(1):30-5. Epub 2006 Nov 14. Review. PubMed PMID:

2: Phelps ME. PET: the merging of biology and imaging into molecular imaging. J Nucl Med. 2000 Apr;41(4):661-81. Review. PubMed PMID: 10768568.

Regards

Dario

Animal research: At the forefront of modern medicine

Several reports in the news over the past week have highlighted yet again the importance of animal research to medical advances.

The BBC reports that gene therapy has been used successfully to treat a patient with severe β-thalassemia.  β-thalassemia is an inherited disorder caused by mutations in the β-globin chain of haemoglobin that lead to ineffective production of red blood cells and profound anaemia, and currently bone-marrow transplant is the only effective long term treatment for severe β-thalassemia. Unfortunately suitable donors are not easy to find, and in their absence patients depend on frequent blood transfusions that in turn lead to problems due to iron overload.  Against this background the news that this disease may be treated by gene therapy in the future is most welcome.

The team of scientists and doctors led by Dr. Philippe Leboulch, of Harvard Medical School in Boston, used a lentiviral vector, based on elements of the HIV virus, to insert copies of a functioning β-globin gene into the patient’s haematopoietic stem cells (HSCs), and then transplanted the modified HSCs back into the patient. Lentiviral vectors have become popular in gene therapy in recent years, indeed last year we discussed the use of a similar vector to treat the brain disorder X-linked adrenoleukodystrophy, and this popularity is due mainly to their improved safety compared to other vectors.  Early trials of gene therapy for X-linked severe combined immunodeficiency (X-SCID) were called into question when several patients developed leukemia when the retroviral vector used integrated into a location in the genome that activated an oncogene – though ultimately the treatment was of  great benefited to most patients – and research comparing retroviral vectors with lentiviral vectors in mice found that the latter had a much lower tendency to activate oncogenes and promote tumor growth (1).

As Dr. Leboulch and colleagues point out in their Nature Biotechnology paper (2) reporting this work, research on mice was not confined to evaluating the safety of the lentiviral vector. Years of work went into developing and refining the β–globin lentiviral vector in mouse models of β-thalassemia and sickle-cell disease (also caused by a mutation in the β-globin gene) before it was ready to test in a human patient.

Lentiviral vectors have proven capable of transferring these elaborate structures with fidelity and high titres (5, 6). Hence, several mouse models of the β-haemoglobinopathies have been corrected, long-term, by ex vivo transduction of haematopoietic stem cells (HSCs) with β-globin lentiviral vectors (5, 6, 7, 8, 9, 10). These advances have prompted the prudent initiation of a human clinical trial.

Such research is now bearing fruit, and it is hard to disagree with gene therapy expert Professor Adrian Trasher, quoted by the BBC as saying:

The good news is that technology is advancing rapidly, and it shouldn’t be too long before diseases such as thalassaemia can be reliably and safely treated in this way.

Another report from the BBC provides hope for the many thousands of patients on waiting on organ transplant lists; speaking at the British Science Festival Professor Steve Sacks announced  the development of a treatment using the drug mirococept to protect the transplanted organ from attack by the immune system , a technique that could potentially double the length of time it survives in the recipient before a new organ is required.  Currently transplanted organs last for about 10 years, and patients requiring replacement organs make up about 20% of those on the waiting lists. A small clinical trial of the technique indicates that is safe and a larger trial is now planned. Mirocosept works by blocking the activation of the complement system, a complex set of approximately 20 interacting enzymes and regulatory proteins found in the blood plasma and body fluids. The complement system plays a key role in fighting infection, but its activation is also a key early event in organ rejection.  Mirococept consists of a complement inhibitor peptide attached to a second peptide that allows it to attach to cell membranes, thus enabling it to remain on the surface of the transplanted organ and prevent complement activation.

The human Heart, washing with mirococept may prolong its life after transplant.

Mirococept itself was initially developed for the treatment of rheumatoid arthritis and ischaemia and reperfusion injury, after basic research in mice and rats demonstrated that the complement system played a major early role in activating the inflammatory response that is characteristic of these conditions, identified the key components involved in this response, and showed that blocking complement activation in several animal models could reduce tissue damage (3,4). Mirococept targets complement inhibition to specific tissues concentrating it where it is needed most and avoiding a more general inhibition that could leave the body vulnerable to infection, and performed well in animal models or arthritis, organ transplant, and ischemia and reperfusion injury (4,5). On the back of these promising results Mirococept has been taken into human trails for rheumatoid arthritis and organ transplant, where as we have seen it has proven to be a safe and reliable treatment. Larger trials to evaluate the efficacy of Mirococept are now underway for rheumatoid arthritis and being planned for organ transplants.

The shortage of organs for transplant is a major challenge, and many approaches are being considered to increase the supply, I have written previously of tissue engineering to build new organs but it will be years before this technology is in widespread use. Until then I would urge you all to sign up as an organ donor, it only takes a few minutes and you might just save several lives.

Our final story comes from the Autism Science Foundation, who write that a new drug named arbaclofen (STX209) improved the social interaction of autistic children, reducing tantrums and agitation, in an early clinical trial.  Unlike existing medications that treat specific symptoms of autism arbaclofen acts to correct an imbalance in the levels of two neurotransmitters, glutamate and GABA,  in the brains of autistic children.  This new approach comes from studies of a mouse model of fragile X syndrome, a common inherited form of mental impairment and a cause of some cases of autism, which demonstrated that excessive activation of group I metabotropic glutamate receptor played an important role in the disorder, as discussed in an overview on the Seaside Therapeutics website. STX209 acts to reduce the excessive levels of glutamate released in the brain and therefore reduce activation of the group I metabotropic glutamate receptor, an approach which worked well in a mouse model of fragile X syndrome.

Mice, a valuable resource in autism research. Image courtesy of Understanding Animal Research.

At a time when the parents of autistic children are bombarded with ineffective, ethically dubious, or downright dangerous “cures”, the development of a treatment that is both safe and effective is very welcome, lets just hope that it works as well in larger trials.

So once again this week the medical news is full of exciting developments that depended on basic and applied  medical research in animals, which is exactly the kind of work that Speaking of Research exists to support!

Paul Browne

1)      Montini E. et al. “Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration” Nature Biotechnology Volume 24, Pages 687-696 (2006) doi:10.1038/nbt1216

2)      Cavazzana-Calvo M. et al. “Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia” Nature Volume 467, Pages 318–322 (2010) doi:10.1038/nature09328

3)      Sahu A. and Lambris J.D. “Complement inhibitors: a resurgent concept in anti-inflammatory therapeutics.” Immunopharmacology Volume 49, Pages 133-148 (2000) PubMed:10904113

4)      Souza G.D. “APT070 (Mirococept), a membrane-localised complement inhibitor, inhibits inflammatory responses that follow intestinal ischaemia and reperfusion injury.” Br J Pharmacol. 2005  145(8): 1027–1034.  doi:10.1038/sj.bjp.0706286

5)      Smith R.A.  “Targeting anticomplement agents.” Biochem Soc Trans. Vol.30(6), Pages 1037-1041 (2002) PubMed:12440967

Speaking Up: Who Does ‘No Comment’ Work For?

It is no secret that activist groups regularly aim for mainstream news coverage by producing sensationalized and misinformed stories about laboratory animals.  Like other topics in science that are generally not well understood, animal research can be a relatively easy target for misrepresentation. This is particularly true when such stories are met with little challenge by those who could contribute essential information, context and knowledge.

Headlines over the last month highlight both politicians and animal activists making savvy use of negative claims about animals in research in order to capture media attention for disparate agendas.  The recent press U.S. Senators John McCain and Tom Coburn garnered by targeting federally-funded animal research in a report on stimulus spending provides one good example of the approach. It also shows that animal research is not alone in the scientific topics that are manipulated as Alan Leshner, chief executive officer of the American Association for the Advancement of Science and executive publisher of the journal Science, pointed out in a response to the Coburn-Mc Cain report:

“As a former director of the National Institute on Drug Abuse, I was stunned that research projects now mocked as government waste included efforts critical to developing medicines to treat cocaine addiction.”

‘Monkeys Get High for Science’ is a funny headline, sure to generate media coverage of the report, which satirizes stimulus bill projects. But it’s a cheap shot at important research critical to finding medications for cocaine addiction.”

“Sens. Tom Coburn (R-Okla.) and John McCain (R-Ariz.) have also ridiculed federally funded research related to global climate change, biodiversity and antibiotic mechanisms.”

One of the major goals of Speaking of Research is to encourage informed public engagement and dialogue about animal-based studies and their role in scientific and medical advances.  The SR blog contains many posts and specific examples about how animal-based research contributes to scientific and medical advances. For example, Paul Browne has recently written about the development of a microbicide gel that reduces HIV infection rates and the use of hypothermia combined with xenon gas to prevent brain damage in newborns who suffered oxygen deprivation, while Dario Ringach has written about the development of Herceptin.

We also offer information, tools and support for those who choose to contribute to public discussion of animal research. In fact, there are many groups and sources for information and conversation about the issue. They include advocacy groups and collaborative networks such as Understanding Animal Research, Americans for Medical Progress, States United for Biomedical Research, the Foundation for Biomedical Research, and Animal Research Information. They also include scientific societies such as the American Physiological Society, Society for Neuroscience, American Association of Laboratory Animal Science, and the Federation of American Societies for Experimental Biology.  As well, a wide range of science bloggers, from philosopher Janet Stemwedel to DrugMonkey to Orac also provide timely, thoughtful discussion of relevant issues. Finally, many academic institutions have actively built outreach and education programs that offer good models for others.  In other words, there are many resources and avenues to support individuals who want to learn more and identify a range of effective ways to contribute to the public discussion of animal research.

Along with others, SR believes that immediate, factual, and vigorous responses to misrepresentative and negative portrayals of animal research are essential, regardless of the source of those stories.  We also recognize that among the many reasons scientists and others refrain from responding publicly to specific challenges is the belief any response will have a range of negative consequences while achieving little in the way of increasing public understanding. For example, responding may legitimize stories that have little basis in reason, increase negative attention, lead to media and activist demands for time-consuming continued responses, and draw fire from animal rights extremists.  All of these are reasonable concerns about likely outcomes.

Less obvious, however, are the unmeasured consequences of not responding to misrepresentation and of ignoring opportunities to provide strong, well-reasoned, and factual information to balance public presentation of issues in animal research.  To be clear, the question is not about changing the views or positions of those committed to ending all animal research. Rather, it is about providing the public with a balanced view of the issues. The response to stories about animal research illustrates high public interest. Unfortunately, what these stories also too often illustrate are major gaps in knowledge and understanding of science and the integral role animal studies play in scientific and medical advances. Moreover, they frequently perpetuate distorted views about how animal research is conducted.  One obvious way to counter those distorted views is to not let them persist unchallenged.

Media portrayals often fail to reflect the reality of the vast majority of animal research:  that it is conducted humanely by compassionate individuals engaged in ethical studies designed to advance scientific and medical progress and working under many forms of local, state, and federal regulation.  The part of that work that grabs headlines and enthusiastic response is found in scientific breakthroughs and medical progress.  The connection may escape public attention, however, because basic research and animal-based studies contributing the foundation for that progress are frequently either ignored or underplayed. This is perhaps understandable, as the story is usually the clinical breakthrough and the benefits that it will bring to patients, rather than the long years of hard work in the lab that made it possible.  As a result, the public is often simply missing information about the importance and the scope of benefits from animal research.  In turn, when confronted with questions about public policy and support of animal research, they are less likely to make informed decisions.

In short, without a solid understanding of how animal research contributes to scientific and medical advances, it is impossible to envision the likely consequences of ending animal research.  This is why all of the people who support animal research and understand its contributions to public health—including not only scientists engaged in animal-based studies, but also other scientists, their institutions, physicians, advocacy groups, educators, science journalists, and others—need to play a vocal role in education that makes the contributions of animal research clear. Although many people do not see animal research as “their issue,” public opinion of it can ultimately shape public policy and have far-reaching consequences.  Thus, it is everyone’s issue because it is foundational to scientific discovery, medical advances, and public health.

There are many reasons to get involved in the discussion and lend strong, informed voices to counter media misrepresentation and activist targeting of animal research. Scientists and institutions engaging in animal research are often reluctant to speak out when inaccurate and inflammatory media portrayals are aimed at them.  Part of the reason is that speaking out carries the possibility of fueling campaigns of harassment and violence by extremists.  In fact, this is where the activities of extremists—including those who directly threaten scientists’ lives as well as those who advocate violent means to achieve their goals—deliver benefits to all animal activist groups who prefer to distribute biased messages without risk of factual counter.  But it is a strategy that doesn’t work if it is countered by individuals, groups, and institutions who are unwilling to remain silent and who instead will speak out in support of research and in support of those who are directly targeted.  Animal extremists may be committed, passionate, and effective in working for their objectives by engaging the media, misrepresenting research, and executing activities designed to produce fear; however, they are less able to target everyone who speaks if that number is large, visible, and resolute. As Society for Neuroscience (SfN) President, Michael E. Goldberg, says:

“The only way we can protect ourselves is to fight back. Teach the public about the essential role of animal research in medical progress. Inform our legislators about the importance of animal research, and invite them to our labs. Our European members should join their own national neuroscience societies to further the policy advocacy in their own countries. We will never convince the animal activists about the importance of our work, just as they will never convince us. But we can and must convince the public and policymakers of the importance of animal research to ensure continuing medical progress, the inanity of animal activist groups like PETA, and the villainy of animal terrorists.”

So who does “no comment” work for?  Ultimately, it works for no one apart from those opposed to animal research.  While it may limit widespread or sustained public attention to a specific issue, individual, or institution, in the long-term it is more broadly damaging to all of us and to the overall goal of providing the public with accurate information from trusted sources with first-hand knowledge and understanding. Animal activists’ goals are not in the best interest of informed public discussion that considers both the merits of animal research, as well as its costs.  What we need are more voices that can deliver accurate information and meaningful context for news.  Foremost among the goals is placing the real objectives and achievements of animal research at the forefront of public consideration.

Allyson J. Bennett, Ph.D.

Speaking of Research

The views expressed on this blog post are mine alone and do not necessarily reflect the views of my employer, Wake Forest University Health Sciences.

Herceptin: When personalized medicine and animal research meet.

Personalized medicine is very popular among medical researchers these days, and it’s not hard to see why. By tailoring treatment to fit an individual patient, for example by using information about their genetic makeup, scientists hope to make treatments more effective while at the same time avoiding or minimizing adverse effects.

Anti-vivisectionist Dr. Greek writes about personalized medicine as if one could do this work without relying on animal research at all.

For example, he writes:

When will personalized medicine become a reality?

We are already seeing it, with breast cancer being a prime example. Breast cancer treatment is now determined in part based on a patient’s genetic makeup. About 25-30 percent of breast cancer patients overexpress the HER2 oncogene, which is a gene involved in the development of cancer. The overexpression results in an increase in the replication of the cancer cells. Physicians are now able to identify which breast cancer patients overexpress HER2 and give them Herceptin, a monoclonal antibody that inhibits HER2

This is true…  but where did Herceptin come from?   Does he know?

Herceptin, a humanized mouse monoclonal antibody. Image courtesy of Andrey Ryzhkov.

The basic research that led to the development of Herceptin (Trastuzumab) goes back to work by Milstein and Kohler who discovered the potential for using antibodies to fight disease.    They developed the first methods to produce monoclonal antibodies using mice.   Both Milstein and Kohler went on to win the Nobel Prize partly for this work.

Harold Varmus (now back as Director of the National Cancer Institute) showed that disturbances in some gene families could turn the cells cancerous.  He also went on to win the Nobel Prize for this work.  Robert Weinberg subsequently discovered in rats that a mutant gene (named “neu”) encoding a tyrosine kinase promoted cancer features in cells, contributing to the development of neuroglioblastoma tumors.

Later, Axel Ullrich and collaborators at Genentech cloned the human HER2/neu gene.  Work at UCLA Dennis Slamon and colleagues showed HER2 over-expression in 25% of patients with aggressive breast cancer.

Through screening studies on monoclonal antibody candidates in vivo in mice implanted with HER-2 positive human tumors the group at Genentech then developed the mouse 4D5 (parent of Herceptin) and showed that 4D5 could suppress the growth of HER2 tumor cells as well as enhance the ability of the host immune system to kill them.   A collaboration between UCLA and Genentech then demonstrated that radio-labeled 4D5 localized to HER2-expressing tumors in both mice and human patients.

With the information obtained from animal experiments, Genentech created Herceptin by humanizing the 4D5 mouse antibody directed at HER2.   The ability of Herceptin to prevent tumor growth was then assessed in mice implanted with HER-2 positive human tumor xenografts, and the concentration of Herceptin required in the blood to achieve anti-tumor activity was determined before starting human clinical trials.

So, you see…  Herceptin was derived from a mouse antibody.

Let me repeat: a mouse antibody!

Clinical trials in humans subsequently showed the effectiveness of Herceptin to treat HER2 positive breast cancer.

Perhaps, Dr. Greek and other animal rights activists should carefully listen to the experts that were actually involved in the process of developing Herceptin (a drug he appears to thinks highly of) which, indeed, benefits so many women battling breast cancer.   A drug derived from mice, and developed in mice.

Here is what Robert Weinberg had to say about Dr. Greek’s views on research:

Dr. Greek says the silliest things, […] implying that people are not studying human tumors, and implying that the kinds of experiments that one can do in mice can be done as well in humans — truly mindless!

I couldn’t have said it better.

Dario Ringach