Category Archives: Science News

Not Difficult To Grasp

Posted on May 16, 2012 by | Leave a comment

Paralysis can have tremendous negative consequences for a person’s quality of life.  In the US alone, there are more than 200 thousand people living with chronic spinal cord injury, which is a cause of immense suffering to them and their families.  The disease generates economic burden for society as well.   Thus, there has been a lot of interest in using our knowledge of how movement is coded in the brain to allow patients to bypass nerve injuries and communicate directly with the environment.  Moreover, when asked about their priorities in terms of regaining motor function the vast majority of patients rank regaining arm and hand function as most important.

It is thus encouraging to read in Nature today an update on how these efforts by scientists have allowed a paralyzed patient to reach for a cup, bring it to her lips, and drink from it.

Critical milestones in the development of motor prosthesis for paralyzed patients

As explained in a nice News and Views piece by Andrew Jackson that accompanies the article, this type of work builds on decades of previous research on the neural mechanisms that control arm movements (here, here and here) (blue on the Fig above), on the development of chronic multi-electrode arrays (orange), their recording properties in animals, and on feasibility studies of neural interfaces in monkeys (here, here, here and here) (green), which opened the way to clinical studies in humans (here and here) (purple).

The value of animal research should not be difficult to grasp. The knowledge that allows us to “read out” the planned movements of the patient from different brain regions in order to guide the movement of the robot is critical in the design of the system.  And it is an indisputable fact that such knowledge has been (and continues to be) obtained by experiments in awake, behaving monkeys.

And for those that doubt the true motivation of scientists for doing their work, it is worth noting what Dr. Leigh Hochberg (one of the leading authors of the study) had to say about their results – “The smile on her face … was just a wonderful thing to see.”   Do you want to see her smile too?  Watch this:

Of course the BrainGate system used by Dr. Hochberg and Dr. John Donoghue - director of the Institute for Brain Science at Brown University - is not the only brain-machine interface system under development to restore function in paralysis. In 2008 we wrote about a similar brain implant developed by Dr. Andy Schwartz at the University of Pittsburgh which enabled monkeys to manipulate robotic hands with unprecedented dexterity. Last year we wrote about how Dr. Schwartz’s team had used a different technology known as electrocorticography to enable a paralysed man to manipulate a robotic arm, while Dr. Chet Moritz and colleagues at Wachington National Primate Research Centre, have coupled readings from individual nerve cells to a technology called functional electrical stimulation to restore control to temporarily paralysed muscles in monkeys, an approach that may eventually supersede the use of robotic arms in some patients. It will be fascinating to watch this technology progress into more widespread clinical use over the next decade, and thrilling to think that, impressive as it appears today, we have barely begun to tap the potential of brain-machine interface technology to change lives.

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Frans de Waal’s Ethical Arguments Need Clarification

Posted on May 12, 2012 by | 2 Comments

In a recent perspective, Professor Frans de Waal argues that chimpanzees deserve “special moral status.”  The statement comes on the heels of a recent report by the Institute of Medicine who proposed strict criteria on the use of chimps on biomedical research.

According to de Waal there are compelling ethical reasons to ban all invasive work on chimps, but he argues that one should “not throw out the baby with the bathwater by also curtailing non-harmful behavioral research” as well.  He defines ethically permissible research in chimps as “the sort of research I would not mind doing on human volunteers.”

While Prof. de Waal ought to be applauded for sharing his views on the use of chimps in scientific research, I think he moves too fast through weak and vague ethical reasoning to reach his main conclusion.

Opponents of animal research, for example, are likely to point out his definition of ethically permissible research should read instead “the sort of research [one] would not mind doing on human volunteers who also agree to live in captivity in the same conditions as the chimps.” 

They will also point out that human subjects that volunteer in scientific research, whether invasive or behavioral, provide their informed consent.  Moreover, human subjects retain a right to withdraw their participation at any point in time, and they are never deprived from their liberties and freedom.  Opponents of research will further argue harm comes to these animals by the mere fact they are forced to live in captivity.

It is unclear how de Waal would defend his work from the stated position in his perspective. Perhaps the “special moral status” de Waal wants to grant to chimps and other great apes is not meant to be interpreted as including the same basic rights to liberty and freedom as those enjoyed by humans.  If so, he should state this clearly.  His position is vague and confusing because in the same perspective he seems to approve some countries granting great apes legal rights.

There are other problems that emerge from de Waal ill-articulated ethical position.  He states the basis for awarding great apes special moral status is based on their high cognitive skills, as well as their capacity to display empathy and pro-social behavior. At the same time he believes the same intrinsic properties are present in varying degrees in other species – “there are many differences between chimps and monkeys in cognitive capacities, but we consider them mostly gradual differences.” Given such graded abilities it is not clear how de Waal would draw a line between those species that deserve such “special moral status” and those that do not.  Or if there are other morally relevant properties that he did not mention.

Finally, I think de Waal correctly points out that humans should not be allowed to blame nature to explain our history of violence, warfare, and male dominance.  The reason is that only humans are capable of reflecting on the question of how is that we should treat others, including non-human living beings.  Yes, we have a moral obligation to consider the interest of other living beings in our actions.  But, as Carl Cohen explained, we should not confuse our moral obligations to other living beings with them having basic rights. Rights entail obligations, but the reverse is not always true.

There is wide agreement (and I concur) that the interests of great apes deserve high moral consideration, more so than those of a mouse or a worm. But it is worth noting that such principle of graded moral status is already implicitly acknowledged in the NIH guidelines which require scientists to use the “lowest” possible species that can yield the information they seek.  In this regard, the IoM panel finding that there is only a minimal need to use chimps in scientific research is not a truly reflection of their inadequacy to model disease (chimps could certainly be used in many studies to answer good scientific questions), but of our existing recognition that they deserve high moral status and that they can only be used under the most  extreme circumstances.

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Polycystic Ovary Syndrome: Lessons From Monkeys

Posted on May 7, 2012 by | 1 Comment

The following guest post is from David Abbott, a scientist at the Wisconsin National Primate Research Center and Professor in the Department of Obstetrics and Gynecology at the University of Wisconsin-Madison.  Professor Abbott recently spoke about the goals of his work and the use of monkeys in research in a public forum series hosted by the university.  The talk was followed by a panel discussion that included a clinician who treats girls with PCOS and Jon Levine,  director of the WNPRC.

David Abbott

I am a scientist leading a biomedical research program investigating the causes of polycystic ovary syndrome (PCOS) in women. I see a balanced consideration at the heart of the argument concerning our humane use of about 200 female rhesus monkeys in experimental procedures over the past 20 years in the service of reducing suffering in approximately 15 million American women who endure PCOS. Our systematic and responsible experimental investigation, which was approved after a thorough ethical evaluation by a University of Wisconsin Institutional Animal Care and Use Committee (IACUC), was the first to conclusively identify developmental origins for this women’s health disorder. It is also the first to provide epigenetic molecular insight into potential mechanisms underlying PCOS that can be targeted by future preventive therapies.

PCOS is one of the most common health disorders affecting women. The PCOS ovary makes too much testosterone and supports increased hair growth on the face and body. The enlarged ovary also grows too many egg-containing follicles, thus providing the enigmatic appearance of the polycystic ovary. PCOS follicles usually fail to mature and frequently fail to release an egg at ovulation, hence the lack of menstrual cycles and infertility associated with the disorder. In addition, PCOS overly contributes to obesity, new cases of type 2 diabetes among young women, gestational diabetes, sleep apnea and metabolic syndrome. All of these increase a woman’s lifetime risk of cardiovascular disease. In the words of leading clinical experts in the field:

It has become increasingly clear over the past several years that PCOS is a complex genetic disease resulting from the interaction of susceptibility genes and environmental factors. The insight that prenatal exposure to androgens can reproduce most of the features of the human syndrome in primates has led to a paradigm shift in concepts about the pathogenesis of the disorder.”1

Our PCOS-like monkeys provide insight into a potential origin for PCOS in women: exposure to too much testosterone during fetal life. This insight cannot be ethically gained from experimentation in humans. The inspiration to explore a fetal origin for PCOS, however, does come from humans. PCOS runs in families. Daughters born to women with PCOS are at increased risk for PCOS. So, I posed the question:  What if excess testosterone production, a hallmark of PCOS and its most heritable trait, is its cause? In other words, could too much testosterone produced by the fetal PCOS ovary reprogram multiple female organ systems as they develop, so that when mature, such widespread organ system dysfunction manifests the abnormalities we know as PCOS? Circumstantial evidence from genetic or tumor anomalies in humans indeed suggests that exposure of fetal girls to excess testosterone, alongside other abnormalities, results in PCOS. Humans, however, cannot ethically be used to test the hypothesis that fetal testosterone exposure, alone, causes PCOS.

A population of female rhesus monkeys housed at the Wisconsin National Primate Research Center at the University of Wisconsin, Madison, held the key to testing this possibility. Between about 1970 and 1985, these otherwise normal female monkeys were exposed to fetal male levels of testosterone during gestation when their mothers were given testosterone conjugate as part of other studies. Independent of this work, I collaborated with an Ob/Gyn specialist, as well as scientists from a variety of biological science disciplines, in a multidisciplinary research approach to examine whether testosterone-exposed female monkey offspring exhibit PCOS traits in adulthood. We proposed controlled and systematic experimental approaches in grant submissions to the National Institutes of Health, who funded this research.

Our work demonstrated that the ovaries of adult female monkeys exposed to testosterone during fetal life produce too much testosterone and, when enlarged, such ovaries grow too many follicles. The testosterone-exposed monkeys also ovulate infrequently, leading to intermittent or absent menstrual cycles. Eggs retrieved from the ovaries of testosterone-exposed monkeys, when fertilized in vitro, show impaired embryonic development. These results from monkey studies led to a human study that demonstrated eggs retrieved from the ovaries of PCOS women had altered gene expression. This was an unappreciated PCOS defect and provided an unexpected mechanism by which PCOS-related abnormalities could be passed from one human generation to the next.

Perhaps the most translatable lessons from the testosterone-exposed monkeys came from examination of their metabolic abnormalities. We found many of the metabolic derangements accompanying PCOS in women, including insulin resistance, impaired insulin response to glucose, type 2 diabetes mellitus (T2DM), hyperlipidemia and increased abdominal fat. As in PCOS women, monkey insulin and glucose impairments were reversed after six months of daily treatment with the insulin sensitizer pioglitazone. The insulin sensitizer approach was so successful that the Primate Center adopted it as the first treatment for all monkeys that developed T2DM naturally since this is known to accompany obesity and aging in monkeys, as well as in humans. Insulin sensitizer treatment of testosterone exposed monkeys also allowed us to normalize their menstrual cycles, demonstrating that insulin is involved in suppressing ovulatory cycles, which also occurs in PCOS women. Thus not only did fetal testosterone exposure create a remarkable mimic of PCOS in monkeys, it emulated a key part of the pathophysiological mechanism found in women with the disorder.

The close replication of PCOS in monkeys prompted examination of what occurs during fetal and infant development before adult PCOS traits emerge, which opens the way to earlier targeting of treatment in humans. We found that testosterone injections given to pregnant monkey mothers actually impaired their ability to regulate blood glucose. In addition, the fatter the monkeys were before they conceived, the more susceptible they were to testosterone diminishing insulin regulation of glucose during pregnancy. As in humans, maternal inability to regulate blood glucose results in increased fetal exposure to glucose and increased fetal and neonatal growth. The infant monkeys previously exposed to testosterone and high glucose as fetuses exhibit high insulin responses to glucose that will likely cause insulin-induced accumulation of fat and muscle and relatively fat offspring beyond their heavier infant weight. Since these infants also have elevated androstenedione levels, reproductive- and metabolic-related antecedents of PCOS in monkeys are pronounced from birth. These findings encourage clinical studies aimed at establishing childhood biomarkers for subsequent adult PCOS, especially since PCOS mothers taking the insulin sensitizer metformin before and during pregnancy give birth to daughters who do not go on to develop ovarian hormonal abnormalities at 2-3 months of age.

More recently, with mapping of the rhesus monkey genome and collection of intra-abdominal (visceral) fat samples from infant and adult monkeys exposed to testosterone as fetuses, we quantified how fetal programming changed the methylation patterns of gene promoter sites, and thus increased or decreased relevant genes expression in a fat depot intimately involved in controlling insulin regulation of glucose. Pathway and network analyses revealed commonalities in changed DNA methylation between infants and adults, implicating altered signaling of transforming growth factor beta (TGF-beta) in determining PCOS-related traits. This is an exceptionally relevant molecular result because a gene variant determining a component of TGF-beta signaling, known as fibrillin 3, has been repeatedly associated with PCOS in women. Fibrillin 3 is also only prominently expressed in human ovaries at a gestational age equivalent to the age at which our monkeys were exposed to testosterone. One aspect of testosterone (and glucose) mediated changes in gene expression in monkeys may therefore provide a molecular mimic of the gene variant associated with PCOS in women. Such molecular mimicry establishes testosterone-exposed monkeys as unparalleled models for establishing preventative therapies targeted at PCOS.

Subsequent testosterone exposure studies on mice, rats and sheep by other scientific teams, undertaken because of the monkey results, emulate some or most of our original findings. While non-primate studies consolidated fetal testosterone exposure as an origin for PCOS traits in adulthood, they also caused fetal growth restriction, something that is not common in women with PCOS and is not found in testosterone exposed monkeys. Fetal growth restriction is caused by diminished placental supply of nutrients and leads to adult metabolic disease distinct from that of PCOS. Testosterone exposed monkeys are thus the most human-like animal model for PCOS and provide an established biological platform for therapy directed studies.

The insight thus gained into developmental programming of PCOS in approximately 15 million women in the US from over 20 years of humane, controlled and systematic use of about 200 rhesus monkeys is substantial and unique. Monkeys are such close human relatives that they best enable translation of research findings into human application. In our case, they permit exploration of insulin regulating therapies during pregnancy, such as metformin, as potential preventative therapies and they permit evaluation of consequences for offspring development, as monkey gestation and infant and juvenile development closely emulate the human. The quality of the scientific findings yielded by our studies was made possible by the highest standards of veterinary care, animal husbandry, nutrition, social housing and environmental enrichment that permit our monkeys healthy and well-cared for lives. Our research program is a humane and considered use of monkeys in the service of reduced suffering in women.

David Abbott, Ph.D.

Department of Ob/Gyn and Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI

1 Dunaif A, Chang RJ, Franks S, Legro RS. 2008. Polycystic Ovary Syndrome. Current controversies, from the Ovary to the Pancreas. Pp. vii. Humana Press, Totowa, NJ.

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OHSU Rhesus macaque embryo research to improve Preimplantation Genetic Diagnosis

Posted on May 4, 2012 by | Leave a comment

Preimplantation Genetic Diagnosis is used by parents to screen embryos produced through in-vitro fertilization (IVF) in order to ensure that the baby will be free of specific genetic diseases.  New research from Oregon Health and Science University on the inheritance of the mitochondrial genome indicates that screening for genetic mutations that are located in the genome of the mitochondria – which is outside the nucleus of the cell where the much larger chromosomal genome id found, and is inherited only from the mother – can be made more accurate by carrying out the screening procedure slightly later than is now the practice.

Dr. Shoukhrat Mitalipov, who led this research project, explains what the project involved and its implications

A press release from OHSU highlights the importance of the Rhesus macaque to this discovery about the inheritance of mitochondial genomes:

“This latest breakthrough, which was conducted in rhesus macaque monkeys because of their similarity to humans, demonstrates the specific stage of early embryonic development when genetic mutations are passed from mother to fetus. This stage, referred to by scientists as “the bottleneck,” occurs when an early embryo called blastocyst, transitions into a fetus.

To conduct the research, Mitalipov and colleagues needed to design a way to mark and track specific mitochondrial genes as they transitioned from egg, through fertilization, to embryo and then to fetus. This was accomplished by combining two separate mitochondrial genomes into one egg cell. More specifically, one-half of an egg cell from a species of Indian-continent rhesus macaque monkey was merged with one-half of an egg cell from a Chinese-continent monkey. Because these animal species have distinct mitochondrial gene sequences (like breeding two distinct species of dogs), their genetics could be tracked closely.

The microscopic manipulation of splitting and uniting two halved egg cells takes specialized skills and expertise, which the Mitalipov lab has developed over a period of several years.

By studying the development of these joined and then fertilized eggs, scientists were surprised to see that eggs transitioned from containing a 50/50 split of genetics to a fetus that contained a nearly 100 percent either Indian or Chinese-based genome.

 We discovered that during early development, each individual cell in the eight-cell embryo would contain varying percentages of the Indian and Chinese rhesus genes. Some would be a 50/50 split. But others would be 90/10 and so on,” explained Mitalipov. “When these percentages were combined as a whole embryo, the average genetic split between the two species was about equal as initially created. However, later during the transition from a blastocyst to fetus, the genetics would swing one way or another. The resulting offspring would have always a genome that is predominantly Chinese or Indian. Our study tells us precisely when this mitochondrial gene switch occurs and how this can lead to disease.”

This finding raises significant questions about validity of currently methods for genetic diagnosis in early embryos, when a woman is known to carry a mitochondrial gene mutation may pass a disease to her children.

The current pre-implantation genetic diagnosis method is to examine genetic disease risk is by taking one cell from an early eight-cell embryo, and then looking for mutations in that one particular cell. This is done to predict if the remaining embryo is mutation-free,” explained Mitalipov.

The problem with this approach is that you may choose a cell that may not have mutations. But that does not mean the remaining cells in an embryo are mutation-free. Our research suggests that such approach could be flawed because diagnosis takes place prior to the stage when an offspring’s mitochondrial genetics is truly established.”

With this new information and with additional data gathered through further research, Mitalipov and colleagues believe that new methods for genetic diagnosis for mitochondrial disease should be located. The research also demonstrates that the Mitalipov lab’s previously developed method for preventing the passing of mitochondrial mutations from mother to child is highly successful.”

It’s an important discovery, one with important implications for preimplantation genetic diagnosis, and we congratulate Dr. Mitalipov and his colleagues at OHSU on their success!

Lee, H., Ma, H., Juanes, R., Tachibana, M., Sparman, M., Woodward, J., Ramsey, C., Xu, J., Kang, E., Amato, P., Mair, G., Steinborn, R., & Mitalipov, S. (2012). Rapid Mitochondrial DNA Segregation in Primate Preimplantation Embryos Precedes Somatic and Germline Bottleneck Cell Reports DOI: 10.1016/j.celrep.2012.03.011

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What GM mice can tell us about pancreatic cancer (and medical charities)

Posted on May 1, 2012 by | 1 Comment

I’ve written on the growing importance of genetically modified (GM) mice in cancer research before, but it’s been a little while since I revisited the subject. So when I saw this BBC story yesterday on how scientists at the Cancer Research UK Cambridge Research Institute has used an elegant study in GM mice to identify a gene whose suppression contributes to the development of pancreatic ductal adenocarcinoma – one of the most lethal cancers – I was all set to write a blog post about it.

Then I noticed that Kat Arney at the Cancer Research Science Blog had beaten me to it, with an excellent overview of the study and its implications. I recommend that you go straight over and read her blog post.

The Nature paper describing this study can be read here.

A fascinating aspect of this work is that human genetic studies had failed to reveal the role of the Usp9x gene in pancreatic cancer, and it was only when the GM mice studies were undertaken that its importance became clear.  Does this mean that the human genetic studies were misleading? Does it mean that they were useless? Well, that would be thinking like an anti-vivisectionist.  While it’s true that the human genetic studies were initially misleading about Usp9x in pancreatic cancer, it was by combining the information from human genetic studies with that from the GM mouse studies, and the additional information from in vitro studies, that the mechanism through which Usp9x suppression contributes to the development of pancreatic cancer was revealed.

This is yet another example of the important role played by animal studies alongside  many other approaches in medical research, and I hope that it soon leads to much -needed improvments in therapy for pancreatic cancer.

There’s another aspect to this story that is almost as interesting as the science itself.  Many animal rights activists like to claim that leading medical research charities conceal their funding of animal research, indeed just the other week the animal rights activist Peter Tatchell wrote a truly execrable article in the Huffingdon Post which included the claim that:

A disturbing desire for secrecy about animal experiments is shared by a number of respected, high-profile medical charities, including the British Heart Foundation, Cancer Research UK and the Alzheimer’s Society. “

Several comments quickly pointed out that this (along with most other aspects of the article) was factually incorrect, indeed it is difficult to see how the British Heart Foundation could be more open about their animal research. So far as Cancer Research UK is concerned, perhaps somebody should ask Peter Tatchell how issuing a press release, and then discussing their animal research with the BBC and in more detail on their science blog is compatible with “desire for secrecy about animal experiments “.  I guess that Peter Tatchell isn’t one to let the facts ruin a good spin!

Paul Browne

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The Golden Goose Awards

Posted on April 30, 2012 by | Leave a comment

Politicians sometimes deride research based on the what they perceive as being “silly” titles of federal funded grants.  If they spot a title that deals with “games”, for example, they may assume it deals with some sort of amusement of little value to society, instead of a deep, powerful branch of mathematics that describes the behavior of competing rational agents with much relevance to voting, economics, cooperation, and so on.  Animal rights activists also enjoy the hobby.  The latest example is IDA’s list of “ridiculous research” ,whose claims were sadly repeated by far too many news journalists who were clearly too lazy check if they were accurate.  There were some honorable exceptions, notably an excellent editorial entitled “When the facts ruin a good spin” in the Times Union, which discusses a project on the role of music as a conditioning stimulus for drug use ends with a statement with which we heartily agree:

What’s “ridiculous,” to borrow the press release’s language, is that we fall for it, over and over, egged on by politicians eager to score easy points. And what’s “wasteful” is the time and energy that could be so much better spent on something other than a cheap shot.”

Back in 1976 the House Committee on Appropriations asked the National Science Foundation “Why does the Foundation persist in supporting research whose results have no apparent value to the American people?“  The NSF responded in part that:

Basic research seeks an understanding  of the laws of nature  without  initial  regard  for specific  utilitarian  value. Ultimately, however, it  is of the  most important  practical significance, because in a broad sense it is the foundation upon  which rests  all technological development.  Applied research builds on the results of basic research, seeking detailed  information  about  a specific situation  whose general laws have  been  discovered by  basic  research.  The  final step  toward  utilization  of research-development is  the systematic  application  of knowledge to  the  design  of  end products. [...]

As we  increase  our  knowledge  of nature  and  mankind,  in order  to adjust  nature  to our survival, safety,  comfort and convenience, we must  depend  upon  scientific research  to clarify the  relationships  of many, many things.  Thus,  we study  atoms,  even  though  they  will never  be seen  by an  unaided  human  eye.  We study  stars  too  faint  to  be  seen without  a  telescope  and  with  wavelengths  which  can  only be  detected  with  radio  receivers  or  photographic  plates. To  understand  geology, we must  look  at  geologic formations  and processes in many  parts  of the world where different  conditions have existed.  To understand  more about the  phenomena  of life, we must  study  the  behavior  of viruses,  single  cells,  plants,  and  animals  of  many  species.

A book was compiled covering various areas of research with Isaac Asimov writing an essay defending the value of basic research.

Thus, it was with some surprise and delight that we read in the news about Rep. Jim Cooper (D-Tenn) understanding the value of basic research.  The Washington Post reports that:

On Wednesday afternoon, Cooper rose to the defense of taxpayer-funded research into dog urine, guinea pig eardrums and, yes, the reproductive habits of the parasitic flies known as screwworms–all federally supported studies that have inspired major scientific breakthroughs.

Together with two colleagues he created the Annual Golden Goose Awards to honor federally funded research  “whose work may once have been viewed as unusual, odd, or obscure, but has produced important discoveries benefiting society in significant ways.”

Studying dog urine, among other stuff deem crazy by animal rights cranks, led to major medical discoveries

The article goes on to describe how research on dog urine led to an understanding of the effects of hormones on the human kidney, how studies in the guinea pig led to a treatment for hearing loss in infants, and how studies on the screwworm led to the effective control of the a deadly parasite that targets cattle.  All these provide additional examples refuting the notion that learning about life processes from animals cannot yield knowledge applicable to human health.

The Golden Goose Award has the backing of the American Association for the Advancement of Science, Association of American Universities (who in 2011 published a series of “Scientific Inquirer” articles skewering dubious politically-motivated attacks on basic science) and the Progressive Policy Institute, who are to be congratulated for this excellent initiative to highlight the importance of basic research.

At the press conference to launch the award Rep. Robert Dold told reporters that “When we invest in science, we also invest in jobs. Research and development is a key part to any healthy economy,” while  Rep. Charlie Dent (R-Penn.) added “It’s critical, and the federal government has an important role to play,” who went on to describe how injecting horses with snake venom might “seem peculiar” but led to the discovery of the first anti-venom.

Taking us, once again, to the concluding words of Asimov’s essay:

Unless we continue with science and gather knowledge, whether or not it seems useful on the spot, we will be buried under our problems and find no way out.  Today’s science is tomorrow’s solution — and tomorrow’s problems , too — and, most of all, it is mankind’s greatest adventure, now and forever.

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Restoring vision in night blindness: Mice point way to stem cell therapy

Posted on April 27, 2012 by | Leave a comment

Impaired vision and blindness are leading causes of disability, affecting over 3 million people in the USA today, so it’s no surprise that biomedical scientists are working hard to develop therapies to improve and restore vision.  Over the past few years we have discussed several therapies that have been developed to treat different types of vision loss, including anti-angiogenic therapies to treat wet age related macular degeneration, a leading cause of severe, irreversible vision loss in the elderly,  and gene therapy to treat Leber congenital amaurosis, an inherited disease characterised by progressive degeneration of the retina. Speaking of Research committee member Dario Ringach has also written on the Opposing Views website on the very promising research now underway to develop electronic prosthesis to restore vision in blind people.

In another important development in this field Professor Robin Ali* and his team at the UCL Institute of Ophthalmology have announced the first demonstration that transplanted retinal rod cells can improve vision in mice with night-blindness, publishing the results of their study in the prestigious science journal Nature1. Rod cells are photoreceptor cells in the retina of the eye that function well in low light conditions, and an absence of rod cells leads to night blindness. Mutations in the gene GNAT1 cause congenital night blindness in humans, and mice in which the Gnat1 gene has been knocked out are night blind.  In the video below Professor Ali show that by transplanting rod cell precursors into the retina of Gnat1 knockout mice his team was able to restore vision – albeit  not fully.

It’s a fascinating piece of work, though as Professor Ali makes clear in comments to the Guardian newspaper last week there is still a lot of work to do before this can be evaluated in humans.

Now we’ve discovered we can restore vision, it gives us impetus to go on and make the process better”

As both the video and Guardian article indicate an important step will be identifying suitable sources of cells for transplantation, with both embryonic stem cells and induced pluripotent stem (iPS) cells under consideration.  This may not take as long as one might think, as we discussed last November a clinical trial was recently launched to assess the potential for transplantation of another retinal cell type, retinal epithelial cells derived from human embryonic stem cells , to improve vision in patients with  Stargart’s Macular Dystrophy, an inherited form of blindness.

The work of Professor Ali and his colleagues at UCL is moving us closer to an effective treatment – and perhaps it is not unrealistic to talk about a cure – for night blindness. Their work will also no doubt drive research on protoreceptor cell transplantation in other forms of blindness, such as dry age related macular degeneration – the most common cause of vision loss in people aged over 50 – which is characterised by loss of both rod and cone photoreceptor cells.

Paul Browne

*        Professor Ali also played a leading role in the development of gene therapy for Leber congenital amaurosis, and led the first clinical trial of this technique.

1)      Pearson RA, Barber AC, Rizzi M, Hippert C, Xue T, West EL, Duran Y, Smith AJ, Chuang JZ, Azam SA, Luhmann UF, Benucci A, Sung CH, Bainbridge JW, Carandini M, Yau KW, Sowden JC, Ali RR. “Restoration of vision after transplantation of photoreceptors.” Nature. 2012 Apr 18. doi: 10.1038/nature10997.

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Mouse study points to effective treatment of Fragile X syndrome

Posted on April 18, 2012 by | 2 Comments

Fragile X syndrome is the most common genetic causes of intellectual disability, affecting about 1 in 4,000 people with more males affected than females, and also the most common genetic cause of autism, being responsible for 2-6% of all cases of autism. While no drugs have yet been approved to treat Fragile X syndrome, there is considerable interest in the biomedical research community in this condition, since as well as being a significant cause of disability in its own right it is a condition whose study may well help medical science to develop effective therapies for other forms of autism.

GM mice have made crucial contributions to our understanding of Fragile X syndrome. Image courtesy of Understanding Animal Research.

Fragile X syndrome is caused by mutations that silence the Fragile X (FMR1) gene and lead to a reduction –or absence – of the fragile X mental retardation protein (FMRP) and by knocking out the corresponding Fmr1 gene in mice and other organisms scientists have been able to generate models for the evaluation of potential therapies for autistic spectrum disorders , such as the drug Arbaclofen whose development we discussed briefly in 2010.

While it was clear quite early on that FMRP plays an important role at the synapse  – the structure that allows nerve signals to be passed from one neuron to another  – the nature of that role was not obvious, though a series of experiments in a variety of animal models had indicated that a class of proteins known as the metabotropic glutamate receptors might be involved.  A key discovery was made by Professor Mark Bear at MIT, who demonstrated that FMRP acted as a counterbalance to metabotropic glutamate receptor sub-type 5 (mGluR5). mGluR5 increases protein synthesis at the synapse as a means to facilitate signal transmission through the brain, and FMRP acts to reduce protein production. In the absence of FMRP signaling at the synapse goes awry, leading to the symptoms observed in fragile X syndrome.  This key scientific breakthrough was made by Prof. Bear by genetically engineering Fmr1 knockout mice halve the production of mGluR5, resulting in a significant reduction in fragile X symptoms in these mice. This linking of alteration in the expression of the gene to changes in fragile X symptoms was an important result, indicating that it may be possible to treat Fragile X by reducing the amount or the activity of mGluR5.

However, using gene modification to knock-down mGluR5 activity in people with Fragile X syndrome is not a practical option at this time, so attention turned to identifying drugs that could block mGluR5.  Last week in a paper in the journal Neuron Prof. Bear’s team, working in collaboration with scientists at the Swiss healthcare company Roche ,announced another major breakthrough. This study used an experimental  mGluR5 inhibitor known as CTEP which had recently been shown in animal studies  to be far more selective for mGlu5 than previous mGluR5, as well as having a longer half-life in vivo making it an ideal candidate for studies where mGLuR5 activity needed to be suppressed for extended continuous periods. They showed that CTEP treatment could not only stop the worsening of the condition but actually reversed the symptoms in FMR1 knockout mice with established Fragile X syndrome (1), including hearing sensitivity, learning and memory, suggesting that the defects in Fragile X syndrome are not irreversible and that it may be possible to effectively treat the cognitive and behavioral disabilities by pharmacological inhibition of mGluR5.

While CTEP is not currently being developed for clinical use, the result of this trial adds further weight to the evidence in favor of mGluR5 inhibition as a means to treat Fragile X syndrome. Two other mGluR5 antagonists – Fenobam and STX 107 – are already being evaluated in early clinical trials following successful evaluation in Fmr1 knockout mice, and this most recent result should encourage further investment in this approach.

The discovery that symptoms can be reversed in established disease in a model of Fragile X syndrome that accurately models the disorder in humans is a major advance, suggesting that the impairments associates with autistic spectrum disorders may not always be permanent  – a result with profound implications for the future of treatment of these disorders.

Paul Browne

1)      Michalon A, Sidorov M, Ballard TM, Ozmen L, Spooren W, Wettstein JG, Jaeschke G, Bear MF, Lindemann L. “Chronic Pharmacological mGlu5 Inhibition Corrects Fragile X in Adult Mice.” Neuron. 2012 Apr 12;74(1):49-56. PubMed 22500629

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