Monthly Archives: September 2011

Mice and macaques pave the way for effective HIV vaccines

There is encouraging news this week on the prospects for an effective vaccine against HIV. A  research team led by Professor Mariano Esteban at the Spanish Superior Scientific Research Council (CSIC) have announced that the vaccine MVA-B elicited a persistent immune response against HIV in  85% of volunteers in a phase 1 clinical trial. MVA-B is a therapeutic vaccine, it is not intended to block infection but rather to keep HIV levels in the body at levels well below those at which the virus can cause illness.

As a CSIC press release published online on EureakAlert! notes the MVA-B vaccine, created by inserting four HIV genes from the B subtype of HIV – the subtype accounting for most HIV infections in Europe and North America – into a vector derived from the Modified Ankara Vaccinia virus (a smallpox vaccine and shown to be safe in both animal studies and extensive human use), notes that:

In 2008, MVA-B already showed very high efficiency in mice as well as macaque monkeys against Simian’s immunodeficiency virus (SIV). Due to it’s high immunological response in humans, Phase I clinic trials will be conducted with HIV infected volunteers, to test its efficiency as a therapeutic vaccine.”

This is indeed true, a 2007 study in mice revealed that the MVA-B vaccine induced a strong immune response , while a paper published in 2008 by the same group demonstrated that a very similar MVA vaccine was able to induce a robust response involving both the HIV-1-specific CD4+ helper T-cells  and CD8+ cytotoxic T cells in Rhesus macaques, and was able to control virus levels in macaques infected with the SHIV 89.6P hybrid virus whereas in unvaccinated monkeys the levels of virus rose and most developed an AIDS-like illness.

There is a question over whether the immune response generated by the MVA-B vaccine will be able to restrict HIV in humans, after all the MRK-Ad5 vaccine which failed to restrict the HIV virus in human trials and the pathogenic SIV MAC239 – considered a better model for HIV infection than SHIV 89.6p – in macaque monkeys had successfully controlled SHIV 89.6P in earlier studies.

Some reassurance on this issue comes from a study at Oregon Health and Science University (OHSU) that was announced earlier this year, where a group led by Dr. Louis Picker used a different vaccine vector – one based on Cytomegalovirus – to elicit a very similar broad immune response , with strong memory T-cell involvement, to that induced by MVA-B, and found that it induced long-term control the highly pathogenic SIV MAC239 strain. This was the highest degree of control demonstrated to date against this SIV strain, and indeed the cytomegalovirus vaccine is one of the first to demonstrate any ability to control SIV MAC239 levels.

Professor Esteban and his colleagues are certainly not resting on their laurels either, further clinical trials of the MVA-B vaccine are planned, to determine whether it can protect against HIV.  In the meantime they are also seeking to improve on this vaccine.  Earlier this year they published a paper in the open-access journal PloS One where they deleted a gene in the MVA vector to yield a new MVA-B  vaccine that showed in mice a substantial increase in the magnitude and breath of the immune response compared with their original MVA-B vaccine, and an even better  memory T-cell response. They now plan to evaluate this improved vaccine in a non-human primate model of HIV infection, and it will be interesting to see if they choose to use a more stringent model of infection such as SIV MAC239 rather than SHIV-89.6P.

Despite the setbacks and disappointments over the past two decades, it is clear from the work being done at the CSIC and OHSU that real progress is being made towards the development of both prophylactic and therapeutic  vaccines against HIV, and it is just as clear that animal research continues to play a vital role in that progress.

Paul Browne

Confronting AR Accusations at a Local and National Level

Charities are regularly targeted by animal rights groups. Currently Animal Aid have been targeting some of the UKs biggest medical research charities including the British Heart Foundation (strong proponents of animal-based research), Cancer Research UK, Alzheimer’s Society and Parkinson’s UK. It was refreshing to see these charities responding to this national press by providing comments about the importance of animal research to their work (see also previous post on this):

Cancer Research UK – “We have strict ethical policies in relation to animals and follow rigorous government guidelines to ensure that animals are only used where there’s no alternative. Millions of people are alive thanks to life-saving treatments for cancer.”
British Heart Foundation – “Research funded by the BHF advances our understanding of the heart and circulatory system in order to improve our ability to prevent, diagnose, monitor and treat cardiovascular disease – saving and improving the lives of those people affected.”
Alzheimer’s Society – “Our research aims to move us closer to a cure and improve the quality of life of people with dementia. We strive to ensure that alternatives are used where possible, that the minimum number of animals are used and that researchers keep to the highest welfare standards.”
Parkinson’s UK – “Experiments involving accurate animal models of Parkinson’s are the key to improved drug screening and swifter movement into clinical trials involving humans for the best drugs that will allow people with Parkinson’s to lead a normal life, free from its symptoms.”

Nonetheless, many charities shy away from dealing with local press accusations, worrying that they may attract more attention, or simply that ignoring them will make the problem go away. So when Animal Aid made a verbal attack on Parkinson’s UK in a local Derby newspaper, it was a nice change to see the organisation respond with an equal measure of vigour.

IN her letter “Campaign seeks an end to research on animals” (Derby Telegraph, September 9) Dawn Spencer, of Animal Aid, makes a number of claims that cannot pass unchallenged.

Ms Spencer claimed that Parkinson’s UK does not wish people to find out how much we spend on research involving animals. I am happy to be open about this. Some 40% of the £4.6m we spend on research each year is on projects involving animals.

Our research work is governed by some of the toughest restrictions in the world, enforced by the Home Office. Details of our UK-funded research are on our website and the research strategy which specifies the development of new models is publicly available. Our policy is also on our website.

Ms Spencer said that “people wanted… alternative research using tissue cells”. We fund the Parkinson’s UK Brain Bank, which supplies donated human brain tissue for Parkinson’s research. However, the use of human tissue is not appropriate in every case.

She comments that “animal experiments can be unreliable and… misleading”. We know that research involving animals has been demonstrated to help to identify improved treatments, help us gain a greater understanding of the causes of the Parkinson’s and ultimately lead to the development of a cure.

Since the 1970s, the lives of millions of people with Parkinson’s have been transformed by taking the drug levodopa, which would not have been developed without the insights gained from research involving animals.

People who give money to Parkinson’s UK can choose to support other areas as we also fund campaigning and support to improve life for everyone affected by Parkinson’s. We’ll keep doing that until we find a cure.

Dr Kieran Breen
Director of research and innovation
Parkinson’s UK

Well done Dr. Breen for this clear and concise reply to Animal Aid.

For those charities considering speaking up in defence of life-saving medical research using animals, I recommend the follwing resources:

1. Understanding Animal Research – A Researchers’ Guide to Communication
2. Association of Medical Research Charities – Medical Research Charities and Animal Studies
3. Understanding Animal Research – Funding Animal Research: Communications Guidelines for Charities

There is no excuse for standing on the sidelines – it is time everyone stood up and spoke of the importance of animal testing.

Cheers

Tom

Speaking of Statistics

We recently updated the statistics page of the website. Here are the highlights:

  • The numbers of dogs used in research was at its lowest rate since measurements began in the 1970s. The current figure is less than 1/3 of its number in the late 1970s.
  • The number of cats used remains at a general low (up very slightly from its historic low in 2009). The figure of 21, 578 is considerably smaller than the 74, 259 used in 1974.
  • Primate research has risen slightly over the past decade, in part due to increasing amounts of research into neurodegerative diseases such as Alzheimer’s, which is expected to affect four times the number people in 2050 as it does today.
  • Cats, dogs and primates together account for around 0.60% of animals used in research, making 2010 the fourth year this percentage has fallen.

The number of animals covered by the Animal Welfare Act used in medical research since 1973. This graph does not include the use of mice or rats.

Check out the statistics page now for more information

Mice show the way to improved stem cell therapy for heart attacks

When the results of clinical trials do not live up to expectations from pre-clinical studies in animals it can be all too easy to ascribe the divergence to species differences, however scientists are increasingly aware that in many, even most cases, the problem may not be species differences but rather differences in the design of studies in animals and humans.  Identifying what those differences are and how they affect the outcome of a study is vital if future treatments are to be more successful.

 

Figure A is an overview of a heart and coronary artery showing damage (dead heart muscle) caused by a heart attack, it is this tissue damage that stem cell therapy seeks to repair. Figure B is a cross-section of the coronary artery with plaque buildup and a blood clot. Image displayed courtesy of the National Heart, Lung and Blood Institute

An excellent example of this process in action is provided by a paper published this week in the Journal Science Translational Medicine.  Seeking to understand why the benefits seen in clinical trials of stem cell therapy for heart attack were far more modest than those seen when the same approach was evaluated in mice, a team led by Professor Xiaoyin Wang of the University of California, San Francisco UCSF looked to the source of the stem cells used in the transplants.

 

They noticed that the stem cells used in the mouse studies had been taken from young healthy mice, while those used in the clinical trials had been taken from the patients themselves, an older population who had suffered heart attacks before their stem cells were harvested. To test whether the health of the stem cell donor made a difference they compared the outcome when they transplanted stem cells from healthy mice into mice with induced heart attacks, with that when the transplanted cells were taken from mice that had suffered a heart attack, and found that in the latter case the therapeutic efficiency of the transplanted cells was greatly reduced.  Further experiments enabled them to identify the cause of this reduction and evaluate potential solutions.

 

You can read more about the work of the UCSF team in this excellent summary on UCSF News, which includes an interview with Prof. Wang

 

Often the differences between species are not so great as they may appear at first glance. Image courtesy of UAR.

It’s a very nice piece of research, and one that may well in the next few years result in the availability of effective stem cell treatments to promote recovery after heart attack.  It is also an excellent example of how thoughtful research can maximize the synergy between laboratory and clinical research.

 

Paul Browne

Blogging the Benefits of Animal Research

I wanted to alert our viewers to a fantastic new blog I discovered recently.

The Ark Hive, written by Dr. Paul Foster, a Lecturer in Molecular Endocrinology at the University of Birmingham in the UK. According to his blog, Dr. Foster is:

“an experienced cancer researcher and pharmacologist with a strong interest in understanding how animals help advance medical research”

It is important that researchers, just like Dr. Foster, use their knowledge to help improve public understanding about the role of animals in research. Foster carefully balances scientific rigour with layman’s language to create a blog that is both enlightening and readable. Taken from his website is a short explanation of why he believes animal research is crucial.

Tests in intact animals are necessary to understand how a drug will work in the context of the myriad metabolic and homeostatic mechanisms that are active in vivo. Screening tests are commonly conducted with in vitro systems and isolated tissues or organs to identify and, in some cases, to act as a bioassay to help purify pharmacologically active agents. However, the variable processes of absorption, distribution within the organism, metabolism to either inactive or more active products, and excretion will modulate the expression of pharmacologic activity in vivo. The only way this modulation can be estimated is by studying the new drug in intact animals.

Aside from studies of pharmacologic activity, side effects of new drugs must be identified and an initial assessment made of their risk-to-benefit ratio. Again, mechanisms of action and effects on specific organs can be studied by using in vitro techniques. However, to identify unexpected adverse effects and to estimate the dosages that may be pharmacologically active without producing unwanted effects, in vivo studies must be conducted.

Speaking up about your own research doesn’t have to involve creating your own blog from scratch – feel free to jump on our bandwagon and offer to write a guest post on the merits of animal research for this blog.

Cheers

Tom

Animal research unlocks the secrets of aging

As populations in many developed countries age an important question facing medical science is whether cognitive decline is insvitible as we age, and whether it can be presented or reversed.

Professor Carol A. Burns of the University of Arizona- who was last year awarded the prestigious Mika Salpeter Lifetime Achievement Award by the Society for Neuroscience – has written a fascinating account of what we have learned about aging and cognitive decline in recent decades. Her essay, which highlights the contribution made by animal research to advancing knowledge in this field, can be read in the September edition of The Scientist.

While developed societies face up to the challengs of an aging population, it is too easy to forget thet despite great advances in healthcare in most countries in recent decades far to many people still die from infectious diseases for which treatments are limited.  One of these diseases is human trypanosomiasis - better known as sleeping sickness – which kills tens of thousands of people every year in sub-saharan Africa, and the current standard therapy for late stage disease, an  arsenic-based medicine named melarsoprol, is highly toxic.

Now, as Understanding Animal Research report, a group of scientists based at the University of Glasgow have developed modified versions of melarsoprol that are highly effective in clearing trypanosome infection in mice, while avoiding the toxicity associated with melarosprol, publishing their findings in the open-access journal PLoS Neglected Tropical Diseases. It is to be hoped that this drug will soon be evaluated in clinical trials, as it has the potential to save many thousands of lives.

Paul Browne

A breakthrough against Chronic Lymphocytic Leukemia…thank the mice!

A challenge that science communicators frequently face when discussing the process whereby a scientific discovery eventually leads to a medical breakthrough is the time that this often takes, indeed by the time that the reports of exciting clinical trial outcomes start to appear in the press the role of the scientists who made the initial discoveries is often relegated to a passing comment…if it is mentioned at all. An example of this comes from the Weizmann Wave blog, produced by the Weizmann Institute of Science.

You may remember reports last month on the very promising results of a small clinical trial where a new immunotherapy technique was used to eradicate cancer cells in patients with Chronic Lymphocytic Leukemia (CLL), a blood cancer for which currently available treatments are often inadequate.  That trial, conducted by scientists at the University of Pennsylvania led by Professor Carl June, involved removing T-cells from the patient, treating the cells with a lentiviral vector that encodes for a Chimeric Antigen Receptor which recognises a protein named CD19 that is found on B-cells, including the cancer cells responsible for CLL, and then infusing the transformed T-cells back into the patients.  As the reported in the Los Angeles Times the results were dramatic, within a few weeks of the infusion the modified T-cells expanded rapidly and targeted the cancer cells in all three paients, so that a year later two of the three patients were still in complete remission.

It’s exciting stuff but as the Weizmann Wave reports the Press Release issued by Penn Medicine noted that this was a “cancer treatment breakthrough 20 years in the making” but “didn’t, however, explain those “20 years in the making.””. The Weizmann Wave goes on to discuss the pioneering basic scientific research undertaken by Professor Zelig Eshhar at theWeizman Institute of Science in the late 1980’s, which you can read about here.

Of course between the basic research undertaken by Prof. Eshhar and his colleagues in the 1980’s and the clinical trial whose outcome was announced last month there was a lot of work to be done. It would be impractical to describe all the different discoveries that made this immunotherapy possible, but one discovery in particular highlights the importance of animal research to this breakthrough.

There have been previous attempts to use Chimeric Antigen Receptors to target T-cells to attack cancer, but these had disappointing results in clinical trials.  A major improvement made by the University of Pennsylvania team was to include an additional motif – named the CD137 co-stimulatory molecule- which greatly enhances the cancer killing ability of the infused T-cells.  In a recent paper published in the Journal of Cancer the University of Pennsylvania team point out that the decision to include CD137 (called 4-1BB in mice) in their Chimeric Antigen Receptor construct was based on promising results in studies undertaken in mice:

 Our group has tested a CAR directed against CD19 linked to the CD137 (4-1BB) co-stimulatory molecule signaling domain to enhance activation and signaling after recognition of CD19. By inclusion of the 4-1BB signaling domain, in vitro tumor cell killing, and in-vivo anti-tumor activity and persistence of CART-19 cells in a murine xenograft model of human ALL (acute lymphoblastic leukemia) is greatly enhanced”

Indeed, in a paper published by Professor June and colleagues in the journal Molecular Therapy in 2009 they describe this work in much more detail, highlighting just how groundbreaking the results were:

Previous in vitro studies have characterized the incorporation of CD137 domains into CARs.10,11,29 Our results represent the first in vivo characterization of these CARs and uncover several important advantages of CARs that express CD137 that were not revealed by the previous in vitro studies. We demonstrated that CARs expressing the CD137 signaling domain could survive for at least 6 months in mice bearing tumor xenografts. This may have significant implications for immunosurveillance, as well as for tumor eradication. For example, in a mouse prostate cancer xenograft model, survival of CAR+ T cells for at least a week was required for tumor eradication.30

Long-term survival of the CARs did not require administration of exogenous cytokines, and these results significantly extend the duration of survival of human T cells expressing CARs shown in previous studies.17,31 To our knowledge, this is the first report demonstrating elimination of primary leukemia xenografts in a preclinical model using CAR+ T cells. Furthermore, complete eradication was achieved in some animals in the absence of further in vivo therapy, including prior chemotherapy or subsequent cytokine support.

The long-term control of well-established tumors by immunotherapy has rarely been reported. Most preclinical models in a therapeutic setting have tested tumors that have been implanted for a week or less before initiation of therapy.32 After establishing leukemia 2–3 weeks before T cell transfer, we found that many animals had long-term control of leukemia for at least 6 months. The efficacy of targeted, adoptive immunotherapy in this xenograft model of primary human ALL compares favorably to our prior experience testing the antileukemic efficacy of single cytotoxic (ref. 27 and data not shown) or targeted agents,26 where we have observed extension of survival but not cure of disease. Additionally, we have not previously observed the ability to control xenografted ALL for a period of as long as 6 months.”

These results led directly to the clinical trial reported last month.

So there you have it, behind the headlines are years of graft by hard-working and innovative scientists, who utilised a wide range of experimental approaches – among which animal studies figure prominently – to develop a novel therapy for CLL. As Professor Bruce Levine points out in the video above, the key to success is often keeping one hand in the basic research lab and the other in the clinic.

Paul Browne

Addendum: Scienceblogger Erv has written an excellent commentary on this study

Interview with a Primate Researcher

Wisconsin National Primate Research Center Director Jon Levine has kindly allowed us to reproduce a piece previously posted in On Wisconsin.

Question and Answer with Wisconsin National Primate Research Center Director Jon Levine

Work flows from “the best of reasons,” says new director of primate research center.

Administering a big research center at the forefront of biomedical science is challenge enough. Running one with 1,500 monkeys is the test of a lifetime. But that is exactly the matchup for Jon Levine, the Northwestern University neuroscientist recruited to UW–Madison in late 2010 to run the Wisconsin National Primate Research Center (WNPRC). For Levine, leading one of the nation’s eight national primate centers is an opportunity to promote the kind of science that led to human embryonic stem cells and remains our best hope for beating diseases such as Parkinson’s and AIDS. At the same time, the center is a magnet for controversy, as the use of monkeys in biomedical research is contentious.

Q: Many people hear about the Primate Center only when there is an issue — or a perceived issue. If there is one thing people should know about the center, what would that be?

A: That researchers and staff are passionate about their work, and that they are wonderful, caring people committed to advancing the cause of human and animal health. The average person knows very well the suffering a family member or friend may endure in disease or injury; unfortunately, few are aware of the importance of biomedical research with non-human primates in developing therapies and strategies for preventing these conditions. I want everyone to know why we do what we do — because we are deeply committed to bringing about a future in which HIV can be prevented, the ravages of Parkinson’s disease can be stalled or reversed, and infertility, complications of pregnancy, and metabolic diseases such as diabetes can be successfully treated.

Q: What do you tell someone — a child, for example — who asks you about the use of monkeys for biomedical research?

A: That we are the good guys. We play by the strictest of rules, intended to ensure the humane and careful utilization of a precious resource. And we have the best of reasons for the work we do. I do not hesitate to give children an explanation in terms they can appreciate. For example, many kids know someone who has been diagnosed with some form of leukemia. We are developing methods to take blood cells from cancer patients and reprogram them into “induced pluripotent stem cells” — make them younger versions of themselves, before they became cancerous. Those induced cells can lead us to an understanding of how blood cells become cancer cells and how we might better treat leukemia.

Q: What do you think we can look forward to in the way of scientific advances from the center in the next few years?

A: I could fill pages with advances I hope will be realized. I’ll mention one that I think could enable progress in many others: transgenesis. The ability to induce, block, or alter the expression of specific genes in the mouse is now routine and has made it the standard for most studies of the genetic mechanisms underlying human disease. However, there are many aspects of human physiology and disease that can only be faithfully reproduced in non-human primates. We are undertaking new approaches to manipulate gene expression in non-human primates. We hope to target genes involved in neurodegenerative diseases such as Parkinson’s, metabolic diseases such as type 2 diabetes, and developmental disorders such as autism.

Rhesus Monkeys are used to try to find treatments for illnesses like Parkinson’s

Q: What will be the greatest challenge for the Wisconsin National Primate Research Center over the next decade?

A: The major challenge for federally funded research institutions is to sustain funding from the National Institutes of Health (NIH) and other sources, especially through times of austerity, flat budgets, and increasing costs. I’m confident, however, that the talented researchers and staff at the WNPRC will keep us positioned to renew our base grant funding from the NIH. I am also certain that researchers who use non-human primates on campus will continue to successfully compete for individual research funding. Nevertheless, given the special costs of research with monkeys, and the preciousness of the resource, we will be looking at new sources of support. Over the longer term, the center’s biggest challenge will be to replace and/or renovate portions of our infrastructure. My vision for a new WNPRC building complex may have to wait until the economy recovers over the next few years — but it is a goal that I hope we can realize.

Article reprinted with permission from Jon Levine and On Wisconsin http://onwisconsin.uwalumni.com/departments/qa/jon-levine/

Photos courtesy of WNPRC