Part I
Part II
Part III

The current standard of pediatric care mandating that all newborns undergo hearing screenings has been applied successfully throughout much of the industrialized world. Early identification of hearing impairments gives valuable lead-time to parents and health care providers during which they can plan medical and educational interventions to improve the child’s development, acquisition of language skills, and general quality of life.

Up to 12% of children born with hearing loss have Usher syndrome. However, diagnosing Usher syndrome as distinct from various forms of congenital hearing impairment is often impossible until the onset of retinal degeneration years later. The considerable number and size of the genes involved makes genetic screening impractical with the current methods, unless there is a family or community history that can shorten the list of targets by implicating a particular Usher gene or subtype.

The educational and medical interventions undertaken to improve a deaf or hearing-impaired child’s cognitive and social development can vary extensively, based in part on whether the child in question is expected to lose his or her vision later in life. Thus an earlier diagnosis of Usher syndrome is an immediate and critical research goal. The most imminent hope for such a diagnostic advance lies in gene chip screening. With this technology, the patient’s DNA can be screened against a microarray of human genes known to cause deafness (and/or Usher syndrome) when mutated, and variances in the DNA sequence of any screened gene would be detected and analyzed. One such chip is already available for commercial use, and another appears to be approaching clinical availability. The rapid and affordable analysis these microarrays offer will be of tremendous benefit in the early diagnosis and management of Usher syndrome.

In spite of the considerable amount of information about the pathophysiology of Usher syndrome obtained over the past 10 years, there are, as of yet, no clinically applicable treatments targeting the molecular underpinnings of the disease. Following the diagnosis of hearing impairment in a child, the parents may consider hearing aids or, in cases of profound hearing loss, a cochlear implant. The timing of the installation of these devices is critical, as speech development can be significantly impacted if the child does not begin to hear and reproduce spoken sounds in the first few years of life.

Hearing aids, which amplify sound, are appropriate in cases of moderate hearing loss, where hair cell function is only partially impaired, or where more severe hearing loss is restricted to a certain frequency range. In cases of severe to profound sensorineural deafness, as is the case in type 1 Usher syndrome, traditional hearing aids are ineffective. Cochlear implants are surgically placed devices that can substitute to some degree for defective hair cells. An externally worn processor converts the sound signals it receives into electrical impulses and transmits them to the auditory nerve, via electrodes threaded through the cochlea. Here’s a short video of the placement and mechanism of action of this device:

And here is a link that contains several MP3 files simulating how different types of auditory stimuli–speech and music–might sound through a cochlear implant.

The technology of cochlear implants has steadily improved since their introduction, but the device was not initially met with unmitigated approval. Some members of the deaf community have expressed reservations about cochlear implants, as many believe that deafness, and the subsequent requirement for non-verbal forms of communication, are not defects in need of repair. Although this opposition has lessened somewhat in recent years, parents facing these choices can still sometimes receive conflicting advice about cochlear implants. Clearly, the cultural identify of the deaf community is important to consider, but the knowledge that a hearing impaired child will suffer from progressive vision loss later in life could have a considerable impact on the decision to initiate education in a highly visual form of communication rather than undergo the cochlear implantation. Communication options for Usher patients without cochlear implants include tactile signing, in which ASL signs are executed while touching hands, or traditional ASL conducted in close proximity to the deaf-blind individual, within his or her narrow field of vision, with consideration for contrasting background colors so that the signer’s hands are easily visible against his or her clothing.

There is no treatment for the progressive vision loss in Usher patients. The first sign of a vision problem usually occurs when patients report difficulty seeing at night–a symptom that rod photoreceptor loss in the periphery of the eye is already underway. Further degeneration occurs from the periphery inward, resulting in an increasingly restricted visual field. The rate of retinal cell loss is monitored through regular ophthalmological examinations, and although supplementing the diet with DHA, the well known Omega-3 fatty acid, appears to slow the progression of photoreceptor degeneration in a number of retinal diseases, including Usher syndrome, there are no preventative or curative therapies available.

Currently, the most tractable research toward finding a treatment for the retinal disorder focuses on gene replacement therapy. There have been encouraging results using viral vectors to deliver functional copies of the myo7a gene into retinal cells of myo7a mutant mice, and the use of nanoparticles as a delivery system should provide another fruitful avenue of research. The progressive nature of the retinal degeneration in Usher patients lends itself to the application of such treatments. In principle, an effective therapy initiated early enough could begin rescuing photoreceptors from dysfunction and eventual death prior to the onset significant vision loss, further underscoring the importance of developing methods for early diagnosis.

Discovering more about where and how the Usher proteins function in the eye will be important in determining the optimal target for gene replacement therapy, and animal models of the disease will continue to be indispensible both for basic study of the molecular and cellular physiology of Usher syndrome as well as for the testing of new therapies in preparation for clinical trials.

Remember that execrable HHS policy document that proposes an extension of the current protections for health care workers who refuse to provide or assist in treatments that they personally find morally objectionable? I did a little back-tracking on this issue, and followed the trail of HHS Secretary Mike Leavitt, who requested this regulation after a “disappointing” interaction with the American College of Obstetricians and Gynecologists. He has since been unwavering in his support of the proposal–which he claims is not about abortion OR contraception, but about conscience rights–and has a recent blog post responding to the feedback he’s received from pro-choice activists as a result of the leaked document.

Here’s the money quote:

Is the fear here that so many doctors will refuse that it will somehow make it difficult for a woman to get an abortion? That hasn’t happened, but what if it did? Wouldn’t that be an important and legitimate social statement?

“Social statement?” I can scarcely get my mind around the fact that he is so openly, unapologetically endorsing a policy in which pious opinion would trump secular law. Once again, though, it shouldn’t be a surprise. After all, he himself states that “The Bush Administration has consistently supported the unborn”. Ah yes, even as they indiscriminately leech the quality of life (if not the life itself) from countless other self-aware, functioning humans on the planet, each and every blastocyst they encounter is ceremoniously wrapped in a mantle of sanctimonious protection.

Somehow even more disheartening are the numerous fawning, unctuous comments on Leavitt’s recent blog entry. One wrote:

Secretary Leavitt,

It is beyond my comprehension that anyone would be offended by a health care professional who valued human life. But the tragedy is our culture has regressed to a form of barbarism unseen in centuries where progress in technology and science has poisoned our minds, hearts and souls where the intentional destruction of innocent and vulnerable human life has become more important than saving it.

Those of us living and working in a society where human life is expendable by government dictate but fail to stand up to protect and cherish life at any and all costs will live to regret it.

You are doing the right thing Secretary by allowing those of us in the health care profession live our moral and ethical consciences rather than forcing us to choose another profession.

Choose another profession like….a PETA supporter working in a meat packing plant?An auto mechanic who doesn’t support the use of fossil fuels?

Keep your eyes on this one. It has ‘lame duck’s parting shot’ written all over it.
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UPDATE: Leavitt has a new blog entry up today announcing that the proposed rule is being filed in the Federal Register. Although the final draft no longer contains the specific language broadening the definition of “abortion” to include anything from “conception” onward, it still threatens to withhold Federal money if health care organizations don’t allow their employees to exercise their rights of conscience.

“Do you believe God’s intervention could save a family member even if doctors say treatment would be futile?”

Naturally, ‘God’ is an assumed reality in this scenario. Go crash that bastard.

~Danio

The time has come to delve into the retinal component of Usher syndrome. In Part II, I briefly described the results of protein localization studies, in which most members of the Usher cohort were found at the connecting cilium of the photoreceptor and at the photoreceptor synapse. The following diagram summarizes these findings:

Usher protein localization in photoreceptor cells. From Reiners, et al. 2006

So, as we saw in the ear, proteins with the equipment for physically interacting with one another are gathering in specific places, and thus multi-protein complexes are likely being formed at these locations. The cluster of Usher proteins around the connecting cilium has been the focus of most of the current retinal studies, and to understand the potential importance of an Usher complex at that subcellular location we must address the importance of the connecting cilium itself.

Recall the structure of the photoreceptor cell described in Part I. The inner segment, just above the nucleus, contains all the standard-issue cell operating equipment–organelles required for producing protein, degrading cellular waste products and performing various other metabolic functions. The outer segment contains the intricately folded membrane discs with which light sensitive molecules are associated. Between these two cellular compartments lies the connecting cilium, which grows out of the inner segment, extends up into the outer segment, and is surrounded by a structure known as the periciliary ridge, which encircles the cilium like a little cuff. The cilium serves as a functional connection between the inner and outer segments, as well as a structural one. Proteins and other cellular materials synthesized in the inner segment need to get to the outer segment in order to perform their particular jobs up there, and materials that are no longer needed in the outer segment need to be carried away and dealt with in the inner segment. The connecting cilium acts as a transport system to which motor proteins can anchor and pull their molecular cargo up or down as needed.

The localization studies of the Usher proteins reveal that they are in the vicinity of the connecting cilium, but a closer look at this region of the cell shows that they are specifically either in the periciliary ridge–the ‘cuff’–or the space between the periciliary ridge and the connecting cilium:

Schematic longitudinal (B) and cross (C) sections of the ciliary/periciliary region of a mammalian photoreceptor cell showing the localization and proposed activity of some interacting Usher proteins. From Märker, et al. 2008

Thus, the model for usher protein function in the retina is that these complexes somehow assist in the cilium-based transport system. Here’s where things get a bit murky, though. Remember that, unlike the congenital nature of the ear problems, the retinal symptoms don’t manifest until much later, in childhood or adolescence,. Furthermore, they progress quite slowly, well into the third decade of life in most cases. How can the same defective proteins that cause such significant developmental problems in the hair cells not cause early problems with retinal cell function as well?

The congenital deafness in human patients and mouse models of the disease, and the defects in stereocilia formation seen in the Usher mice are nicely explained by the model of protein interaction and function in the developing hair cells, discussed in Part II. The retinal cells, however, survive development and, apparently, function normally until they begin to degenerate. I say ‘apparently’ because the ‘pre-death’ state of the photoreceptors has been difficult to observe thus far. In human patients, the first sign of a problem occurs when the hearing-impaired child or teenager begins to experience night blindness due to a loss of rod photoreceptors in the periphery of the eye. By the time this can be detected clinically, the degeneration is already well underway, and although the progressive vision loss is gradual, ophthalmic examinations haven’t yet been able to identify any problems that precede the cell death.

At this point you might well ask what clues the Usher mice, which proved so valuable in adding to our understanding of the disease progression in the ear, can tell us about the events leading up to retinal degeneration. To our great consternation, most of the Usher mice do not undergo retinal degeneration at all! The Usher mutant lines have all been examined expectantly until the end of their natural lives (around 2 years) and most do not exhibit any abnormality in their retinas. The exceptions to this are older mice with mutations in the cadherin 23 (ush1d) gene, which show a slight reduction in visual function older ages, and myo7a mutant mice, which exhibit a fairly distinct defect in protein trafficking, lending support to the model of usher proteins at the connecting cilium as described above. Neither line shows any retinal degeneration, however.

Several theories have been put forth to explain this discrepancy between the mouse and human forms of the disease. One possibility is that mice, being nocturnal animals and usually raised in low-light laboratory conditions, may not endure the bright light exposure that human retinas must withstand. Another explanation may lie in the slow, progressive nature of the human disease and the relatively short life cycle of the mouse–perhaps two years just isn’t long enough for the retinal defects to manifest in the mouse retina. A third theory centers on the fact that all of the known Usher proteins actually exist in multiple isoforms. The genetic code that specifies each of these proteins can be cut and spliced in a few different ways. The exact roles of the different isoforms of every gene aren’t yet clear, but some of them do appear to be more important in the ear than in the eye. It’s possible that the mutations in mouse Usher genes that give rise to such a strong ear phenotypes don’t affect the part of the protein that’s important for retinal cell function, and thus the mouse is spared the vision loss that characterizes the human disease. In further support of this latter theory is that fact that many of the Usher syndrome genes are also linked to non-syndromic deafness in humans–hearing loss without associated blindness.

None of the above theories are mutually exclusive, and it may turn out to be a combination of genetics, environment and life-span that has limited the retinal phenotype of the Usher mutant mice. Encouragingly, significant progress has been made through the use of genetically engineered mice, in which an Usher protein is removed completely (see knockout mice for more on this technique) or, alternatively, a targeted mutation is introduced into a particular Usher gene that renders the encoded protein non-functional. Thus far, these genetically modified mice show late-onset retinal degeneration, usually detectable at around 20 months of age. Exhibiting the full range of Usher syndrome symptoms, these new mouse models will provide hitherto unavailable opportunities for exploring the still mysterious function of the Usher proteins in the retina.

Hopefully, the above summary has illustrated that there are still a great many unanswered questions surrounding the pathophysiology of Usher syndrome, particularly with respect to the timing and progression of the retinal defects. To complement the data being collected from the current mouse models, I have chosen to investigate the function of various Usher proteins in the zebrafish. There are some differences in the retinal anatomy of zebrafish and humans, but basic cell structure and function is conserved between the two species. Additionally, there are some similarities that make zebrafish an especially appealing organism for this type of study, including the fact that fish are diurnal animals with rich color vision–even better than humans, in fact, as they can see light in the ultraviolet range of the spectrum. Other advantages to using zebrafish are related to their development. Zebrafish embryos undergo fertilization and development outside the mother’s body, and usually several hundred embryos are produced from a single mating. They develop rapidly and are able to swim, see and hear just a few days after fertilization. Thus, I am able to begin conducting tests on their visual function within the first week of development and obtain results quite rapidly compared to the work being done in mammals.

I am in the process of making Usher mutant zebrafish lines using a new technique for targeted mutagenesis. In the meantime, I am able to use established techniques to study the consequences of depleting Usher proteins in larval zebrafish. Although most of these data have yet to be published, I can report that, along with balance and hearing defects, I am seeing problems with retinal cell function, and I am able to detect photoreceptor death in young fish in which the various Usher proteins have been disabled. Once the starting point of the cell death is pinned down for each of the genes, I examine various aspects of retinal cell structure and function prior to that time point to see if I can detect any abnormalities. Manuscripts are in preparation, so stay tuned.

Understanding the molecular events that precede the death of these cells will be crucial in identifying ways to improve diagnosis and treatment of Usher syndrome. In the conclusion of the Usher story, and of my Guest Blogging stint, I’ll discuss current clinical practices for managing Usher syndrome, and the direction of the research efforts designed to enhance these treatments.

Figure credits: 1. Reiners J, et al. 2006Experimental Eye Research Volume 83, 97-119.
2. Märker T, et al. 2008 Human Molecular Genetics Volume 18, 71-86

To clarify, as it’s been brought up that this is a poorly worded poll: based on the story behind it, it is referring to doctors who refuse their patients medical treatment that will help them based on their religious beliefs.

But nevermind anyways. Apparently this poll was closed just after I posted it. So ignore the link, but feel free to comment on the topic if you like.

Now luckily common sense is already winning out with 61% of the ~2300 voters voting no. However, that still leaves close to 40% of voters who believe this practice is OK. Let’s get to work!

This poll brings up a good point of discussion, I think. I personally have heard of many stories of, for instance, unmarried women having to find a new family doctor because they wouldn’t prescribe her birth control, due to the doctor’s religious beliefs. Obviously, I think this situation is beyond ridiculous.

From LisaJ.

Wow. Now here’s a story that just disturbed me to no end. Little Javon Thompson’s mother, 21 year old Ria Ramkissoon, became a Christian at a young age, but when her local pastor disappointed her by pleading guilty to molesting young boys, she left her church and was taken in instead by what is now being described as a dangerous religious cult (I’d like to make the point that even plain ‘ole regular Christianity is a dangerous cult, but that’s beside the point). This cult, called 1 Mind Ministries, is headed by a 40 year old, I’m assuming woman, who calls herself Queen Antoinette, and it appears that the relatively small group lives together and operates under the extremely god-driven Queen’s direction.

What happened to Javon, Ms. Ramkissoon’s little boy, in 2005 is what has me so disturbed. The ONE year old child was denied food and water for two days because he wouldn’t say “Amen” after finishing his meals. This outrageous punishment killed him, and none of his caretakers intervened to save him. Police say that the group viewed this child as a demon, and that they left his lifeless body in a backroom of their apartment for more than a week while they simply prayed to god to raise Javon from the dead. Instead, the boy’s body began to decompose and no resurrection occurred, obviously.

Reportedly, after the cult members accepted that Javon would not be resurrected they stuffed his body in a suitcase. His mother lovingly added mothballs and fabric softener to the contents of the suitcase, and occasionally sprayed some disinfectant inside. The case, with the child’s body still inside, was found earlier this year, after it had been stored behind a home in Philadelphia when the cult relocated to New York City, over a year earlier.

Javon’s mother Ria and four other cult members face first degree murder charges in this case. Ria’s mother, however, contests that her daughter was brainwashed by the cult. Her attorney has recently declared that “the members of this cult, who were more than twice her age, were calling the shots,” and that “she bought the program hook, line and sinker.” So because this young woman was reportedly brainwashed, does this then mean that she should not be prosecuted with her child’s murder? To put this into perspective for myself, I was raised catholic, and there are certainly many faulty decisions I made while growing up that I consider to largely be the fault of my indoctrinated mindset. But murder? I have a really hard time swallowing the brainwashing excuse as justifying your active involvement in your child’s murder. And besides, even if her supposed brainwashing is really at fault here, someone this stupid to allow someone to talk her into effectively killing her child, under the guise of god, should be put away where she is no longer a danger to herself or anyone else.

This disturbing story highlights perfectly the dangers that society faces for teaching people to believe in whatever god they’re confronted with, instead of thinking for themselves.

LisaJ’s Danio’s (hangover error) posts about Usher Disease (I and II), as well as my own syllabus preparation for the upcoming semester, have gotten me thinking about issues of intersexuality. In particular, her noting of the geographic issues related to the prevalence of various forms of Usher disease reminded me of the concentration of five-alpha-reductase deficiency in parts of Turkey, Papua New Guinea and the Dominican Republic.

Some folks are probably asking, “What is this intersexuality thing?” Basically, it’s a range sexual development disorders in which people’s bodies develop in such a way as to place them in a “border region” of sex. Hermaphrodism is what people usually think of, but there is a wider range of conditions, including hypospadias and congenital adrenal hyperplasia.

If any of you have read the novel Middesex you already have an idea of what I’m talking about with five-alpha-reductase deficiency. People with this condition are genetically XY, but during fetal development something happens such that in many people the testicles may not descend, the scrotal sac may not fuse, and the penis can appear more like a clitoris (such an ambiguous thing is often called a microphallus). Because of these developmental issues, people with this condition are given a female gender designation at birth. Once puberty hits, though, the testicles descend, the penis may enlarge, the “labia” fuse to form a scrotum, and other male secondary sex characteristics appear. One of the things I find so interesting about this particular condition is the way that it has been routinized in the patterns of life and cultural systems in parts of the Dominican Republic. The people living in these areas have their own term for the condition, “guevedoce” (“eggs/balls at 12″).

In class, I often use a video produced by the Intersex Society of North America, an organization that shut its doors this years in favor of a different advocacy organization, the Accord Alliance. In particular, this segment of that video talks about, and interviews, someone who identifies as a guevedoce, as well as his family. (YouTube won’t allow it to be embedded.)

It’s this issue of how people with various conditions are integrated into social life that is my primary concerns. One of the things intersex activists have been challenging for the past decade or so is infant genital surgery. When children with some sexual development disorders are born with ambiguous genitals they are quite literally made to fit into one of the existing gender categories. “Fixing” them means surgery to make their genitalia more closely resemble “normal” genitals. If the phallus falls inside the middle range, where it’s “too long” for a clitoris or “too short” to be a penis, well, it’s snip-snip time. Many of the decisions to engage in surgery are based not on medical necessity, but social preference. Questions such as, “Will he be able to stand to urinate?” or “Will her partners be turned off by such a large clitoris?” or “How will the parents deal with looking at such a strange body while changing diapers?” can become more important issues when determining whether to operate than such things as “Will cutting part of the phallus off affect this child’s sexuality later in life?” (Ann Fausto-Sterling has an excellent discussion of these issues.)

Not surprisingly, surgeries do affect folks. Many report a loss of sensitivity from having such operations performed on them. (As one of my students once said to the other women in the class about the possibility of having half a clitoris and no sensitivity, “Wouldn’t it just make you tense all the time!”) It’s more than loss of sensitivity, though. There are often other complications that require more than one surgery. Ongoing pain or recurrent infections are not uncommon.

This is one of those spaces where I get all anti-normalization. These people’s bodies are being normalized–they are being reconstructed so they fit within normative assumptions about what genitalia must look like based on statistical averages. And, it’s done without their consent. Intersex activists have been successful in increasing awareness in the medical profession, but there are still issues. Many of these flow from the gender order we have in this society. The problem with such medically unnecessary genital surgeries isn’t these babies’ bodies, but social beliefs about what those bodies are supposed to look like.

msnbc asks: Should the phrase ‘In God we Trust’ be removed from US currency?

Right now the poll is at 49% yes, and 51% no. Obviously we have some work to do. Get to it!

From LisaJ

Everyone seems to love a little Sonic Hedgehog around here. Whenever PZ discusses another function that this fascinating gene is capable of, much excitement ensues in the comment posts. So I thought I would take this opportunity to talk a bit about what I study, and how my seemingly unrelated favourite protein pathway is also connected to the Shh gene.

The main protein that I study was originally identified through studies of a pediatric eye cancer, called Retinoblastoma, as loss of function of this protein (termed the Retinoblastoma protein, or pRb for short) was found to be causative in the formation of this tumour type. What we know now is that pRb is required to control normal cell division in all cell types; its functional loss leads to the formation of many types of tumours, and is thought to be involved in the development of at least half of all human cancers. Not only is pRb essential in preventing uncontrolled cell division that can lead to cancer, but it is also essential for embryonic development, as mice deficient for the Rb gene die by about the 15th day of gestation, about 5 days before they would be born.

To explain how pRb functions in the cell, I thought that I could easily pull out a figure from a review paper that diagrams a simplified cell cycle pathway and the protein interactions that take place. But instead, I’m going to show you this beautiful piece of work that a few of my talented previous lab mates created for me one day, as a means of cheering me up after a year’s worth of protein purifications and binding assays did not give me the result I was hoping for. Although a simplistic depiction of cell cycle regulation, I think it really drives home the point well of how pRb functions.

This figure shows that pRb, or ‘RB Boy’ as is the case here, is stopped in his tracks in G1 (Gap 1) phase of the cell cycle. His watch and the stop light ahead of him are telling him to stay put for the moment until the cell’s DNA is fully repaired and ready to be duplicated, at which time he may initiate entry into the DNA synthesis phase (S phase). You’re probably wondering what that is sticking out of his pocket. Well, it’s an E2F transcription factor complex, and pRb binds E2F proteins through a domain that forms a pocket like structure. The manner by which pRb inhibits entry into S phase is by physically binding E2Fs while they are sitting on DNA; this binding interaction inhibits the activation of genes required for DNA synthesis to occur by E2Fs. Once any DNA damage has been repaired and the cell is ready to enter into S phase, a cyclin/cyclin dependent kinase (cdk) complex, shown here by the ‘cyclin/cdk bird’, phosphorylates pRb. This phosphorylation disrupts the physical interaction between pRb and E2F, and thus E2F is free to activate expression of pro S phase genes. These are the basics of how pRb regulates the cell cycle.

As I said previously, we know that pRb, by virtue of its regulation of E2F transcriptional activity, is a very important tumour suppressor. The role of these proteins in regulating tumour development has been, and still is, very heavily studied. We’re also discovering, however, that pRb has other important functions besides regulating the cell cycle and suppressing cancer. For instance, pRb/E2F proteins play an important role in regulating cellular differentiation and cell death, as well as the expansion of stem cells in a number of tissue types, including the haematopoeitic system, intestinal epithelium, and the brain (which I am most partial to). Additional functions that we’ve found for pRb/E2F in the brain include regulation of the differentiation of neurons and neuronal sub types, the migration of neurons through the brain, progenitor cell division, and the patterning of the ventral forebrain. We’re finding some very exciting functions for these proteins in the developing brain, and what’s even cooler is that the mechanisms through which pRb/E2F regulates neural development are emerging to be very similar to those that are involved in cancer development.

So of course, since the Sonic Hedgehog (Shh) gene does so many exciting things, we have also found an important functional link between E2Fs and Shh. When you knock out the E2F4 gene in mice and examine how embryonic development proceeds in the brain, you notice a very similar phenotype to what is seen when you knock out the Shh gene. The brain is quite reduced in size, and you see a large defect in the patterning of the ventral telencephalon (which is a part of the forebrain). Basically, the most prominent ventral structures, which are normally rich in neural stem and progenitor cells, are totally absent. Not surprisingly, these embryos do not survive to birth. You can see this gross defect in the figure below.

What you’re looking at here is an un-dissected embryonic mouse brain, at day 11 of gestation, in the first column, with the brain from a normal mouse on top and a much smaller E2F4 mutant brain on the bottom (TE in this figure stands for ‘telencephalon’). In the second column you are looking at a coronal, or frontal view cross section, of normal and mutant brains at the same embryonic stage; you can see that those bumpy structures (called the ganglionic eminences) present in the bottom half of the normal brain are almost totally absent in the E2F4 mutant.

PZ has discussed here before theimportance of Shh function in patterning the nervous system during embryonic development, by initiating its expression ventrally. What was ultimately determined about this observed E2F-Shh interaction is that the E2F protein is responsible for activating expression of the Shh gene within the ventral telencephalon at the correct time point during embryogenesis. Without this transcriptional activation, Shh is not adequately expressed and forebrain patterning is severely disrupted. This second figure shows really nicely how important the timing of Shh expression by E2F is.

You’re looking first at a side view, and then a frontal view, of a mouse embryo at day 9 of development. The wild type and E2F mutant mice in this experiment have been bred with mice that carry a transgene containing regions of the Shh promoter that are known to be essential for directing expression of Shh specifically to the brain regions that are affected in the E2F mutant. When these promoter ‘enhancer’ regions are bound by activating transcription factors, they direct expression of the beta-galactosidase gene, which is also present on the transgene downstream of the Shh enhancer sequence. Embryos are subsequently stained with a compound called X-gal, which is enzymatically cleaved by beta-galactosidase to produce a bright blue precipitate. Thus, the blue markings that you see in the figure indicate the locations that Shh is expressed in the ventral forebrain, and this expression is almost completely absent in the E2F4 mutant (lower panel). In the third column, you can see that one day later in the developmental time course, Shh expression is starting to appear in the E2F mutant mouse. It’s not an all or nothing effect here, but this seemingly short-lived dysfunction in Shh expression is what leads to the disastrous developmental effects to the animal that are described above.

This is a great example of two molecular pathways that were originally thought to do very different things converging to perform an essential, developmental function together. The number of gene products that function in our cells is huge, and it’s incredible to think of how immensely this complexity is increased when we find that many proteins are performing multiple functions on their own and in cooperation with other proteins or pathways. The wonders of biology never cease to amaze.

E2F/Shh figures from Ruzhynsky et al. Journal of Neuroscience. 2007. 27(22): 5926-35

An author named Sherry Jones has written a book, called The Jewel of Medina, that will never see the light of day because it novelizes the life and times, with particular focus on the marital details, of the prophet Mohammed.

The Jewel of Medina was bought by Random House and primed to be a best-seller – before a University of Texas teacher saw proofs and declared it “a national security issue”. Random House had visions of a re-run of the Rushdie or the Danish cartoons affairs. Sherry Jones’s publisher has pulped the book. It’s gone.

Hari goes on to criticize the kid gloves with which Islamic issues are dealt the world round, contrasting it to the relative ease with which people question the tenets of Christianity and other more ‘docile’ world religions. Although his East End perspective may not allow him to fully appreciate the rebounding resistence to criticism sought by Christians in America, his general conclusions are spot on:

It is condescending to treat Muslims like excitable children who cannot cope with the probing, mocking treatment we hand out to Christianity, Judaism and Buddhism. It is perfectly consistent to protect Muslims from bigotry while challenging the bigotries and absurdities within their holy texts.

There is now a pincer movement trying to silence critical discussion of Islam. To one side, fanatics threaten to kill you; to the other, critics call you “Islamophobic”. But consistent atheism is not racism. On the contrary: it treats all people as mature adults who can cope with rational questions. When we pulp books out of fear of fundamentalism, we are decapitating the most precious freedom we have.

Naturally, he is receiving a quantity of shrill concern-troll style email for daring to sing a refrain that might sound a bit familiar ’round these parts: NOTHING IS SACRED. The responses of anger and fear are as predictable as they are sad, and just as many, if not more, of the complaints are coming from the uber-tolerant left. It is frustrating how glibly the term ‘bigot’ is now deployed, from a seemingly untouchable ultra-politically correct position. I long as much for the freedom to call ‘bullshit’ when warranted as I do for the day when, through efforts of vocal rationalists and moderates, the chinks in Religion’s armor have been widened enough to let the light stream in, and words and symbolic actions challenging the merits of any faith or philosophy can be spoken, read and conducted with impunity.

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Just in case it’s not clear from the title, this post was authored by Guest Blogger Danio.