april 2005
The Institute of Science in Society
General Enquiries sam@i-sis.org.uk Website/Mailing List press-release@i-sis.org.uk ISIS Director m.w.ho@i- sis.org.uk
ISIS Press Release 01/04/05Call on European Commission to Support Independent ScienceDozens of prominent scientists from all over the world are calling on the European Commission to support independent science in its next round of science funding, and to ensure maximum transparency and democratic input in deciding funding and research priorities. The scientists want Europe's next round of public ressearch funding - Framework Programme 7 (2007 to 2013) - to establish broad funding criteria that put public interest ahead of 'wealth creation', and to include ethical and safety considerations before the research is funded. They are demanding a redistribution of the research budget away from industry and technology driven areas like genomics and information technologies towards sustainable agriculture, ecology and energy use in sustainable systems, and holistic health. In particular, they would like to see top priority given to scientists working with local communities to revitalize and protect traditional agricultural and healthcare systems. The detailed Comment follows. Please add your name and/or your organisation to endorse the comment here. Independent Science PanelThe Overriding Need for Independent ScienceComment to European Commission on Framework Programme 7The Independent Science Panel (ISP), launched 10 May 2003 at a public conference in London, UK, consists of dozens of prominent scientists from all over the world, spanning the disciplines of agroecology, agronomy, biomathematics, botany, chemical medicine, ecology, epidemiology, histopathology, microbial ecology, molecular genetics, nutritional biochemistry, physiology, plant biotechnology, taxonomy, toxicology and virology (http://www.indsp. org/ISPMembers.php). They share a deep concern over the commercialisation of genetic modification (GM) and other technologies without the due process of thorough scientific assessment, informed public consultation and public consent; and are dedicated to researching and actively promoting science for a sustainable world through education, advocacy and social engagement. The overriding need for independent scienceScience has been playing an increasingly major role in national and international policy decisions that affect not only our everyday lives but also the very survival of our planet. Unfortunately, science has also become more and more closely tied to industrial interests that all too often conflict with public good and public safety. Science wars are being fought at national and international forums over global warming, nuclear wastes, industrial pollution, and GM crops in the name of ‘national competitiveness’, ‘national security’, ‘free trade’ and ‘feeding the world’. There has never been a greater need to re-establish independent, disinterested science that can both protect the public from the negative impacts of emerging technologies and genuinely deliver a safe, secure, equitable and sustainable world. This presents the European Union (EU) Framework 7 programme for funding scientific research with challenges and opportunities in equal measure. The ISP propose the following measures for the EU Framework 7 funding programme to go some way towards meeting the challenges and opportunities. 1. Establishing broad funding criteria that put public interest ahead of ‘wealth creation’ The following explicit criteria should be used both in setting priorities for areas of research, and in funding specific programmes and projects:
All too often, questions on safety, in particular, are being raised after the research has been done, and worse, after the technology has been commercialised. At that stage, it is very difficult to reach a consensus on account of the large amount of investment at stake. Recent cases in point include the safety of electromagnetic radiation from mobile phones and masts, and the safety of GM crops. 2. Ensuring the greatest transparency, independence and public participation in deciding research priorities Committees deciding funding priorities and areas must include representatives of appropriate public interest organisations. No member of any committee making decisions on funding priorities and areas should have, or should recently have had, a financial interest in the outcome of the decision being made. More than that, the membership of such committees must include scientists with relevant expertise who are not involved directly or indirectly in the research area to be funded. 3. Ensuring the greatest transparency and independence in deciding research funding No member of any committee making funding decisions on specific projects should have current or recent-past financial or commercial link with an industry involved in the proposal under consideration. 4. Ensuring support for independent science and scientists The increasing tendency to fund big research programmes in big established research groups has served to reinforce entrenched scientific opinions that are often not in the public interest. This has resulted in the wrong decisions being made, excessive delays in applying appropriate regulatory or remedial measures, and the lack of precaution, all of which have cost the taxpayer hundreds of billions in compensation for damages to health and the environment. The cases that have been resolved against the entrenched scientific opinions include asbestos, thalidomide, cigarette smoking, BSE and foot-and-mouth disease. These entrenched opinions have colonized our academic institutions, where they are ruthlessly deployed to persecute independent scientists who try to report their research results honestly or to tell the public what they know. This not only intimidates staff and students, it is stultifying innovation and obstructing real progress in understanding nature, resulting in a deterioration of science education at all levels. It has also contributed to a growing, pervasive mistrust of science and scientists across the globe. To protect the integrity of science and scientists, 10% of Framework 7’s budget should be earmarked for supporting independent scientists adopting novel approaches, and in particular, scientists who have been persecuted for research findings ‘uncomfortable’ for industry, and to ensure that research funding is not concentrated exclusively in big, mainstream research groups. To overcome the public mistrust of science and scientists, Framework 7 should give priority to research partnerships between scientists and local communities so that people’s concerns and aspirations can help shape the research, and importantly, scientists could benefit from local knowledge. For the same reasons, top priority should be given to revitalising and protecting traditional agricultural and healthcare systems from biopiracy and globalisation, and to developing sciences and technologies appropriate for the local community. 5. Redistributing the research budget to give priority to science and technologies that contribute to sustainability The research spending of Framework Programme 7 (FP7) is expected to double that of Framework Programme 6 (FP6) to nearly €40 billion over 5 years. While the funding priorities are yet to be decided, there will be a continuation of the FP6 areas with the addition of ‘security’ and ‘space’ and ‘basic’ research. These priorities have already been thoroughly criticized as being predominantly led by industry and technology, with little regard for solving real problems in society or addressing safety concerns. The two top priorities are "Information society technologies" and "Life sciences, genomics and biotechnology for health". The first includes telecommunications, mobile phones and masts, now raising serious safety concerns all over the world. The second, biotechnology and genomics research, was heralded to "revolutionize" healthcare, but the entire sector has failed financially as well as scientifically to deliver its promises. In contrast, environmental health and nutrition are completely missing from the list, as are whole areas of biophysics research into sustainable systems, cell biology and health. We propose the following additions to the list of priorities, some of them may overlap with those already included under "Sustainable development, global change and ecosystems", but we want to give them more specific emphasis. Sustainable agricultureIn the ISP’s recent briefing to the European Parliament, we have emphasized the need to invest in sustainable agriculture as a matter of urgency in order to feed the world under global warming. Here are some general areas in sustainable agriculture that require dedicated research
Ecology and energy use in sustainable systems Sustainable systems refer ultimately to entire ways of life, including agricultural and industrial production, transport, health and economic and social relationships. Of course, subsystems within the whole could also be studied in their own right. The need for energy efficient production and transport technologies is widely accepted. Not as well acknowledged are the following topics:
Science of the organism and holistic health Many new research programmes fall potentially within the general area of "science of the organism". The emphasis is on non-linear complex dynamics, feedback and coherence, which are necessary for understanding complex systems in general. Especially important is the scientific underpinning of complementary and alternative medical practices, in view of the fact that homeopathy is entering mainstream medicine. The biological effects of mobile phones and other electrical installations in the environment, for example, also require an appropriate biophysical understanding of the organism. We have identified the following topics:
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ISIS Press Release 21/03/05
Gene gold turning to dust?
No Biotech Revolution in Sight
Governments are sinking further billions into genomics and related research but a new study finds no sign of revolution in healthcare Dr. Mae-Wan Ho
The sources for this article are posted on ISIS members’ website. Details here
What revolution?
Over the past decade, consultants, policy makers, academics and industrialists have united in telling the world how biotechnology, and genomics in particular, are "revolutionizing" drug discovery and bringing about radical changes in healthcare involving predictive and even personalized medicine. These euphoric expectations underpin science and technology policy not only in the rich countries of the OECD and the European Union, but also some of the less rich countries such as Malaysia (see "Biotech fever grips Asia" SiS 16).
UK’s Prime Minister Tony
Blair had described the human genome map as "a
revolution in medical science whose implications far
surpass even the discovery of antibiotics"; and said
his government had made available an extra £100 million
in 2003 to speed the introduction of new drugs, and would
boost investment in research.
But a study on the impact of biotechnology on medical
treatments published at the end of 2004 concluded that
the objective evidence provides no support for the idea
of a biotechnology revolution, and warned of
"substantial mismatch between the real world and the
unrealistic expectations of policy- makers".
The tens of billions invested produced only a handful of useful drugs over the past 20 years; and despite a 10-fold increase in research spending worldwide, the total number of new drugs has remained virtually unchanged.
The "breakthroughs" that weren’t
The scientific "breakthroughs" have been equally disappointing: Dolly the cloned sheep was supposed to bring identical "elite herds" as ‘bio-factories’ for pharmaceuticals; but the cloning process proved extremely difficult. Dolly became seriously ill and had to be put down, extinguishing any hope of animal pharming (see "Animal pharm folds" SiS 19).
Dolly’s creator Ian Wilmut gave up cloning animals (see "Death sentence on cloning", SiS 19). He applied instead to the Human Fertilisation and Embryology Authority (HFEA) and was awarded a licence to clone human embryos for stem cells research, holding out hope of curing diseases by embryonic stem cell transplant.
But there is little moral or scientific justification for such ‘therapeutic’ human cloning, especially given the technical difficulties of the cloning process and the known risks in using embryonic stem cells for transplant, in contrast with the proven successes and promise of adult stem cells that can easily be obtained from patients requiring the transplant (see "Human cloning & the stem cell debate", SiS 16).
The clinical successes of the patient’s own adult stem cells have been amply confirmed recently (see "Which stem cells" series, SiS 25), at the same time that the technical, economic, safety and ethical concerns over embryonic stem cell have multiplied (see "No case for human embryonic stem cells research", SiS 25).
Gene therapy has yet to cure any person of major genetic disorders such as cystic fibrosis or sickle cell anaemia. To-date, nine children with X-linked severe combined immune deficiency had apparently been successfully treated, by re-implanting the patient’s bone marrow cells that were genetically modified in the lab. But three of the treated children have developed leukaemia; and the full risks of gene therapy are coming to light.
Gene therapy vectors provoke immune reactions that target viral gene products, transgene products as well as plasmid DNA (see "Gene therapy woes" this series). It was an acute immune reaction that killed a healthy teenage volunteer in a gene therapy clinical trial in 1999 (see "Failures of gene therapy", SiS 16). Five years later, serious safety concerns have emerged over a new gene therapy technique hailed as a breakthrough in 2002 (see "Controversy over gene therapy breakthrough", this series).
Mapping the human genome and the enormous expansion in ‘bio-informatics’ brought little in the way of miracle cures or wonder drugs. In October 2004, another draft of the human genome map was announced; and we are told it is only "the end of the beginning". But even that is not certain; for the new genome map, though much improved in accuracy, is still not complete. The ‘finishing’ procedure roughly doubled the total time and cost of the human genome project. And a lot more investment is necessary to really bring about the revolution in healthcare. ‘Health genomics’ is indeed in danger of being the "financial and scientific black hole" I had predicted five years ago.
Facing the stark evidence
Paul Nightingale from the Science Policy Research Unit, University of Sussex, and Paul Martin from the Institute for the Study of Biorisks and Society, Nottingham, looked at relevant indicators that might support the idea of there being a biotechnology revolution.
The explosive increase of scientific publications in genomics between 1978-2002 clearly indicated a major, and possibly revolutionary, change in some of the scientific inputs that may lead to drug discovery. But data from the US Patent Office (USPTO) in the same period showed only a steady rise in the number of patented compounds. Patenting increased approximately seven-fold, while R and D spending increased roughly ten-fold.
So, even if one takes into consideration the expected lag of 4–8 years between R and D investments and patenting, there is no evidence of dramatic improvement in drug discovery. On the contrary, there is a decline in R and D productivity as measured by the number of patents per dollar spent on R and D, and hence, a possible decline in research productivity, at least in the short term.
Several other indicators followed the same trend.
The number of drugs approved by the FDA in the period 1983–2003 showed an increase until the mid 1990s, followed by a sharp decline, so that roughly the same number of drugs was approved in 2002 as two decades earlier. Set against the substantial increase in R and D expenditure that took place between 1970 and 1992 (i.e. allowing for the 8–12 year lag between research investment and new product launches) there is further evidence of a decrease in productivity rather than the revolutionary increase we have been told to expect.
In terms of therapeutic proteins and antibodies that have reached the market since 1980 and sold more than $500m a year in 2002 and 2003, there are only 12 recombinant therapeutic proteins and three monoclonal antibodies. Moreover, three of the therapeutic proteins were already characterized in 1980, with biotechnology simply leading to new production techniques.
Other researchers in Edinburgh University and the Open University using data that evaluate the performance of new drugs, found only 16 drugs evaluated between January 1986 and April 2004 that were better than ‘minimal improvements’ over pre- existing treatments.
In short, the evidence provides no support for a biotechnology revolution.
The biotechnology bubble
"The emergence of the biotechnology industry has rested heavily on the creation of these high hopes and many people in the sector have been active in promoting the idea of a biotech revolution." Nightingale and Martin wrote, "Management consultants, financial analysts and venture capitalists all clearly have a vested interest in hyping new technologies. Similarly, the promise of a biotechnology revolution provides government policy makers with simple, but as our analysis suggests, probably ineffective ways of promoting regional development, improved healthcare delivery and economic growth."
Nightingale and Martin continued: "Unrealistic expectations are dangerous as they lead to poor investment decisions, misplaced hope, and distorted priorities, and can distract us from acting on the knowledge we already have about the prevention of illness and disease."
We remain caught in the
biotechnology bubble created around the scientific myth
of genetic determinism that was untenable even before the
human genome was mapped, and thoroughly exposed as such
since then. The vast domains of complexity that connects
the genome to the rich tapestry of life are refusing to
yield to mechanistic analysis ("Biotech wonder tool
in disarray", this series). But the scientific
establishment and our policy-makers lack the moral and
intellectual courage to admit that to themselves or to
the public. So, governments continue to sink billions of
taxpayer’s money into raising false hopes of gene
therapy and personalized medicine and putting society at
risk from eugenics. This money can be much more
effectively invested instead to address the real causes
of ill-health, which are overwhelmingly social and
environmental ("Why genomics won’t
deliver", this series).
ISIS Press Release 23/03/05
Biotech Wonder Tool in Disarray
DNA sequence information can’t predict the rich tapestry of life, and researchers are turning to analysing downstream processes using the biotech microarray wonder tool, only to end in disarray Dr. Mae-Wan Ho
Sources for this article are posted on ISIS members’ website. Details here
Gene microarray studies (Box 1) have been growing exponentially since the mid-1990s. By 2003, thousands of studies were carried out; but that was when things started to unravel.
| Box 1 Microarray for comparing gene transcript A microarray of short DNA sequences stuck on a glass plate allows two populations of gene transcripts coding for proteins from different cells (e.g., disease versus controls), or the same cells exposed to different conditions, to be compared. One of them is labelled with a green fluorescent dye, the other with a red fluorescent dye. Spots that appear green are genes expressed preferentially in the green-labelled population; those that appear red are preferentially expressed in the red-labelled population. Those that appear yellow are expressed to the same extent in both populations. The intensity of the colour is proportional to the degree of gene expression. |
Margaret Cam, director of DNA Microarray Core at the National Institute of Diabetes and Digestive and Kidney Diseases wanted to use microarrays to study gene expression in pancreas cells. She and her research team used the same RNA samples on DNA microarrays from 3 leading suppliers: Affymetrix, Agilent, and Amersham, and got wildly discordant results. Out of 185 genes common to all three arrays, the expression pattern of only 4 genes agreed with one another. In other words, the noise level could be as high as 98%. The results were in Nucleic Acids Research in 2003.
Marc Salit, a physical chemist at the National Institute of Standards and Technology said Cam’s findings caused "one’s jaw to drop". Hers was not the first paper to find such inconsistencies. A few ex-enthusiasts think that the promise of gene arrays may have been oversold, especially for diagnostics. Richard Klausner, former director of the National Cancer Institute, now at the Bill and Melinda Gates Foundation in Seattle, Washington, admitted to having been "naïve" to think that new hypothesis about disease would emerge spontaneously from huge files of gene-expression data. The more data he gathered on kidney tumour cells, the less significant they became.
Each company used different short DNA sequence probes spotted onto the array; and they were not telling what exactly these sequences were, so each sequence could be picking up different genes.
Supposedly different probes were responding to pieces of the same gene. Targeting different parts of the same gene can be a problem because genes contain many components that can be spliced into variant mRNAs. The probes have not been designed to be specific to gene-splice variants, and no one has even created a master list of variants for any gene.
Another confounding factor is promiscuous matches. Probes often respond not only to gene products that exactly fit the sequence but also to those that cross-hybridize with near matches. Moreover, many probes don’t correspond to the annotated sequences in the public database.
The results from several high-profile papers have already proved difficult to reproduce. Statistician Ulrich Mansmann and his team in the University of Heidelberg pointed out that a series of papers published in high prestige journals like Nature, NEJM, and The Lancet base their impressive results on ad hoc methods, so it is nearly impossible to assess the quality of the studies. They referred to microarray studies as "a methodological wasteland".
"So, despite considerable hype, the published studies are far from the level of evidence that would be accepted for virtually any other medical test." Said the senior editors of PloS Medicine, one of whom, Virginia Barbour is on the advisory board of the Microarray Gene Expression Data Society.
The problem doesn’t end there. Many aspects of modulation and regulation of cellular activity cannot be investigated on the level of DNA or RNA transcripts, but require analysis of the proteome (complete profile of proteins). So microarrays of antibodies to proteins have already been contemplated.
Several studies in yeast and
higher organisms demonstrated a poor correlation between
mRNA and protein, due to a number of additional processes
such as posttranscriptional control of protein
translation, post-translational modification of proteins,
and protein degradation. The current estimate is that
there are more than 200 types of protein modification;
and that 5-10% of the 
mammalian genes code for proteins that
modify other proteins.
Consequently, the human proteome is expected to range from 100 000 to several million different protein molecules, in striking contrast to the small number of genes. Furthermore, no function is known for more than 75% of the predicted proteins of multicellular organisms, and the dynamic range of protein expression can be as large as 107.
"Knowledge of genomic sequences and transcriptional profiles do not allow a reliable description of actual protein expression, let alone an examination of protein-protein interaction or prediction of the protein’s biochemical activities." Said Wlad Kusnezow and Jörg Hoheisel of Functional Genome Analysis in Heidelberg, Germany.
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