Monthly Archives: July 2009

The limits of fMRI

Animal rights groups often argue (Warning: AR Website) that new imaging technologies, such as fMRI, provide an alternative to invasive brain research in animals, accusing those doing animal work of failing to adopt these modern methods.  Such a position reflects a misunderstanding of what these instruments measure and their limitation in studying how the brain works. [More information on the limitations of replacement technologies can be found in the "Alternatives?" Section]

Our perceptions, thoughts, speech and decisions are carried out by a complex network of neurons that communicate through brief electrical impulses about one millisecond in duration (so called action potentials or ‘spikes’).  These electrical impulses allows the brain to perform all its amazing computations in real time, such as recognizing faces, keeping your balance, and understanding speech.  In other words, spikes are the currency of computation in the brain.  To study how the brain is capable of these feats we need, therefore, to measure directly how populations of neurons communicate with each other by means of spiking activity.

fMRI

fMRI

A central problem here is that neurons are very small (their bodies are about 25 micro-meters in diameter) and they are tightly packed together.  As an analogy, consider a football stadium full of spectators.  The problem is akin to developing a method to listening to the conversation of two individuals in the middle of this noisy crowd.  Clearly, without getting a microphone close enough to them, the background noise would make the measurement nearly impossible.  You cannot listen to an individual conversation with a microphone hanging in the middle of the stadium.  The micro-electrode, an insulated wire with a diameter smaller than a human hair, is such a “microphone” that allows us to record the spikes of individual cells in the working brain by getting close enough to the individual cells.

Is there a way to measure the activity of single neurons non-invasively?  The short answer is no.  What about fMRI?  fMRI does not measure neural activity directly, but instead relies on indirect changes in blood flow and volume triggered by modulation in neural activity.  To begin with, one problem is that we still do not know how fMRI measurements relate to neural activity.  Clearly, to be able to understand how fMRI signals relate to neural activity we need to measure both simultaneously, work that will also require the use of animals.  This exemplifies that without animal research there will be no alternatives either.  In addition, fMRI has a limited spatial resolution of about a cubic millimeter.  In such a volume, one can find 100,000 neurons.  In other words, the ‘fMRI microphone’ cannot listen to individual cells, but to a whole stadium full of them.  Finally, we already know that fMRI signals are much slower than neuronal activity, as the time course of hemodynamic signals is in the order of 5 seconds.  As neurons work tens of times faster (you can recognize an image in about 200 ms), the dynamics of fMRI signals are too slow to understand how brains compute in real time.  Instead, fMRI provides useful information about what brain areas might be involved in certain tasks.  After these areas are identified, electrophysiological measurements can be used to measure the activity of single neurons in those areas.  Such a strategy is now proving extremely useful in neuroscience research.

When animal rights activists demonstrate at UCLA carrying a sign stating “Support alternatives to animal research” they don’t need to convince us.  We fully support  and work towards the development of alternative, non-invasive methods.  Their sign is designed to suggest to the public that such methods currently exist and some scientists refuse to use them.   As we explained above this is not true.  Furthermore, the development of alternatives cannot be done without the use of animals.  The relationship between neural activity and the BOLD response in fMRI signals is one example of this process.   Only after such validation takes place, could one then proceed to apply the method with confidence in humans.

Regards

Prof. Dario Ringach (bio)

Open Letter to Michael Budkie

Michael Budkie

Michael Budkie

On June 1, 2009, animal rights activist, Michael Budkie, submitted a letter of complaint (AR Website) to the United States Department of Agriculture (USDA), with the charge that scientists are performing duplicative research.  Mr. Budkie’s complaint was based upon his own analysis of the publicly available information about research funded by the National Eye Institute, a division of the National Institutes of Health. Budkie’s complaint, related information, and press releases are posted on the website of Stop Animal Exploitation Now (AR Website)(S.A.E.N.).  We feel that it is essential to point out that his analysis, through omitting critical details, presents a remarkable illustration not only of bias, but also a fundamental misunderstanding of the scientific process. Here, we identify his omissions and mis-representations and request a response to our challenges.

An Open Letter to Michael Budkie, Animal Health Technician, Stop Animal Exploitation Now

re:  Research industry next to meltdown, charges watchdog; urges federal probe after study shows fraud in 26 laboratories, including Harvard, University of California

Dear Mr. Budkie,

You have recently requested that the federal government investigate what you represented as wasteful spending on health-related research. You believe you have identified an enormous problem with duplication of research, based on your perusal of some of the grant applications that the National Institutes of Health have funded over the past five years.

In an effort to understand your position, we have read your recent complaint to the USDA and looked closely at what you offer as supportive documentation.  Here are some of our reflections.

Your spreadsheet shows that scientists engaged in research often use some of the same tools and methods to conduct their work.  You are correct. The conclusion that their efforts duplicate one another, using more animals than is minimally required to advance science, is not.

Information on the approaches used to conduct a research project is found in the “Methods Section” of a grant application or manuscript. Unfortunately, you appear to have missed the pages of text that came before the Methods; in these sections, you find the nature of the problem being addressed by each research proposal. It goes without saying that – with respect to human health – there are lots of problems needing to be addressed, so part of what is discussed in a grant first is which ones are important and why. These sections also delineate what is already known and what isn’t.  All of these points are addressed in grant applications and journal articles. They are found under sections such as Introduction, Specific Aims, Background and Preliminary Data. Together, all of those parts give the context and rationale for why each particular research project is needed and why the specific methods chosen are the best possible means of addressing the identified problem.  According to your letter and spreadsheet it would seem that you have limited yourself to the methods used in the research, which does little to explain its context.

What you claim is that your “analysis” demonstrates that a large number of scientists are doing the same study (in some cases, over and over again for years). Essentially, you figure that if scientists are using the same kind of animals, the same kind of methods and the same kind of equipment, they must all be doing the same experiment.  In turn, you suggest that the government is paying for the same experiment many times. You conclude that this is needless duplication—a waste of animals, time, and money. However, once again, you misunderstand, or misrepresent, that each of these projects is addressing very different problems, each with independent implications for our understanding of human biology. Indeed, to ignore the question and focus on the similarities of methods is kind of like saying that two farmers, both of whom are planting seeds in soil and using the same kind of tractor, are growing the same crop to feed the same family.

If ten scientists all use microscopes in their research and look at cells from the same kind of animal, are they all doing the same research?  Maybe. Or perhaps one is looking at cells from breast tissue to determine whether they are cancerous, while another is looking at cells from brain tissue to determine whether they have abnormalities associated with Alzheimer’s disease.

Or maybe they are both looking at cells from breast tissue to determine whether it is cancerous. One is comparing the cells of an animal exposed to environmental toxins to cells from an animal that has not been exposed. That scientist’s goal is to learn how to make environments safer and reduce the risk of breast cancer.  Meanwhile, the other scientist is evaluating the cells of an animal who received an experimental drug to treat breast cancer. This scientist’s goal is to determine whether a new drug, one that might be effective in treating breast cancer, is effective and safe.

Are these two scientists—both working with the same kind of animal, using some of the same tools and techniques, same type of cells, and studying the same disease—doing duplicative research?  Is it the “same” experiment?  Should we choose to do one and not the other because it would be wasteful to have two studies that might help prevent and treat breast cancer?

You must appreciate that while the scientific method requires replication of findings to assess their reliability, scientists cannot succeed in making breakthroughs that improve human and animal health if they simply duplicate what others have done.  Furthermore, in exercising its responsibility for federal funds, the NIH will not provide support for grants that are not advancing research boundaries. What the concerned reader should know is that each of the grants listed by Budkie is among less than 10% of all applications that underwent rigorous review by a panel of scientists who made a recommendation to professional program officers at the NIH who are responsible for distributing tax-payer money effectively and equitably across scientific projects.

The scientific projects funded by the grants listed in your spreadsheet relate to one another as must all good science, but they certainly do not duplicate one another.  For example, different grants support research on different parts of the visual system and different brain regions—all of which are important to vision.  The diverse grants support research on basic visual processes, interactions of vision with other senses, mechanisms of visual attention, decision making, how movements of the eyes are controlled and how these processes affect vision.  Many grants support basic research on fundamental processes, while others fund work focusing on clinical disorders such as amblyopia and strabismus.

If you add a couple of columns to your table – ones that focus on the problem that the research addresses, you would not only provide a more honest portrayal of the science you criticize, but you would also provide the basis for reasonable discussion.  As it stands, your poorly-formulated complaints, self-referential, hyperbolic media releases and selective presentation of information all start to suggest that it is your industry trying to avoid meltdown, that is being rather too creative with the information you have at your disposal.

Yours Sincerely,

Speaking of Research

ALF’s clever website trickery

The ALF web person has been up to some fairly deceitful tricks. Look closely at the screen shot below from the ALF website (Warning: AR Website). The article is about two scientists who have apparently been barred from their university. The interesting thing to note is the link to the Speaking of Research committee webpage at the bottom of the article.

ALF Website

ALF Website

Now I had never heard of Dr. Contreras or Dr. Judith Thomas before I read this webpage. They have certainly never been affiliated with, or even ever contacted, Speaking of Research (SR). If you have a look at the Committee webpage on this website you will not find either of those names on the list of SR committee members.

Sadly this is yet another example of misrepresentation. The ALF have tried to take a rather cheap shot at us by insinuating a (nonexistent) link between SR and these two scientists (and whatever negative activities they may have been involved in). Why else is a link to our committee list at the bottom? Well the ALF can continue their silly misrepresentations and SR will continue to try and unravel them for what they are.

Cheers

Tom Holder

Addenum:
For anyone interested in reading more about the two scientists, Dr. Stemwedel, in her blog Adventures in Ethics and Science,
has written a piece about the Thomas and Contreras which I personally agree with.

Scientists discover AIDS in Chimpanzees

The discovery of the human immunodeficiency virus (HIV) by the French scientists Luc Montagnier and Françoise Barré-Sinoussi in 1983, and the, and the subsequent confirmation by the American scientist Robert Gallo that it caused AIDS was a shock to doctors and scientists around the globe, and begged the question as to whether or not similar viruses existed in other species. They did not have to wait long, in 1985 a virus was identified that caused AIDS in Rhesus macaques. Analysis of the new virus showed that it was a retrovirus closely related to HIV and it was christened simian immunodeficiency virus (SIV). Since then more than 40 different strains of SIV have been identified in a number of African primate species but a curious pattern was quickly noted; individual SIV strains rarely cause disease in their natural host, for example SIVsmm naturally infects sooty mangabeys but does not cause AIDS in them. On the other hand Asian macaques in the laboratory are infected by a strain of SIV closely related to SIVsmm they develop AIDS. It is thought that over thousands of years natural hosts of SIV have evolved ways of restricting the spread of SIV in their bodies and limiting the damage it can do. If we can identify the mechanisms through which primates limit virus infection we might be able to order to develop treatments that work along similar principles for those of us not fortunate to have natural resistance, and perhaps develop powerful new anti-viral medicines. Five years ago scientists found that some of the variability between species in the ability to restrict HIV or SIV is due in part to differences in the structure of a protein known as TRIM5alpha that prevents the virus from reproducing within the cell, the structure of TRIM5alpha in African monkey species makes it an efficient blocker of SIV and HIV but different structures in macaque TRIM5alpha mean that it has a low blocking effect against SIVmac while human TRIM5alpha only weakly blocks HIV (1,2). With greater understanding of the differences in TRIM5alpha structure between species and how this effects function we may be able to develop new drugs that replicate its action and block HIV in humans.

Chimpanzees - Handout photo provided by Nature magazine

Chimpanzees - Handout photo provided by Nature magazine

So are humans the only primate in which naturally occurring retroviral infection causes AIDS? Until this week the answer would have been “probably”, because no one knew for sure whether the SIV found in chimpanzees, SIVcpz causes AIDS. There had been reports that it might but no firm evidence one way or the other. In this week’s issue of Nature an international team of scientists from institutions including the, Yerkes National Primate Research Centre and the Jane Goodall Institute and lead by Dr Beatrice Hahn of the University of Alabama at Birmingham report that SIVcpz does cause AIDS in a subspecies of chimpanzee found in Gombe National Park in Tanzania (3). In infected animals it was associated with a 10-16 fold higher risk of that, lower than that seen in humans infected with HIV-1, the main cause of the AIDS pandemic, but higher than that seen in humans infected with HIV-2. Comparison of the number of CD4+ T-lymphocytes, the same immune cells killed by HIV in humans, in SIVcpz infected monkeys with that in uninfected humans and chimpanzees showed that SIVcpz infection lowered CD4+ T-lymphocyte dramatically. By contrast they found that in sooty mangabeys infected with SIVsmm the CD4+T-lymphocyte count stayed high and there was no progression to AIDS.

This report is important for a number of reasons. First of all SIVcpz is the strain of SIV most closely related to HIV-1, indeed phylogenetic analysis indicates that it is the direct ancestor of HIV-1. The scientists involved in this study hope that by studying the course of SIVcpz infection and comparing how it interacts with the chimpanzee immune system with the behavior of HIV in humans and other SIV strains in monkeys they can gain a better understanding that will lead to improved treatments and the development of effective vaccines. Secondly SIV is thought to have crossed into chimpanzees from monkeys that they eat only about 500 years ago, so the observation that it still causes disease in chimpanzees will be of great interest to those studying the evolution of resistance to viruses. This brings us on to the third reason why this study is important, chimpanzees are an endangered species and this disease is a threat they could do without, so scientists are keen to determine whether infection with SIVcpz leads to AIDS in other chimpanzee subspecies, and whether it has a significant impact on the overall number of chimpanzees. If the threat is found to be serious than perhaps we should be thinking about developing a vaccine against SIVcpz as well as against HIV.

Regards

Paul Browne

1) Stremlau M. et al. “The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys” Nature Vol. 427, Pages 848-853 (2004) PubMed: 14985764
2) Song B. Et al.“Retrovirus Restriction by TRIM5alpha Variants from Old World and New World Primates” Journal of Virology Vol. 79, No.7, Pages 3930-3937 (2005) PubMed: 15767395
3) Keele B. et al. “Increased mortality and AIDS-like immunopathology in wild chimpanzees infected with SIVcpz” Nature, Vol. 460, Pages 515-519 (2009) DOI:10.1038/nature0820

SR at SSR

SSR Heading

On Monday July 20th Tom Holder gave a presentation as part of the President’s Sympozium at the Society for the Study of Reproduction‘s 42nd Annual Meeting. The presentation was attended by around 500 members of the society, ranging from undergraduates up to well established professors. The talk provided suggestions on how to talk about science to those without a science background, as well the importance of speaking out. After the talk a number of members of SSR have been in contact to ask how they can get involved with Speaking of Research’s activities – a positive result all round.

SR at SSR

The rest of the conference provided an interesting overview of some of the research going on to tackle illness such as infertility, cancer and endometriosis. Animal models varied from fish and rodents, through to cattle, pigs and primates, with scientists careful to explain why their particular choice of animal was the most suitable for their particular research. GnRH (Gonadotropin-releasing hormone) agonists are a good example of the crucial role that animals have played in fighting disease in reproductive biology. After significant work with monkeys, mice and sheep scientists were able to come up with some of the leading treatments for prostate cancer, breast cancer and endometriosis – such as Leuprolide (Market Name: Viadur/Lupron) and Goserelin

You can read the abstract for Holder’s speech here.

Regards

Dave

SR to speak at SSR Conference in Pittsburgh on 20th

SSR Heading

On Monday July 20th, Tom Holder will address the Society for the Study of Reproduction (SSR) at their 42nd Annual Meeting in Pittsburgh. Holder will speak as part of the President’s Symposium on “Reproductive Policy and the Public Good” alongside Mary Wooley President of Research!America and John Peterson Myers founder of Environmental Health News.

No doubt Tom will report back on the conference next week. For the time being I leave some food for thought in the form of his abstract:

Animal research has been a divisive issue for many years, however much of the problem lies with a general mistrust of science by the public. This mistrust itself reflects the average person’s lack of understanding about how science works and the animal research issue is no exception. Many people are unable to see the connection between the animal experiments and the huge array of medical drugs that most people take for granted. If we are to convince people to support scientific activities such as animal research then we need to be more active in explaining how it affects the lives and welfare of the public. In order to improve public understanding on this issue we need those who are involved to speak up and become advocates for science. From the scientists doing the research to the animal care technicians whose sole priority is the welfare of the animals, we need people in the industry to explain the unspun truth of what goes on in research facilities and why it’s so important to all of us. Speaking of Research engages the scientific community in order to assist them in explaining animal research. The focus on “science for the non-scientist” aims to help researchers to find the best way to present the issue to those who may not find themselves directly immersed in it in everyday life. The public in Britain has united behind medical research and beaten animal rights extremism. If the US is to do the same then its scientists must stand up and publicly defend their research.

Regards

David

Three Young Advocates Step Up

Americans for Medical Progress (AMP) decided to fund three new Hayre fellows on two Hayre Fellowships. This is a fantastic chance for three students to stand up and motivate the people in their community and beyond. AMP created the Fellowship in honor of its late Chairman, Michael D. Hayre, DVM.  Its aim is to foster young voices to speak in support of science and advancing medical knowledge through responsible animal research.

Gillian Braden-WeissBreanna CaltagaroneGillian Braden-Weiss (left) and Breanna Caltagarone (right) are two veterinary medicine students at the University of Pennsylvania. Both have extensive experience in animal sciences and have worked in shelters, clinics and laboaratories to gain crucial insights into the importance of animal welfare.

Both Hayre Fellows will work together to start the “Thank a Mouse” campaign aimed at educating private practise vets and their clients about the importance of animals in research. They have a great opportunity to reinforce the role that animals play in the development of veterinary medicine.

Megan WyethThe third Hayre Fellow might be recognizable from the Committee list. Megan Wyeth is studying for a PhD in Neurobiology at UCLA, studying epilepsy in mice. Megan was a crucial player in the highly successful UCLA Pro-Test rally in April. She plans to use the Hayre Fellowship to expand UCLA Pro-Test, now renamed Pro-Test for Science, across to other universities in California. Megan has the passion and the commitment to become a driving force for change in California.

You can read more about all three candidates.

Dr. McConnell, a long time friend and classmate of Dr. Hayre said:

We welcome Megan, Breanna and Gillian and the contributions they will make to research advocacy during their tenure as Hayre Fellows. Mike Hayre was an inspirational leader and mentor who valued the contributions students made to biomedical science and animal welfare.  He believed the future of medical advancement depended on the public’s understanding and acceptance of animal research in medicine.  I’m confident that Mike would view the work of this year’s Fellows as essential to that vision.

On behalf of Speaking of Research, we wish all three Hayre fellows the best of luck over the next year, and offer them our full support in changing public opinion in their local communities and beyond.

Regards

Tom Holder

Public views on Science and Research

On July 9th, the Pew Research Center for People & the Press, in collaboration with the Americans Association for the Advancement of Science (AAAS) released its findings (full report) regarding the public perception of science. In this post I will reflect on some of the interesting aspects of the report. To give some context, the report interviewed over 2,500 scientists, and over 3,000 members of the public.

To kick off, the report showed that 84% of the public felt that “science’s effect on society” has been mostly positive, with only 6% considering it mostly negative. Furthermore 70% of the general public considered that that scientists contributed a lot to society’s well being (interestingly medical doctors fared slightly worse on 69%).

Moving over to the views of scientists, the report found that 85% of scientists consider the public’s lack of knowledge about scence to be a major problem. This is likely to link to the 76% of scientists who think that the news does not distinguish scientific foundings which are well-founded and findings which are not – good examples could include various media sources jumping on the (poorly thought out) anti-vaccination bandwagon. The result is that 83% of scientists consider TV coverage of science to be either of poor or fair quality.

59% of scientists did not consider the regulation on animal research to be a major barrier to high quality science (only 6% considered it “very serious”) which sugests that researchers believe we have found a good balance between animal welfare and the needs of biomedical research. On the other hand 87% considered the lack of funding to be a very serious or serious concern to the future of quality research. In these times of economic thrift it is easy to overlook science funding as being crucial to our well being, but around 2/3rds of those interviewed considered basic research to pay off in the long run – he public must realise that pumping money into, say, cancer research is unlikely to bear fruit for many years, but that money is still crucial if we are to find a cure down the line.

Now for the most relevant information!!

Reproduced from Report: http://people-press.org/reports/pdf/528.pdf

93% of scientists support the use of animals in scientific research (which is to be expected given their higher understanding on WHY we use animals in research). However more concerning is the relatively low (52%) support for animal research by the general public. It is worth remembering that the question asks about views on “animals in scientific research” and not “animals in medical research”, which may have improved the numbers somewhat. It is also worth pointing out that the more education someone has, the more likely they will support animal research – as does age. I would assume that as one gets older they start to see the benefits of research in medicine for themselves, and also see the areas (such as Parkinson’s) which are great need of further research.

Overall we have a mixed bag – the US public has reservations about science, but are generally positive. The stats on animal research shows that groups like Speaking of Research still have a long way to go in educating the public about the role that animals play in the development of medical treatments.

Cheers

Tom Holder