A season of retractions, a question of accountability
So early in the year and already so many high-profile retractions in the biomedical field.
Retraction 1 [1]: A review paper [2] published in Best Practice & Research Clinical Rheumatology was retracted by the Harvard researcher Lee Simon after the software eTBlast and the database Déjà vu [3] marked the paper as a possible plagiarism. The paper supposedly had 55% text similarity with another paper published in 2003.
Retraction 2 [4]: Nobel prize winner Linda Buck retracted a 2001 Nature paper on the olfactory system [5] which she co-authored due to inconsistencies and inability of other researchers to reproduce the published results. Although Buck was named co-author, the primary author Zhihua Zou was cited “as solely responsible for providing data and figures for the paper” [4]. Buck won together with Richard Axel, the Nobel Prize in physiological medicine in 2004.
Retractions 3 and 4 [6]: One paper in Science [7] and another in Nature Chemical Biology [8] are being retracted by Korean researchers after doubts over the “scientific truth” of these molecular biology papers arose. The team of researchers in question works at the prestigious Korea Advanced Institute of Science and Technology (KAIST), led by the senior scientist Tae Kook Kim.
Issues to be linked to these stories are scientific integrity and author(s) [and co-author(s)!] accountability. Especially the accountability part. Who is accountable in cases of doubts and disputes? The supervisor or the PhD student? The team leader or the junior researcher?
References:
- Review article retracted amid plagiarism claims. Nature 451, 619 (2008).
- Simon LS. The treatment of rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2004 Aug;18(4):507-38.
- Errami M. Déjà vu–a study of duplicate citations in Medline. Bioinformatics. 2008 Jan 15;24(2):243-9.
- Nobel prizewinner’s paper retracted. Nature 452, 13 (2008).
- Zhihua Z et al. Genetic tracing reveals a stereotyped sensory map in the olfactory cortex. Nature 414, 173-179 (8 November 2001).
- Korean institute inquiry prompts two retractions. Nature 452, 267 (2008).
- Won J. et al. A magnetic nanoprobe technology for detecting molecular interactions in live cells. Science 309 (5731):121 – 125; July 2005.
- Won J. et al. Small molecule-based reversible reprogramming of cellular lifespan. Nature Chem. Biol. 2, 369–374; 2006.
How Genetic Variation is Affecting Drug Development
In the March 2 issue of the Swiss newspaper “SonntagsZeitung” is an interesting article entitled “Pillen in Massanzug” which can be translated as “Custom-made Pills” [1]. The article basically explores how increased knowledge of human genetics is creating changes in drug development and speculates on the possibility of personalized medicine.
Here are some examples:
Carbamazepine
In December last year, The US FDA recommended genetic testing in connection with the prescription of the drug carbamazepine. Carbamazepine is commonly used for the treatment of epilepsy, bipolar disorder and neuropathic pain. Recently, certain patients – notably of Asian ancestry - were observed to develop serious skin disorders as adverse reaction to the drug. “Studies have found a strong association between certain serious skin reactions and an inherited variant of a gene, HLA-B* 1502, an immune system gene, found almost exclusively in people with Asian ancestry.” [2] Prior to this recent recommendation, genetic testing was recommended for all patients regardless of ethnicity. However, with the recent results of genetic studies, genetically high-risk patients have been narrowed down to an ethnic group, making life easier for health professionals and their patients, as well as the drug manufacturers themselves.
Statins
The use of the anti-cholesterol drugs statins has been associated with muscle pains and weakness. Researchers have recently identified the gene that may hold the key to statin-induced muscle toxicity. The atrogin-1 gene is associated with different types of muscle atrophy. In vitro and in vivo studies show that statins activate atrogin-1 gene leading to skeletal muscle damage [3]. Atrogin-1 gene expression may differ in different people, explaining the wide range of muscle symptoms (from very mild to debilitating) in statin users.
Trastuzumab
The anti-cancer drug Herceptin (trastuzumab) is a HER2/neu receptor antagonist and is indicated only for patients with HER2-overexpressing breast cancer. The drug specifically targets a gene (HER2) that causes breast cancer so that patients with other types of breast cancer cannot benefit from this drug. Considering the rather serious side effects involved (cardiomyopathy and pulmonary toxicity), HER2 gene testing is highly recommended before chemotherapy can be started. [4]
Ezetimibe
Ezetimibe is one of 2 combination drugs tested by the controversial ENHANCE trial. The study participants have heterozygous familial hypercholesterolemia, a genetic disorder characterized by cholesterol deposition and high plasma concentrations of low-density lipoprotein cholesterol [5]. Unfortunately, the trial results did not show any benefit from ezetimibe. However, drug testing on genetically distinct populations is becoming a common practice in drug development.
So how far are we from personalized medications? I personally think this will soon be technologically possible but whether it`s financially feasible is a different matter.
References:
1. SonntagsZeitung, 2 March 2008, p.73
2. FDA News, 12 December 2007.
3. Hanai et al. J Clin Invest. 2007 December 3; 117(12): 3940–3951.
4. Herceptin prescribing information, Jan 2008.
5. Yuan et al. CMAJ • April 11, 2006; 174 (8).
Latest approvals by the US FDA
• The proton pump inhibitor (PPI) Nexium (esomeprazole magnesium) is indicated for short-term treatment of gastroesophageal reflux disease (GERD) in children ages 1 to 11 years old. Nexium is manufactured by AstraZeneca [1].
• Xyntha Antihemophilic Factor (Recombinant) Plasma/Albumin Free is a new treatment for hemophilia A. Hemophilia A is a hereditary blood-clotting disorder that affects mainly males. It is caused by a mutation of the factor VIII, resulting in clotting factor VIII deficiency. Xanthia is a genetically engineered version of factor VIII. It is manufactured by Wyeth Pharmaceuticals Inc. [2].
• The Interleukin-1 blocker Arcalyst (rilonacept) is an orphan drug indicated for the treatment of two Cryopyrin-Associated Periodic Syndromes (CAPS) disorders. CAPS are very rare conditions of inflammation. Orphan drugs are drugs intended for the treatment of rare diseases. To make it worthwhile for drug companies to develop such drugs in the US, manufacturers of orphan drugs enjoy tax incentives and longer period of exclusivity as provided for by the US Orphan Drug Act. Arcalyst is manufactured by Regeneron Pharmaceuticals Inc. [3].
References:
R-I-I-N-G: The latest on the health and environmental impacts of mobile phones
The health and environmental impacts of electromagnetic radiation from mobile phone handsets and base stations have been a topic of controversy for years now. Scientific studies produced conflicting results but conflicts of interests among researchers are common considering the financial and political clout of the telecom industry. A few of the latest developments are summarized here.
Impact on sleep
Short-term exposure to GSM wireless communications signals seems to have an immediate effect on sleeping patterns. Researchers in Sweden and the US observed that sleep disturbances frequently occurred in individuals who were exposed to 884 MHz frequency signals comparable to those emitted by mobile phone hand sets. Adverse effects on sleep quality as measure by EEG were observed. Sleep stages 3 and 4 were especially affected.
Data was based on self-reported symptoms in a study group of blinded 35 men and 36 women [1].
Impact on fetuses and neonates
Egyptian researchers observed that the use of mobile phones by pregnant women can increase heart rates and decrease cardiac outputs of the fetuses. The same was also observed in neonates [2].
Impact on birds
The population of the house sparrows Passer domesticus in Europe has been on the decline for years now and electromagnetic radiation from mobile phone base stations might be partly responsible for this. Researchers in Belgium [3] and Spain [4] observed that spatial variation of these birds is significantly correlated to the strength of EMR in a certain area.
A more comprehensive review of the problem was initiated by a group of experts in 2007 who wrote the BioInitiative Report: A Rationale for a Biologically-based Public Exposure Standard for Electromagnetic Fields (ELF and RF) [5].
“The current guidelines for the US and European microwave exposure from mobile phones, for the brain are 1.6W/Kg and 2W/Kg, respectively.” Based on recent findings and the BioInitiative Report, “a new biologically based guideline is warranted.” [6].
References:
- Arnetz et al. 2007. The effects of 884 MHz GSM wireless communication signals on self-reported symptom and sleep (EEG)- An experimental provocation study. Progress in Electromagnetics Research Symposium
- Rezk et al. 2008. Fetal and neonatal responses following maternal exposure to mobile phones. Saudi Medical Journal 2008 Feb;29(2):218-23.
- Everaert & Bauwens, 2007. A possible effect of electromagnetic radiation from mobile phone base stations on the number of breeding house sparrows (Passer domesticus) Electromagnetic Biology and Medicine January 2007; 26(1): 63-72
- Balmori & Hallberg, 2007. The urban decline of the house sparrow (Passer domesticus): A possible link with electromagnetic radiation Electromagnetic Biology and Medicine April 2007; 26(2): 141-151
- BioInitiative Report:A Rationale for a Biologically-based Public Exposure Standard for Electromagnetic Fields (ELF and RF). www.bioinitiative.org
- Hardell & Sage, 2008. Biological effects from electromagnetic field exposure and public exposure standards. Biomed Pharmacother. 2008 Feb;62(2):104-109.
Move more, live longer: the latest on the benefits of an active lifestyle
Springtime is coming, the days are getting longer and warmer, and we are running out of excuses not to be up and moving again. Here is a short review of recent studies on the benefits of physical exercise.
Exercise and BP in children [1]
A recent UK study, the Avon Longitudinal Study of Parents and Children, shows that physical activity in children lowers childhood blood pressure (BP). Furthermore, it’s not the intensity of the activity that counts but the total amount of physical activity while performing normal daily chores. It could be just as simple as walking to and from school. The important thing is that kids should be mobile and not spend long periods of time in front of the TV or the game boy console. High BP in children can result in adult hypertension.
Aerobics and cholesterol levels [2]
A meta-analysis study by Japanese researchers shows that doing aerobics regularly increases serum concentrations of high-density lipoprotein cholesterol (HDL). This increase in HDL levels lowered the risk of cardiovascular disorders by about 5.1% in men and by 7.6% in women. The rise in HDL depends on duration but not intensity or frequency of the exercise. This beneficial effect of aerobics is most pronounced in people with initially high total cholesterol levels and low body mass index (BMI).
Exercise and telomeres [3]
British researchers found a correlation between physical activity and leukocyte telomere length (LTL) in healthy individuals. LTL is a biological measure of aging in humans.
Researchers at Twin Research Unit at St Thomas’ Hospital in London found that individuals who are inactive, smokers and with high BMI tend to have shorter telomeres than active, non-smoking individuals. The difference in biological age between couch potatoes and physically active people can be as high as 10 years.
Exercise and alcohol [4]
A Danish study followed up 11,914 adults for over 20 years. Their results show that leisure-time physical exercise combined with moderate alcohol intake actually lower risks of fatal ischemic heart disease (IHD). Nondrinking, sedentary individuals have the highest risk of IHD while physically active moderate drinkers have the lowest risk.
The study defined “moderate” drinking as 1 to 14 drinks of alcohol a week. One drink is equivalent to “one bottle of beer, one glass of wine, or one unit of spirit.”
Sources:
Leary SD et al., 2008. Physical activity and blood pressure in childhood: findings from a population-based study. Hypertension 51:92-98.- Kodama S et al., 2007. Effect of aerobic exercise training on serum levels of high-density lipoprotein cholesterol. Arch Intern Med 167:999-1008.
- Cherkas LF et al., 2008, The association between physical activity in leisure time and leukocyte telomere length. Arch Intern Med 168: 154-158.
- Pedersen JØ et al.., 2008. The combined influence of leisure-time physical activity and weekly alcohol intake on fatal ischaemic heart disease and all-cause mortality. European Heart Journal January 2008 29(2):204-212
The year that was: major events in 2007
Nature`s Daniel Cressey listed several events as among the most newsworthy in 2007. Some of these events are discussed below.
Biotechnology
November was a good month for biotechnology. American and Japanese researchers derived pleuripotent stem cells from human skin. American researchers also finally succeeded cloning primate embryos in the same month. Both events are major breakthroughs in stem cell research.
This year, two big names in genomics - James Watson and Craig Venter – had their full genome sequenced. In the meantime, American start ups are offering personalized genetic information service (see October post).
Climate Change
The Intergovernmental Panel on Climate Change (IPCC) was co-winner of the Nobel Prize for Peace. In the meantime, the Northwest Passage that connects Atlantic and Pacific Oceans was practical ice-free and passable – a record low in the arctic ice cover. If the IPCC reports and this ice shrinkage do not convince people of the reality of global change, nothing ever will.
Pharmaceutical scandals
China’s former head of food and drug regulatory agency was executed in July after having been convicted of corruption. In the USA, the Avandia scandal rages on. The USA FDA required an additional black box warning for the diabetes medication Avandia (rosiglitazone) labelling last year but Avandia`s troubles didn’t stop there. The latest involved a US senate inquiry and a leak by an NEJM reviewer.
Safety issues
The July earthquake in Japan caused a leak in a major nuclear reactor, reawakening concerns over nuclear energy safety in general.
Two incidences of major biosecurity lapses were reported this year. In the UK, a leaky pipe caused an outbreak of foot-and-mouth disease. In a bioweapons research lab at the Texas A&M University, researchers were exposed to biohazards.
Space technology
Japan and China launched moon probes in 2007 though there were doubts whether China’s claims of success were authentic. China also tested a space weapon by shooting at one of its defunct satellites, scattering potentially dangerous debris in space.
Wired magazine considered the following as the top 10 scientific breakthrough of 2007:
10. Transistors Get Way Smaller
9. Scientists Clone Rhesus Monkey to Produce Stem Cells
8. Planet Discovered That Could Harbor Life
7. Engineers Create Transparent Material as Strong as Steel
6. Soft Tissue from T. Rex Leg Bone Analyzed
5. Laboratory Mice Cured of Rett Syndrome
4. Enzymes Convert Any Blood Type to O
3. Mummified Dinosaur Excavated and Scanned
2. Chimpanzees Make Spears for Hunting
1. Researchers Turn Skin Cells to Stem Cells
References:
Cressey D. News 2007. Nature 450, 1134-1135 (2007)
Rowe A. Top 10 Scientific Breakthroughs of 2007. Wired 27 Dec 2007.
“Something is rotten in the state of…
…science” if I may borrow from and rephrase Shakespeare.
The highest ethical standards – we expect no less from men and women of science. Yet, recent events brought to light just how short they can fall from these expectations.
“Neither a borrower nor a lender be: For loan oft loses both itself and friend.”
Case # 1: Duplication and plagiarism.
Borrowing from the works of others and our own without proper citation is, in the scientific community, unethical behaviour of the highest magnitude. Using the software eTBLAST, bioinformatics searched through 62,213 Medline entries and found 0.04% cases of potential plagiarism and 1.35% cases of potential duplication [1, 2]. These citations are recorded on Déjà vu, a database of potentially duplicated and plagiarized scientific articles.
One of its first victims comes from no less than that icon of higher learning – Harvard itself. Two review papers, published about 1 year apart by different authors in 2 different journals have 55% similarity [3].
The countdown is running for other papers listed in the Déjà vu database as scrutiny continues. The journals are suddenly waking up to the fact that unethical behaviour in science is more rampant than previously thought. But isn’t it ironic that anti-plagiarism software - the very tool that academia is using to prevent plagiarism by students – is the one that would cast serious doubt on scientific credibility?
“To tell, or not to tell, — that is the question.”
Case #2: Breach of confidentiality.
A referee for the New England Journal of Medicine committed a major breach of confidentiality by leaking an unfavourable manuscript to a drug company [4]. I’m referring to the Avandia (rosiglitazone) issue (see 25 Nov 2007post) and how a referee faxed a copy of the manuscript [5] to the drug’s manufacturer GSK before it was officially published. The confidentiality of the peer review process is sacrosanct and breaching this confidentiality is a major scientific misconduct.
This reflects current concerns about conflicts of interest among authors, editors, and referees (who are most of the time, all one and the same) due to financial support from pharmaceutical companies. Another reason to call for non-industry-sponsored clinical research.
“There is nothing either good or bad, but thinking makes it so.” And getting caught.
References:
[1] Errami M et al. (2008). Déjà vu—A study of duplicate citations in Medline. Bioinformatics 24(2):243–249.
[2] Errami M & Garner H (2008). A tale of two citations. Nature 451:397-399.
[3] http://www.boston.com/news/health/blog/2008/01/a_harvard_rheum.html
[4] Vastag B (2008). Reviewer leaked Avandia study to drug firm. Nature 451:509.
[5] Nissen SE & Wolski KN (2007). NEJM 356:2457–2471.
Pediatric clinical trials: damned if you do, damned if you don’t
Drug regulators are in a quandary. On the one hand, they’d rather spare children from being used as test subjects in clinical trials. On the other hand, recent developments show an urgent need for pediatric testing.
There have been recent reports of adverse side effects, some of them fatal, attributed to OTC drugs for children. These concerned seemingly innocuous cough and cold medications containing active ingredients such as pseudoephedrine, paracetamol [1,2], and camphor [3]. But prescription drugs for children`s ailments such as asthma and ADHD are incriminated as well.
This brought to light how very little we actually know about pediatric pharmacology.
The problem lies with the fact that many drugs with well-established efficacy and safety profile have only been tested in adults. With an aging population and low birth rates in developed countries, the pediatric drug market is not really top priority for pharmaceutical industries. Very little money is allocated for pediatric R&D. Pharmacological results were simply extrapolated to pediatric population as “miniature adults.”
The issue is compounded by lack of test subjects. Very few parents in developed countries would ever consent that their children be enrolled in a clinical trial. Most pharmaceutical companies turn to developing countries for testing. Although there are strict guidelines regulating pediatric testing, there are still concerns about adherence to GCP in those countries.
The regulators are now scrambling to come up with solutions to plug this knowledge gap on pediatric drugs.
Last year, the US passed the Best Pharmaceuticals for Children Act 2007 and an amended version (2007) of the 2003 Pediatric Research Equity Act. The Acts empowered the US FDA to require drug companies to test new drugs on children before approval [4]. However, there is still a lack of knowledge on drugs approved before 2003.
In Europe, the EMEA is requiring a pediatric investigation plan for all new drug applications starting July 2008 (unless a non-pediatric use waiver is justified). In addition, it is funding research on off-patent drugs as well as looking into pediatric clinical data that may not have been previously published [5, 6].
In the meantime, millions of children need medications while drugs against cancer, infections, asthma, high blood pressure and hyperactivity currently available are waiting to be tested for pediatric use. Do we use these drugs or not ? Quandary for doctors and parents as well.
Damned if you do. Damned if you don’t.
References:
1. Wingert WE, Mundy LA, Collins GL, Chmara ES. Possible role of pseudoephedrine and other over-the-counter cold medications in the deaths of very young children. J Forensic Sci. 2007 Mar;52(2):487-90.
2. Centers for Disease Control and Prevention (CDC). Infant deaths associated with cough and cold medications–two states, 2005. Morb Mortal Wkly Rep. 2007 Jan 12;56(1):1-4.
3. Press Release, NYC Department of Health. January 17, 2008. Health department warns parents to keep camphor products away from children.
4. US FDA, Pediatric Drug Development. Retrieved 27 Jan 2008.
5. Sinha G.J. EU law mandates drug testing in children. J. Natl Cancer Inst. 2008 Jan 16;100(2):84-5.
6. EMEA Press Release Paediatric Committee (PDCO), 25 Jan 2008.
Fast food and CVD: where`s the connection?
Be it burgers, pizza or fries, what is it with fast food diet that makes it a major CVD risk factor? In the recent issue of the Journal of the American College of Cardiology, researchers published the answers [1].
Consumption of high-calorie, low-nutrient food causes a sudden increase in blood glucose and triglyceride levels and results in a state known as postprandial dysmetabolism. These after-meal spikes in sugar and free fatty acids “overwhelm the body’s ability to handle the surge, resulting in a flooding of the Kreb’s cycle and the production of superoxide anions. The postprandial production of these free radicals acutely triggers atherogenic changes, such as increases in LDL oxidation, sympathetic tone, vasoconstriction, and thrombogenicity [2].”
At the end of the scale, traditional Mediterranean or Okinawan diets (consisting of lean protein, fish oil, whole grains, vegetables and low to moderate amounts of alcohol among others) has been shown to be anti-inflammatory and to lower CVD risks [1].
References:
1. O’Keefe JH, Gheewala NM, O’Keefe JO, 2008. Dietary Strategies for Improving Post-Prandial Glucose, Lipids, Inflammation, and Cardiovascular Health. J Am Coll Cardiol, 2008; 51:249-255, doi:10.1016/j.jacc.2007.10.016
2. O`Riordan M. Big Macs and Whoppers: Spikes in after-meal glucose and lipid levels lead to inflammation and CVD. HeartWire 16 Jan 2008.
Symposium on Publishing Clinical Trials
What: A one-day symposium jointly organized by the Institute of Clinical Research and the European Medical Writers`Association.
Theme: Publishing Clinical Trials: Ethics and the Pharmaceutical Industry.
When and where: 27 February 2008, Novotel Hammersmith, 1 Hammersmith International Centre, London.
“This symposium will be presented by a panel of experts including medical writers, journal editors, academics and pharmaceutical industry managers. Topics will include publication policy, ghostwriting, fraud and other ethical issues of publishing clinical trials.”
Details and registration at www. icr-global.org