Moving on

This post almost got postponed to the New Year, given that this week has been so, so tiring in the wake of Ruzbeh’s epileptic attack. But I couldn’t bear the thought of letting Norrie disease get the better of me, so here goes…

In the aftermath of my discussion with the retina specialist (read my previous blogpost), I felt a pall of gloom descend upon me. What now? I wondered.

For a while I pondered reading up on other symptoms of Norrie disease (ND), something that I’ve been putting off for sheer lack of time.

And yet. And yet.

My thoughts were in turmoil: What about all the hours I spent reading stuff. What about my conviction that one day it will be possible to reverse the blindness associated with ND.

Research is not about saying it can’t be done, research is about saying it needs to be done, and then finding a way to do it. Or so I believe.

And then my thoughts turned to the NEI (National Eye Institute). If you have never heard of the NEI, this is what it says on their website:

As part of the federal government’s National Institutes of Health (NIH), the National Eye Institute’s mission is to “conduct and support research, training, health information dissemination, and other programs with respect to blinding eye diseases, visual disorders, mechanisms of visual function, preservation of sight, and the special health problems and requirements of the blind.” The NEI was established in 1968. It has a budget of approximately $675 million (FY2014).
What if they could gather a few researchers for a small problem solving session? The objectives of this meeting would be the following:

i) To lay down step by step, what needs to happen for vision to be restored in a case of ND

ii) To identify from step (i), those areas where research is currently going on & those which are not the subject of current research

iii) To identify from step (ii), those areas where some ND specific research needs to be done in conjunction with ongoing research

If funds need to be arranged for this brainstorming to happen, then I would be happy to try and secure them. I don’t know how, but I’ll cross that bridge when I come to it.

My point is this: It is true that I can’t put a million dollars on the table for ND related research, but if we could define the way to solve the problem of vision (or lack of), then maybe I could find a way to obtain funds for individual projects.

So I went ahead and hammered out a letter to this effect. 

Then I pondered for a bit about who to address it to. I figured I would send it to Dr. Paul Sieving, Director, NEI. 

Then I pondered a bit more – what if the Norrie Disease Association (NDA) has had some dealings with the NEI in the past? In that case maybe they could tell me who to get in touch with. So I wrote to John Miller, President, NDA. No, the NDA has not been in touch with the NEI. 

And yet I hesitated. I really want this brainstorming to happen. No more no’s. Perhaps I ought to route my request through the NDA? Perhaps that would strengthen my case? Hmmmm. Yes, I think I will try the NDA route. Let’s see where it leads.

Till next time then,

Meenu.

A conversation with a retina specialist

Since the time that I penned my last post, I have had the opportunity to speak with a retina specialist on the subject of vision restoration. In today’s post I would like to share with you, his view on this subject. Please note that this is not a transcript of the conversation. Scattered here and there, are words and phrases in italics, and these are simply my thoughts and not part of the discussion.

First question: Would it be right to say that we would have to recreate the entire visual pathway - retina, optic nerve, visual parts of the brain - in order to restore vision in ND?

The answer: No. The eye undergoes histological changes and dysplasia. We cannot hope to restore vision in this manner.

Histology is the study of the microscopic anatomy of cells and tissues of plants and animals.
Dysplasia is an ambiguous term used in pathology to refer to an abnormality of development.

[Source: Wikipedia]

In his opinion, the best (and only) strategy for a person affected by Norrie disease, would be to opt for non-visual development of visual ability. 

What? 

He went on to explain that non-visual senses could be used to provide an ability similar to sight. Sensory substitution, in other words. He referred to a device which has been developed to provide visual information to the brain via electrodes placed on the tongue. He suggested I look it up on the internet, which I did, and it seems that such a device has even been approved by the FDA last year. 

I think we all know the drill by now – mount a camera on a pair of glasses, transmit the image (by a wire or wirelessly) to a processer which converts it to electrical pulses, then use these pulses to stimulate some part of the body or brain thereby giving the person some sense of what he/she is ‘seeing’. Here are a couple of links which provide all the details:

Device That Helps Blind People See With Their Tongues Just Won FDA Approval

Loser: Tongue Vision

The latter article is a critic’s point of view with the subheading “A fuzzy outlook for an unpalatable technology”!

This is really useless, I’m thinking. Is this the best that researchers can come up with? Because if it is, then I’m all for packing up my bags. 

Oh well, I’ll let you decide for yourself. 

So this ought to have been the end of my discussion, but since I had my list of questions before me, I decided to go ahead and ask them anyway.

So, I know that a retinal detachment implies separation of the neural retina from the RPE (retinal pigment epithelium) and I wondered if after several years of detachment - as in the case of ND – would the RPE be dead or alive? Alive. In other words, if one had to go down the retina transplant route – which route the specialist advised me not to go down – then it is the neural retina which would need to be transplanted and not the RPE and not the choroid.

The neural retina consists of several layers of cells including the photoreceptors and the ganglion cells. It sits on top of a single cell layer called the RPE, whose function is to nourish the neural retina cells amongst other things. The RPE, in turn, is firmly attached to the choroid, which is a vascular structure filled with blood vessels which bring nutrients and oxygen to the eye. So the sequence is as follows:

Cornea – Lens – Vitreous – Neural Retina – RPE – Choroid

On to the next question.

From what I have read on the subject these past few weeks, I believe that the biggest hurdle to a retina transplant is that the connection of the retina to the brain (the optic nerve in other words) is not going to happen on its own. Because the optic nerve is nothing but the axons of the retinal ganglion cells (RGCs) which extend all the way back to the brain, and we know that once there is damage to the optic nerve, as in the case of glaucoma, the nerve does not regenerate on its own. So something would need to be done, in order to persuade these axons to regrow. Not only that, they would have to make the right connections in the brain.

I also know that the NEI (National Eye Institute) has launched an initiative titled Audacious Goals Initiative (AGI). As part of this initiative, the NEI has funded six projects (a total of $12.4 million) to identify biological factors which influence optic nerve regeneration.
[Aside: MaryAnn, should you be reading this: remember the press release from the NEI you had sent me? This is it.]

My question to the specialist: Shouldn’t this, at some point of time, enable researchers to experiment with retina transplants in an animal model at least?

His answer: No. What researchers are exploring is the possibility of regenerating the optic nerve when the other components of the visual system – the eye and the brain – are intact. Even if they were to succeed, it does not imply success in a case like ND where the retina is detached and consequently the visual circuitry of the brain too is impacted. The two situations are not comparable as it were.

On the subject of a cortical implant, his view was that it won’t work for those who are blind from birth, and this is something I have read elsewhere too. Not sure what is the reasoning behind this.

End of story. Almost. I think I will try and speak to a few more people, in case they have a different perspective to offer. I need to finish what I have started.

Till next time then,

Meenu.

To see or not to see (Part II)

In my previous blog post I had written about what – in my opinion – could be done to restore vision for a person with Norrie disease. 

However, even if we had the perfect method to correct the optics in the eye,  functional vision would still be determined by the retina-brain interaction. This is because vision involves perception (which in turn involves the brain), and not just an optically perfect image. Unfortunately, normal development of the visual cortex (the part of the brain responsible for seeing) requires visual inputs to have been present during the early years of development. Scientists refer to this early period as the ‘critical period’ for vision.

How do we know all this? 

Well, from experiments conducted by dark rearing animals. The following links provide examples of some such experiments:

Visual acuity and visual responsiveness in dark-reared monkeys (Macaca nemestrina) [Regal et al., 1976]

Development of visual acuity in infant monkeys (Macaca nemestrina) during the early postnatal weeks [Teller et al., 1978]

Long-term effects of dark rearing on a visually guided reaching movement in cats [Fabre-Thorpe M et al., 1990]

Functional postnatal development of the rat primary visual cortex and the role of visual experience: Dark rearing and monocular deprivation [Fagiolini et al., 1994]

The role of visual experience in the development of columns in cat visual cortex [Crair et al., 1998]


We also see the effects of early sensory deprivation on vision in the case of amblyopia or ‘lazy eye’. In amblyopia, one eye fails to achieve normal visual acuity even with prescription glasses. The reason for this is reduced visual inputs to the affected eye during infancy or early childhood. This can happen for many reasons, cataracts for example. In the absence of visual inputs during the critical period, the visual circuitry of the deprived eye is permanently compromised. The result is normal vision for one eye and blurred vision for the other.

So would this compromised vision be better than no vision at all? I honestly do not know the answer to this. But I find myself veering towards ‘yes’.

Why?

Firstly, because even light perception has some benefit. Secondly, because there may come a time when scientists are able to rewire the brain to its childlike state, thus enabling visual circuits to develop as they normally would in childhood.

Oh wow, what’s this all about? 

Well, if you want details, I refer you to an article titled The Power of the Infant Brain. The article is authored by Prof. Takao Hensch of the Center for Brain Science at Harvard University and it was published in the journal Scientific American. Here are the salient points of the article:

• The child brain develops vision and other abilities during “critical periods,” when the brain is primed to undergo lasting change in response to sensory and social stimuli.
• Critical periods open at defined times during the course of childhood and adolescence to allow the molding and shaping of neural connections - a property known as brain plasticity.
• Growing understanding of the molecules that both start and stop critical periods has let scientists gain a measure of control over their timing, restoring plasticity even in adulthood.
• Regulating the biology of early development may one day allow drugs or medical procedures to restart critical periods later in life to correct early developmental problems.

So this is as far as my thinking goes on the subject of vision restoration. As I’m not an expert of any kind, I would like to speak with those who are (ophthalmologists, retina specialists…..), in order to have some clarity on this subject.

If you would like to suggest someone with whom I could speak about what can be done for restoring vision in the case of ND, do get in touch. You can either drop me an email or write a comment at the end of the post.

Till next time then,

Meenu.

To see or not to see (Part I)

Will it ever be possible to restore vision to a patient of Norrie disease?

 

I think at some point of time it will be. I don’t know if this will happen in my lifetime, but the research leading up to it is certainly very fascinating.

 

There appear to be two problems which need to be addressed. Firstly, the optics in the eye, i.e. the detached retina, and secondly, the neuronal circuitry in the visual cortex (the part of the brain which is responsible for seeing).

 

In this post, I talk about the first problem. The problem relating to the visual cortex will be taken up in a subsequent post.

 

[Aside: Although in a typical case of Norrie the blindness is complete (i.e. no light perception), there are a few cases of Norrie in our online community where the affected person has some light perception. It is probable that the neuronal circuitry in these individuals is well developed and so that would be one less problem to worry about in this subset of the community.]

 

To restore the visual circuitry in the eye, we would either have to put a new retina in place, or come up with a solution which bypasses the retina. Going by current research, there appear to be the following 3 possibilities: 

• Cortical implant
• Retina transplant
• Whole eye transplant (no, I’m not joking, there is such a project underway)

 

 

Cortical implant

 

This approach to restoring vision bypasses the eye (& the optic nerve) completely.

 

Cortical implants (also known as IntraCortical Visual Prostheses – ICVPs) aim to provide patients with visual information by stimulating neurons in the brain’s visual areas. An ICVP comprises a digital camera on a glasses frame. The camera is connected (either by a wire or wirelessly) to a small computerized vision processor, which is kept in a pocket or worn on a belt. Images from the camera are transmitted to the processor which in turn converts them into waveform patterns, which are then transmitted wirelessly to the implant in the brain. The implant is typically a chip that is implanted into the visual cortex (located at the back of the brain).

 

It must be stated that a cortical implant will provide “artificial” vision - a pixelated version allowing the user to perform elementary visual tasks such as navigation and object recognition. Depending on the number of electrodes on the implant, it might even allow for reading large print and recognizing people.

 

Groups developing ICVPs include the following:  

• Monash Vision Group in Melbourne, Australia
• Illinois Institute of Technology
• École Polytechnique de Montreal in Canada
• Second Sight Medical Products, California

A press release from Second Sight states that the first human clinical trials are planned to commence by the end of the first quarter of 2017.

 

Human trials for the Monash University’s ICVP are expected to take place sometime in 2016 according to an article published in the Sydney Morning Herald.

 

The above list is not exhaustive. ICVPs are being created by a few other groups as well. One such group is the Visual Prosthesis Lab at Massachusetts General Hospital. A notable difference here is that this group proposes to implant the electrodes in the lateral geniculate nucleus (LGN) and not the visual cortex. The LGN is a relay center on the visual pathway. It is located in the thalamus (a structure in the middle of the brain). We can think of the visual pathway like this:

 

Retina --------- LGN --------- Visual Cortex

 

There are pros and cons of this approach versus the one which places the implant on the visual cortex. One obvious difficulty is in getting to the LGN since it is located deep inside the brain, whereas the visual cortex, being located at the back of the brain, is easily accessed. 

 

 

Retina transplant

 

Researchers have succeeded in creating functional three-dimensional retinal organoids using stem-cells.

  

An organoid is a three-dimensional organ-bud grown in vitro that shows realistic micro-anatomy. The technique for growing organoids has rapidly improved since the early 2010s, and it was named by The Scientist as one of the biggest scientific advancements of 2013.

[Source: Wikipedia]

 

 

The organoids show the architectural organization of the retina, and include functioning photoreceptor cells capable of responding to light.

 

However, in order to have a retinal model which resembles the real thing, the lab grown organoid needs to (1) include a network of blood vessels, and (2) be able to transmit the electrical impulses which can be interpreted by the brain as images. Once this happens - or if this happens - retina transplantation will perhaps become a reality.

 

Researchers who have successfully created retinal organoids:  

• Dr. Masayo Takahashi, Professor of ophthalmology, RIKEN Center for Developmental Biology, Kobe, Japan

         Media coverage:

         Japanese woman is first recipient of next generation stem cells, Sept 2014

         Scientists use skin cells to restore patient's vision for the first time, May 2016

• Dr. Maria Valeria Canto-Soler, Assistant Professor of ophthalmology at the Johns Hopkins University School of Medicine

         Media coverage: 

         Mini-Retina Created with Stem Cells, June 2014 

         Light-Sensing Retina in a Dish, June 2014   

• Dr. Mike O. Karl, Research Group Leader, German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany  

         Media coverage: 

         Hoping to cure blindness, scientists develop 'mini retinas', April 2016 

 

 

 

Whole eye transplant

 

The U.S. Department of Defense has awarded $1.25 million to University of Pittsburgh School of Medicine (UPMC) researchers co-led by McGowan Institute for Regenerative Medicine faculty members Dr. Vijay Gorantla, associate professor of surgery in the Department of Plastic Surgery at the University of Pittsburgh and the administrative medical director of the Pittsburgh Reconstructive Transplant Program at UPMC, and Dr. Joel Schuman, chair of the Department of Ophthalmology, Pitt School of Medicine, and director of the UPMC Eye Center, to establish the groundwork for the nation’s first whole-eye transplantation program. 

 

The Pitt researchers will lead a multidisciplinary consortium (dubbed the Audacious Restorative Goals in Ocular Sciences (ARGOS) Consortium) that includes clinicians and scientists from Harvard University and the University of California, San Diego.  

 

In the following excerpt from an article published online, Dr. Jeffrey Goldberg, director of research at the Shiley Eye Center at University of California, San Diego, and Dr. Vijay Gorantla talk about the main problem with a whole eye transplant, that of reconnecting the optic nerve: 

 

"The chief problem," Goldberg explained, "is that when you switch out an eyeball you have to completely cut all connections between the optic nerve and the eye. So then you need to reconnect the donor eye's nerve fibers back to the recipient's brain in order to achieve vision restoration. But we know that once you make that cut, the nerve fibers just do not regrow on their own. That doesn't happen automatically." 

 

"That's what distinguishes an eye transplant from most other types of transplants," Gorantla added. In other organ transplants, the chief hurdle is simply reconnecting a proper blood supply. "For example, if you get the plumbing connected and the blood going, then a transplanted heart will beat in the recipient patient immediately," Gorantla said. 

 

"But an eye transplant actually has more parallels with a hand or face transplant," he said. The eye may appear healthy because of a renewed blood supply, but without reconnecting the optic nerve, "there's no motor activity and no sensation or eyesight," Gorantla said. "The result is functionless and lifeless." 

 

Luckily, various laboratories "have made significant progress" in fostering the long distance regrowth of nerve fibers, Goldberg said. "In animals with optic nerve injury or degeneration we've even started to see fibers regrow all the way back to the brain," he noted. 

 

You can read more about this project by clicking on the following links: 

 

UPMC exploring future of eye transplants - Pittsburgh Post-Gazette, July 2015 

Second Sight - Science Magazine, March 2015

 

 

And with that I wrap up today's post. 

 

Till next time then, 

 

Meenu.

Where it all began

This week I’m heading to Zurich to meet Prof. Dr. Wolfgang Berger, Director, Institute of Medical Molecular Genetics, Medical Faculty, University of Zurich.

Prof. Berger is no stranger to the Norrie community, having presented the advances made by researchers studying the norrin protein at the 2009 & 2012 international conferences organized by the NDA. His lab has a longstanding interest in Norrie disease. The lab boasts two important 'firsts' - the gene for Norrie disease was first identified here in 1992 by positional cloning and the first mouse model for the disease was generated in the lab in 1996. Click here to see the Norrie disease research webpage at the Institute of Medical Molecular Genetics‘ website.

As I have yet to attend an NDA conference, this is the first time I will be meeting Prof. Berger. This is an amazing opportunity and I intend to make the most of it. My list of questions and stuff to discuss is growing by the minute!

Till next time then,
Meenu.

A little bit of hope

A few months back, I sat down to watch the proceedings of the 3rd international Norrie disease conference held in August, 2015 in Boston.

I listened to Dr. Xin Ye’s presentation on Norrin/Frizzled-4 signaling in vascular development and maintenance. This covered research conducted by the Nathans lab at Howard Hughes Medical Institute, John Hopkins University School of Medicine, over a period of many years.

As the presentation inched towards the final few slides, I sat riveted to my seat. One of the results of the research study was making me want to whoop with joy.

No, wait, I thought. Perhaps I’ve got it all wrong. Rewind. Listen to it again. 

Nope, I hadn’t made a mistake.

Even so I found it hard to believe. It was time to go online and dig out the research study corresponding to the latter part of the presentation.

If you’re still reading, here is what this is all about:

The Norrie gene (NDP) codes for the protein Norrin. Norrin attaches to another protein called Frizzled-4. The two proteins fit together like a key in a lock. When Norrin attaches (binds) to Frizzled-4, it initiates a pathway called the Wnt/β-catenin signaling pathway. This in turn promotes certain target genes. The genes that Norrin helps activate are implicated in maintaining the blood brain barrier (BBB) (amongst other things). 

The blood brain barrier allows substances such as glucose and oxygen to enter the brain but blocks toxic substances from getting into the brain.

What is the blood brain barrier?

Dr. Nathans explains that, normally, the cells which line the inside of blood vessels (endothelial cells) contain permeable "windows" and relatively loose "bolts" connecting the cells together. In the brain and retina, endothelial cells have no "windows" and their "bolts" connect them tightly. "We now know that endothelial cells that make up the blood-brain barrier have to receive signals constantly from nearby brain or retinal cells telling them, 'You're in the brain. Tighten your bolts and close your windows.'" This reinforcement of the endothelial cells is what is known as the blood brain barrier.

[Source: ScienceDaily]

A compromised blood brain barrier leads to neuronal damage and disturbed brain function.

This should explain the cognitive impairment and autistic traits seen in some Norrie cases.

Additionally, as I have seen numerous studies linking blood brain barrier dysfunction to seizures and epilepsy, I’m guessing that the seizures and epilepsy experienced by some Norrie patients are also an outcome of the loss of integrity of the blood brain barrier. Click here to see one such study.

So. Back to the Nathans lab research.

Simply put, this research establishes that supplying Norrin to the brain in adult Norrie mice completely restores the integrity of the blood brain barrier.

In other words, OH MY GOD. This could be the solution to all the brain related problems associated with Norrie disease. (There are lots of other very significant findings of this study, and I hope to bring them up in subsequent blog posts).

Three cheers for the Nathans lab for this brilliant research!

So, um, where is it, this wonder drug?

I have come to understand from Prof. Nathans that this matter is under consideration by the lab, and that the problem which needs resolving is how best to deliver the drug to the brain.

How much longer before we have a viable treatment?

Till next time then,

Meenu.