Video: A Celebration of 50 Years of DNA in Medicine: The Genome and Human Rights

Video: A Celebration of 50 Years of DNA in Medicine: Stem Cell Biology and Human Disease

Video: "DNA and the Brain" - Dr. James Watson

BoTox Receptor

From Science 28 April 2006:Vol. 312. no. 5773, pp. 592 - 596

Botulinum neurotoxin type A (BoNT/A) is one of seven neurotoxins produced
by the bacterium Clostridium botulinum. BoNT/A has a long half-life within
cells and is widely used in treatments of wrinkles to chronic pain.
Moreover, BoNT/A can cause paralysis that persists for months. BoNT/A is
known to block neurotransmission by cleaving the protein SNAP-25 in
presynaptic terminals, but it is not clear how this toxin selectively
recognizes and enters neurons. Dong et al. (p. 592, published online 16
March; see the Perspective by Miller) now identify a protein component of
the cellular receptor for BoNT/A as a synaptic vesicle protein, SV2. BoNT/A
enters neurons via recycling synaptic vesicles by binding to SV2 isoforms,
and cells and animals lacking SV2 are resistant to intoxication.

The cellular mRNA expression of GABA and glutamate receptors in spinal motor neurons of SOD1 mice

From Journal of the Neurological Sciences Volume 238, Issues 1-2 , 15 November 2005, Pages 25-30

Abstract
ALS is a fatal neurodegenerative disorder characterized by a selective loss of upper motor neurons in the motor cortex and lower motor neurons in the brain stem and spinal cord. About 10% of ALS cases are familial, in 10–20% of these, mutations in the gene coding for superoxide dismutase 1 (SOD1) can be detected. Overexpression of mutated SOD1 in mice created animal models which clinically resemble ALS. Abnormalities in glutamatergic and GABAergic neurotransmission presumably contribute to the selective motor neuron damage in ALS. By in situ hybridization histochemistry (ISH), we investigated the spinal mRNA expression of the GABAA and AMPA type glutamate receptor subunits at different disease stages on spinal cord sections of mutant SOD1 mice and control animals overexpressing wild-type SOD1 aged 40, 80, 120 days and at disease end-stage, i.e. around 140 days) (n = 5, respectively). We detected a slight but statistically significant decrease of the AMPA receptor subunits GluR3 and GluR4 only in end stage disease animals.

Alzheimer Disease And The Blood Brain Barrier: Is Abeta Transport The Key?

From Journal of Clinical Investigation

Increased production of the amyloid-beta (Abeta) peptide can lead to Abeta aggregation and buildup in the brain and rare familial forms of early onset Alzheimer disease (AD). Aggregation and buildup of Abeta also appears to contribute to the common, late-onset form of AD, which accounts for 99% of cases, however, there is not strong evidence of Abeta over-production in late-onset AD.

This suggests that there is an age-associated alteration in brain Abeta clearance that contributes to late-onset AD. There is substantial clearance of Abeta from the brain to the blood via the blood-brain-barrier (BBB). Thus, understanding which molecules at the BBB are responsible for Abeta clearance is important. Several transporters have been identified on the BBB that mediate Abeta efflux, however if and how these transporters contribute to Abeta deposition as plaques remain unclear.

In a paper appearing online on October 20 in advance of print publication of the November issue of the Journal of Clinical Investigation, David Holtzman and colleagues from Washington University demonstrate that P-glycoprotein is required for Abeta transport across the BBB and that ablation of this transporter at the BBB increases Abeta deposition in a mouse model of AD.

P-glycoprotein has been a major pharmaceutical target by conferring resistance to many chemotherapy regimens, as well as its role in eliminating a wide variety of medicines via liver uptake. It is possible that chronic treatment with these types of drugs could alter P-glycoprotein function, thereby altering Abeta transport and the risk of developing AD. The findings in this manuscript, in addition to its implications in understanding Abeta transport via the BBB and its therapeutic implications, suggests that researchers should begin to explore whether drugs currently being utilized in humans that affect PgP activity, alter risk for AD.

Gene For B-Cell Development Factor Might Be Involved In Multiple Sclerosis

From Biomed Central

A gene involved in B-cell development might play a role in multiple sclerosis. The results of a large study published today in the open access journal BMC Neurology reveal that multiple sclerosis (MS) patients are more likely to carry two specific genetic variations in the Early B-cell factor gene (EBF-1), than healthy individuals.

These variations – or polymorphisms - could play a causative role in MS or be located near other polymorphisms that do play a causative role in the disorder. As such, they could be used as genetic markers for MS.

Alfonso Martinez and colleagues from the Hospital Clinico San Carlos, in Madrid, Spain, who carried out the research, suggest that EBF-1 might be involved in MS due to its role in axonal damage. "Axonal damage is a hallmark for multiple sclerosis," write the authors, and EBF is involved in the expression of proteins essential for axonal pathfinding. How axonal damage occurs in MS, however, is not well understood.

In their study, Martinez et al. compared the occurrence of a polymorphism at a single point in the DNA sequence of the gene EBF-1 – also called a single nucleotide polymorphism (SNP) - in 356 patients diagnosed with MS and 540 healthy individuals acting as controls. Both groups consisted of white Spanish individuals. The authors also compared the variants of a microsatellite – a highly variable, short stretch of non-coding DNA within the EBF-1 gene - in the two groups.

Their results show that patients with MS are more likely to carry the base adenine in the SNP analysed, than controls (p=0.02). In addition, one specific version (allele) of the microsatellite was more frequently found in MS patients than in controls (p=0.08). The authors confirmed this finding with a Transmission Disequilibrium Test: a study of the transmission rate of the allele in 53 patients and their parents, which showed that the allele was more likely to be present in both patients and their parents than other alleles.

Protein Aggregates In Lou Gehrig's Disease Linked To Neuron Death

From Northwestern University

French neurologist Jean-Martin Charcot first described amyotrophic lateral sclerosis (ALS) in 1869, but, nearly 140 years later, little is known about the cause of the devastating neurodegenerative disease, and there is no cure.

What is known about Lou Gehrig's disease, as it is commonly called, is that misfolded and damaged proteins clump together in cells to form aggregates and motor neurons die. But scientists have long debated whether or not the protein aggregates actually kill the cells.

Now a research team at Northwestern University, using mammalian neurons and live-cell time-lapse spectroscopy, has become the first to clearly link the presence of the ALS-associated mutant SOD1 protein aggregates with neuronal cell death. This evidence could help explain the disease process and eventually lead to new therapeutics.

In the study, published this month in the Journal of Cell Biology, the scientists looked one at a time at neuronal cells expressing the mutant SOD1 protein and found that in cells where the protein accumulated and aggregates formed, 90 percent of the cells went on to die. (They died between six and 24 hours after aggregates were visually detected.) Cells that did not form aggregates did not die.

The study also provides a new understanding of the structure and composition of the deadly aggregates -- one of the first studies to do so.
"We found that these aggregates are quite peculiar and very different from the aggregates formed in Huntington's disease," said Richard I. Morimoto, Bill A. and Gayle Cook Professor in Biological Sciences, who led the study. Morimoto is an expert in Huntington's disease and on the cellular response to damaged proteins.

"In Huntington's, the aggregate is very dense and impenetrable and binds irreversibly with other molecules in the cell," he said. "In ALS, the aggregates are amorphous, like a sponge. Other proteins can go through the structure and interact with it, which may help explain why mutant SOD1 is so toxic." Morimoto believes this surprising finding indicates that the structure of aggregates associated with other neurodegenerative diseases such as Parkinson's and Alzheimer's will be found to be different as well.

Looking at individual cells in a population, the researchers also found that cells side by side did different things. In cells expressing the same amount of damaged protein, some cells formed aggregates and died and others did not form aggregates and lived. Only a certain subset of at-risk cells went on to lose function and die.

"It would be terrifying if 100 percent of the cells expressing mutant proteins died," said Morimoto. "This means that in many cases the cell's protective machinery suppresses the damaged proteins, keeping the cell healthy. This discovery will be important to scientists looking to develop genetic suppressors and therapeutics."

Morimoto's team focused on SOD1 because it is a form of familial (hereditary) ALS in which a mutation in just one gene and its associated protein has devastating consequences to the cell. (Approximately 10 percent of ALS cases are familial.) This provides experimentalists with a powerful framework. For the other 90 percent the disease is not the result of one mutation but rather a series of many genetic events that debilitate motor neurons. With non-familial forms it is extremely difficult to design hypothesis-based experiments, said Morimoto.

The next question the researchers plan to address is what are the events that lead to cell death once mutant SOD1 protein aggregates form in the cell? This knowledge would help scientists identify small molecules that could halt, arrest or reverse the disease process.

Myelin Suppresses Plasticity In The Mature Brain

From Yale University

Yale School of Medicine researchers report in Science this week genetic evidence for the hypothesis that myelination, or formation of a protective sheath around a nerve fiber, consolidates neural circuitry by suppressing plasticity in the mature brain.

This finding has implications for research on restoring mobility to people who have lost motor functions due to spinal cord injury, multiple sclerosis, Lou Gehrig's disease, and other central nervous system disorders.

"The failure of surviving neurons to reestablish functional connection is most obvious after spinal cord injury, but limited nerve cell regeneration and plasticity is central to a range of neurological disorders, including stroke, head trauma, multiple sclerosis, and neurodegenerative disease," said senior author Stephen Strittmatter, professor in the Departments of Neurology and Neurobiology. "Recovery of motor function after serious damage to the mature brain is facilitated by structural and synaptic plasticity."

Strittmatter's laboratory studies how myelin in the central nervous system physically limits axonal growth and regeneration after traumatic and ischemic injury, when blood supply is cut off. A physiological role for the myelin inhibitor pathway has not been defined.

Blocking vision in one eye normally alters ocular dominance in the cortex of the brain only during a critical developmental period, or 20 to 32 days postnatal in mice. Strittmatter's lab, working in collaboration with Nigel Daw, M.D., professor of ophthalmology and neuroscience, and his group, found that mutations in the Nogo-66 receptor (NgR) affect plasticity of ocular dominance. In mice with altered NgR, plasticity during the critical period is normal, but it continues abnormally so that ocular dominance later in development is similar to the plasticity of juvenile stages.

Neural Stem Cells Are Long-Lived

From Howard Hughes Medical Institute

New studies in mice have shown that immature stem cells that proliferate to form brain tissues can function for at least a year — most of the life span of a mouse — and give rise to multiple types of neural cells, not just neurons. The discovery may bode well for the use of these neural stem cells to regenerate brain tissue lost to injury or disease.

Alexandra L. Joyner, a Howard Hughes Medical Institute investigator at New York University School of Medicine, and her former postdoctoral fellow, Sohyun Ahn, who is now at the National Institute of Child Health and Human Development, published their findings in the October 6, 2005, issue of the journal Nature. They said the technique they used to trace the fate of stem cells could also be used to understand the roles of stem cells in tissue repair and cancer progression.

Joyner said that previous studies by her lab and others had shown that a regulatory protein called Sonic hedgehog (Shh) orchestrates the activity of an array of genes during development of the brain. Scientists also knew that Shh played a role in promoting the proliferation of neural stem cells. However, Joyner said the precise role of Shh in regulating stem cell self-renewal — the process whereby stem cells divide and maintain an immature state that enables them to continue to generate new cells — was unknown.

In the studies published in Nature, Joyner and Ahn developed genetic techniques that enabled them to label neural stem cells in adult mice that are responding to Shh signaling at any time point so they could study which stem cells respond to Shh.

Other researchers had shown that transient bursts of Shh signaling caused neural stem cells to proliferate and create new neurons. But a central question remained, said Joyner. At issue was whether resting, or quiescent, cells — which are important for long-term function — responded to Shh signaling. Or was the response limited to the actively dividing stem cells with a short life span involved in building new tissue? To test these options, the researchers used a chemical called AraC that selectively kills fast-dividing cells, leaving only quiescent cells.

“This was an important experiment, because by giving AraC, we could kill all the cells that were actively dividing for a week,” said Joyner. “And since the quiescent cells only divide every couple of weeks, they were spared.” The researchers' observations revealed that the quiescent cells did, indeed, respond to Shh signaling, expanding to produce large numbers of neural cells. Even when the researchers gave the mice two doses of AraC separated by a year, the quiescent cells recovered — demonstrating that the cells could still respond to Shh signaling.

That the quiescent stem cells remained capable of self-renewal after a year in both normal and AraC-treated mice was a central finding of the study, said Joyner. “It has been assumed that these cells probably live for some time, but it has never really been known whether they keep dividing, or divide a few times and give out,” she said.

The researchers also found evidence that neural stem cells in vivo responded to Shh signals by giving rise to other neural cell types, including glial cells that support and guide neurons. “An important point is that earlier studies indicating that neural stem cells could give rise to multiple cell types had been done in vitro,” said Joyner. “Before our work, it had never been formally shown that they normally make those different cell types in vivo.” Joyner and Ahn also found that the neural stem cell “niches” — the microenvironments in tissue that support and regulate stem cells — were not formed until late embryonic stages.

Joyner said that the new findings have important clinical implications. “In terms of using neural stem cells for therapeutic purposes and to regenerate tissue, it's important that they can continue to proliferate, and that these stem cells can make different cell types,” she said.

In further studies, the researchers plan to use their technique of marking stem cells and tracing their fate to explore their role in repairing injured brain tissue in animal models. Such studies, she said, could reveal whether growth factors that influence stem cell growth could be used to treat brain injuries. “If these stem cells do produce cells that contribute to injury repair, it is fairly easy to infuse growth factors to coax these stem cells to do more in repairing injury,” she said.

Joyner and her colleagues are already discussing how to apply their genetic fate-mapping techniques to stem cells in the spinal cord and other organs. They are hopeful that since Shh signaling has been implicated in spurring the metastatic progression of cancer, the technique might also be used to explore the role of Shh signaling in tumor progression.

CENTRAL NERVOUS SYSTEM INJURY-INDUCED IMMUNE DEFICIENCY SYNDROME

From Nature Reviews Neuroscience 6, 775-786 (2005); doi:10.1038/nrn1765

Abstract

Infections are a leading cause of morbidity and mortality in patients with acute CNS injury. It has recently become clear that CNS injury significantly increases susceptibility to infection by brain-specific mechanisms: CNS injury induces a disturbance of the normally well balanced interplay between the immune system and the CNS. As a result, CNS injury leads to secondary immunodeficiency — CNS injury-induced immunodepression (CIDS) — and infection. CIDS might serve as a model for the study of the mechanisms and mediators of brain control over immunity. More importantly, understanding CIDS will allow us to work on developing effective therapeutic strategies, with which the outcome after CNS damage by a host of diseases could be improved by eliminating a major determinant of poor recovery.

Summary

1. Infections are a leading cause of death in patients suffering from acute CNS injury, such as stroke, traumatic brain injury or spinal cord injury. In affected patients infections impede neurological recovery and increase morbidity as well as mortality.
2. CNS injury induces a disturbance of the normally well balanced interplay between the immune system and the CNS.
3. Brain injury leads to a characteristic immunological phenotype, which is immunodepressant.
4. During systemic inflammation, either as a result of bacterial infection or injury, the CNS mounts a homeostatic, counter-regulatory anti-inflammatory response. However, when triggered by CNS injury, in the absence of systemic inflammation, this response may be detrimental because it shuts down defence mechanisms, rendering the affected organism susceptible to infection. Under these conditions, the immunodepression exerted by the brain is not balanced by general immunostimulation.
5. CNS injury suppresses cell-mediated immune responses via three major pathways of neuroimmunomodulation: the hypothalamo–pituitary–adrenal (HPA) axis, and the sympathetic and parasympathetic nervous systems.
6. We propose that 'neurogenic' mechanisms are involved in the induction of CNS injury-induced immunodepression (CIDS). Damage to sites in the nervous system that control neural–immune interactions (such as the hypothalamus) may lead to anti-inflammatory signals, without initial involvement of immune mechanisms.
7. CIDS is an important, independent contributor to the negative outcomes of patients with brain injury.
8. Recognizing and understanding CIDS could lead to novel treatment strategies to improve outcome in patients with CNS injury.

THE NEURAL BASIS OF HUMAN MORAL COGNITION

From Nature Reviews Neuroscience 6, 799-809 (2005); doi:10.1038/nrn1768

Moral cognitive neuroscience is an emerging field of research that focuses on the neural basis of uniquely human forms of social cognition and behaviour. Recent functional imaging and clinical evidence indicates that a remarkably consistent network of brain regions is involved in moral cognition. These findings are fostering new interpretations of social behavioural impairments in patients with brain dysfunction, and require new approaches to enable us to understand the complex links between individuals and society. Here, we propose a cognitive neuroscience view of how cultural and context-dependent knowledge, semantic social knowledge and motivational states can be integrated to explain complex aspects of human moral cognition.

At a time of increasing awareness of the different value systems in multicultural societies and across nations, a deeper understanding of the cognitive and brain mechanisms that guide human behaviour is of general interest. Recent social cognitive neuroscience reviews have emphasized perceptual and emotional abilities that are shared by humans and other animals. However, social neuroscience has largely avoided dealing directly with the complex aspects of human moral cognition, including MORAL EMOTIONS and MORAL VALUES. Here, we review current theoretical accounts of social cognition and put forth a framework designed to overcome the main limitations of earlier accounts. We argue that moral phenomena emerge from the integration of contextual social knowledge, represented as event knowledge in the prefrontal cortex (PFC); social semantic knowledge, stored in the anterior and posterior temporal cortex; and motivational and basic emotional states, which depend on cortical–limbic circuits. Our framework offers new interpretations for social behaviour patterns in healthy individuals and in patients with brain dysfunction, and makes testable predictions for neuropsychological dissociations in moral cognition.

Characterization of the caspase cascade in a cell culture model of SOD1-related familial amyotrophic lateral sclerosis

From Neuropathology & Applied NeurobiologyVolume 31 Issue 5 Page 467 - October 2005

There is increasing evidence that apoptosis or a similar programmed cell death pathway is the mechanism of cell death responsible for motor neurone degeneration in amyotrophic lateral sclerosis. Knowledge of the relative importance of different caspases in the cell death process is at present incomplete. In addition, there is little information on the critical point of the death pathway when the process of dying becomes irreversible. In this study, using the well-established NSC34 motor neurone-like cell line stably transfected with empty vector, normal or mutant human Cu-Zn superoxide dismutase (SOD1), we have characterized the activation of the caspase cascade in detail, revealing that the activation of caspases-9, -3 and -8 are important in motor neurone death and that the presence of mutant SOD1 causes increased activation of components of the apoptotic cascade under both basal culture conditions and following oxidative stress induced by serum withdrawal. Activation of the caspases identified in the cellular model has been confirmed in the G93A SOD1 transgenic mice. Furthermore, investigation of the effects of anti-apoptotic neuroprotective agents including specific caspase inhibitors, minocycline and nifedipine, have supported the importance of the mitochondrion-dependent apoptotic pathway in the death process and revealed that the upstream caspase cascade needs to be inhibited if useful neuro-protection is to be achieved.

Sgk1, a cell survival response in neurodegenerative diseases

From Molecular and Cellular Neuroscience Volume 30, Issue 2 , October 2005, Pages 249-264

Serum and glucocorticoid-regulated kinase 1 (sgk1) belongs to a family of serine/threonine kinases that is under acute transcriptional control by serum and glucocorticoids. An expanding set of receptors and cellular stress pathways has been shown to enhance sgk1 expression, which is implicated in the regulation of ion channel conductance, cell volume, cell cycle progression, and apoptosis. Recent evidence for the involvement of sgk1 in the early pathogenesis of MPTP-induced Parkinson's disease (PD) prompted us to investigate in more detail its expression and role in animal models of different neurodegenerative diseases.

Here, we show that transcription of sgk1 is increased in several animal models of PD and a transgenic model of amyotrophic lateral sclerosis (ALS). The upregulation of sgk1 strongly correlates with the occurrence of cell death. Furthermore, we provide evidence that the Forkhead transcription factor FKHRL1 and some of the voltage-gated potassium channels are physiological substrates of sgk1 in vivo. Using a small interfering RNA approach to silence sgk1 transcripts in vitro, we give evidence that sgk1 exerts a protective role in oxidative stress situations.

These findings underline a key role for sgk1 in the molecular pathway of cell death, in which sgk1 seems to exert a protective role.

Clues To Parkinson's, Huntington's, And ALS May Be Found In The Walking Patterns Of Affected Mice

From Mouse Specifics, Inc. (MSI)

In a published report in the Journal of NeuroEngineering and Rehabilitation, scientists from Harvard Medical School and Mouse Specifics, Inc. (MSI) in Boston have characterized gait dynamics in mice with Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). Gait analysis is the process of quantification and interpretation of locomotion. In humans, gait analysis is widely used to quantify patients' movement disorders to provide diagnosis and treatment options. The distinct gait patterns of mice with Parkinson's, Huntington's, and ALS reflect impairment of specific neural pathways involved in the different aspects of the diseases, and provide the basis for testing new therapies.

Gait disturbances are characteristic of patients with Parkinson's disease, Huntington's disease, and ALS. Sudden falls due to unsteady gait are major hazards for the affected patients. Mouse models of these human diseases are essential to their understanding and treatment, yet gait disturbances in diseased mice are seldom described. The scientists from Harvard and MSI used a high speed digital imaging system and a recently patented treadmill with a transparent belt (The DigiGait™ Imaging System) to quantify gait indices in mice treated with toxins to mimic symptoms of either Parkinson's or Huntington's disease, and in mice genetically modified to replicate symptoms of ALS. As in patients, mice with Parkinson's and Huntington's disease exhibited less steady gait than healthy mice, with greater stride-to-stride variability of gait cycle timing. As in patients, upper limb dynamics were more variable in mice with Huntington's disease than in mice with Parkinson's disease. As in patients, gait variability was less disturbed in mice with ALS than in mice with Parkinson's. The altered gait dynamics in the different mouse models indicate that specific neural pathways are involved in the different observed gait pathologies.

"The ability to quantify and distinguish measures of 'walking' in mice with, say, Parkinson's disease and mice with Huntington's disease provides a new opportunity to zero in on the mechanisms underlying their distinct pathologies and characteristics," said Visiting Professor Ivo Amende, Medical University Hannover, Germany, lead author of the study. "Our hope is that gait analysis in mouse models of human movement disorders and neurodegenerative diseases will accelerate the development of drugs to prevent or reverse gait disturbances." The publication can be accessed via the Journal of NeuroEngineering and Rehabilitation website at http://www.jneuroengrehab.com/content/2/1/20 .

Molecule protects against developing Alzheimer's Disease

A molecule expressed by nerve cells may protect humans from developing Alzheimer's Disease (AD). In particular, it may reduce the risk of the formation of senile plaques in the brains of patients with AD, as researchers from the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch (Germany) and their collaborators in Denmark, Australia, and the USA have been able to demonstrate. The findings by Dr. Olav M. Andersen, Professor Thomas Willnow (both from the MDC) and Dr. Anders Nykjær (University of Aarhus, Denmark) have been published online in PNAS* (doi:10.1073).

A hallmark of Alzheimer disease are protein plaques in the brain which accumulate over many years. They are derived from the amyloid precursor protein (APP) which for unknown reasons is chopped up into smaller fragments, including the amyloid beta peptide, which forms these dangerous plaques. The plaques destroy the patients' nerve cells and lead to dementia, impairing the patients memory, thinking, and behaviour. According to the National Institutes of Health (NIH) more than four million Americans suffer from AD, an incurable disease.

The older one gets, the greater the risk of developing this disease. It is estimated that about half of the individuals over 85 years of age are affected. Professor Willnow and his colleagues were able to demonstrate that the molecule, named sorLa (abb. sorting protein-related receptor), binds to APP in nerve cells and thus prevents its dissection into the amyloid beta peptide. They could also show that genetically modified mice which cannot produce sorLA have increased levels of amyloid beta peptides because APP is destructed at a much higher rate than in healthy animals.

The researchers also looked at the brains of patients who died from AD and compared them with subjects who had not suffered from this disease. Surprisingly, the nerve cells of the AD patients had not produced sorLA, but the nerve cells of the control group had done so. The researchers conclude that in individuals whose brains produce little or no sorLA, the uncontrolled production of amyloid beta peptides likely accelerates onset and progression of neurodegenerative processes, making sorLA an important risk factor for AD.

Ongoing research is directed towards identification of substances that could increase the production of sorLA in the brain of those people that produce insufficient amounts of the molecule. The researchers hope that in the future it will be possible to pharmacologically reduce the formation of these dangerous plaques in the brain by modulating sorLA levels.

The most infectious prion protein particles

From Nature Volume 437 Number 7056 pp169-294

The prospects of limiting the spread of transmissible spongiform encephalopathies such as Creutzfeldt−Jakob disease depend in part on identifying the most infectious forms of the prions that carry the diseases. A study of modified scrapie prions shows that clusters of 14 to 28 prion proteins are the most infectious and that clusters of less than six molecules have virtually no infectivity. That could have implications for the treatment of diseases such as Alzheimer's and Parkinson's, characterized by deposition of prion-related amyloid fibrils. It's possible that efforts to alleviate symptoms by destabilizing these large protein aggregates might make things worse by producing smaller, more infective particles. Two other papers in this issue tackle fundamental aspects of the biology of prions and amyloid fibrils. The conversion of the yeast protein Sup35 to its prion form does not need to happen during the synthesis of Sup35 — mature and fully functional molecules can readily join a prion seed. This remodelling of the mature protein is accompanied by the immediate loss of its activity. And a study of a 'designed' amyloid fibril made from ribonuclease A reveals that amyloid containing native-like molecules can retain enzyme activity. This involves a domain swap with the neighbouring protein, and supports the 'zipper-spine model' for -amyloid structures.