Cell Mates

In 2006, mouse fibroblasts were successfully transformed from a fully differentiated state to a state of pluripotency. These cells were designated induced pluripotent stem cells (iPSC).Since that news, human cells were successfully transformed and techniques to increase the safety and efficiency of production have been found. Other techniques have been developed which can correct genetic defects in iPSCs with the eventual goal of repairing or replacing defective tissues.

iPSCs still have issues to be resolved such as:

• certain methods of inducing pluripotency are tumorigenic
• iPSCs appear to have "memory" of their original cell type
• there is some data showing that iPSCs express certain proteins on their surface resulting in immune rejection even in cells donated from the host's own tissue
• other complications such as efficiency (allowing sufficient numbers of cells to be generated within a clinically acceptable time at a clinically acceptable cost).

Some of these issues are already being addressed and quite frankly the pace of research has been astonishingly rapid. iPSCs are already being used to model disease and aid drug discovery. Due to the novelty of cell-based therapies and the fact that implanted cells are difficult or impossible to remove (unlike dosages of drugs which can be ceased in the event of adverse reaction), regulatory hurdles are necessarily high. However, as more trials are performed giving more data on safety these hurdles can be lowered somewhat and/or more easily surmounted. There are cell-based therapies already in or going through the regulatory process for trials using a variety of stem cell types. Not only do these prospective treatments face regulatory hurdles, they must also cross the Valley of Death of pharmaceutical research. Some researchers are finding ways of doing this on their own with intellectual property partnerships, and the NIH has been working to bridge the gap with new programs such as TRND.

This is a very exciting time for regenerative medicine.

FUS and ALS: What's the Connection?

A very interesting article from the MDA. Discusses some exciting work regarding the role of FUS in ALS. The article also mentions TDP43 and a possible convergence in the pathologies of both.

The Cost of Breath

Despite having a "fatal illness", with a little technology and someone to keep an eye on me for the inevitable adjustments, I can live until age draws the final curtain on the story of my life. My quality of life remains high regardless of my current certain physical limitations. There is nothing wrong with my mind: I am still as intellectually productive as ever. Nothing would please me more than to earn my own keep (and I am not alone in this desire), but people classified as terminally ill don't appear to be considered viable members of the workforce. So I volunteer my time to raise awareness and try to understand relevant research, sharing what I learn with others (a part of my previous career and the genesis of this blog). I find this work fulfilling and it keeps my opinion of my quality of life quite high, focusing on accomplishment rather than loss. Those close to me can attest that I can get cranky between projects when I have nothing to do so I try to stay busy. As I am quadriplegic I must use a computer system that tracks my eye movement to approximate the use of a mouse. With this computer I write and respond to email and online chat offering technical advice and answering questions from other PALS, scour the Web for research information, create videos to promote awareness, created a website (with coding assistance from a friend far more skilled than I), and play with my home computer network among other projects. The decision to vent or not is a highly personal one with many factors contributing to the decision. I chose to live on a vent for a few reasons. First, I had finally recently achieved real happiness in life and didn't want the dream-come-true to end so soon. Second, I saw some hope on the horizon with the state of research into the disease and possible ways to overcome it and I still hold this view more than ever. Last, and important to my perception of quality of life, I still had a contribution to make to the world and I have only grown more intense in that belief. I am simply not done living, with all which that experience entails. But my every breath now comes at a price. Because I cannot move to assist myself I must have an able-bodied person within hearing distance of any alarms or signals from my equipment. The skill requirements aren't high and can be taught in a weekend, but nevertheless someone must be alert and on duty 24/7. Family is often preoccupied by the demands of daily living, volunteers are few and far between, and government assistance is non-existent for people in my condition. The one factor which should NOT be involved in deciding whether to live on a vent is the cost of attendants. Medicare will not provide for in-home attendants. There are even very few institutions which will take people on mechanical ventilation and hospice is not an option due to the vent being a life support device. With the enormous wealth floating around our for-profit healthcare system it is astounding that no insurance (not even my high-end corporate policy) will cover the cost of attendants. So my only option, given my desire to live, is to become a beggar on an offramp of the information superhighway. This is terribly humiliating to me.

Nerd Factor Five

As an Information Technology professional I tend to accumulate equipment. I have a couple of old laptops lying around (some dating back to 1998). One of the slightly newer ones I connected to my TV via the external SVGA port (with an associated stereo sound cable connected to the headphone jack). Now I can stream Netflix and other online content to my big flatscreen TV while not using up the resources on my communication system. For independence I installed VNC which gives me full control over the remote machine. All I need is someone to power on the laptop and I am up and running. Currently I am watching live surfing being streamed from Bells Beach, Australia. Think I'll crack a Foster's and enjoy!

More Press

As many of you may already know, I was recently featured in an article in the Santa Cruz Sentinel. There was a lot of information to cover and I applaud Laura for getting it all in there. I did want to clarify some points: First (and least), I was the web group sysadmin for Lutris, building and maintaining the internal and external web infrastructure, and the I.T. manager for Mercedes-Benz Research & Development. Second, regarding vents, my point was that due to the costs involved, many never have a choice. Some make a choice not to vent, and I respect that. However, due to the financial expense, for many the choice is made for them regardless of their desire. This deprives the world of many potentially productive and engaged people, and is an ongoing concern of mine.

Another Victory

This is why we do it. Olya in the Ukraine needed a biPAP which she couldn't possibly afford. She contacted ALS Guardian Angels. I chat with the ALSGA coordinator quite frequently, heard the story, and donated my old biPAP. ALSGA shipped it to Poland and Olya's friends got it to her from there. Another PALS given more time alive by cooperation and action within the global PALS family. Although I appear in this story, it is not about me: It is about how we as PALS can change our own lives and the lives of each other. Without the new communications technologies now available (and the ability to use them) this could not have happened. The following is an email trail following receipt of the biPAP and a technical issue resolved. Some of the discussions took place over real-time chat and so aren't shown here. Total time from request to receipt and use was less than a month. -------------------------------------------------------------------------- From: Olya@.ru To: @.com Subject: I want to say thank you Date: Thu, 31 Mar 2011 00:19:27 +0400 Hello, Lisa! I can't wait to share my happiness with you. Today I've used the bipap for an hour or so for the first time and I felt excellent. Much better than without it. I learned how to do settings. I find my mask to be comfortable too. I feel deep relief now. I'm not scared any more not being able to breath normally and sleepless nights are the past. I've attached a picture of me while bipap therapy. Now I'm thinking back and understand that is would not be possible without ALS GuardianAngels, Stu and your priceless help. There were obstacles to ship the bipap and receive it, but you were so patient and sympathetic to me and to all this process. I sometimes can't believe it's true. When I tell people, that an American organisation helped me with the bipap and tell them this story,they say: "It's something unbeliveble, it's really hard to believe that miracles do happen". You can't imagine how much your help means for me and my family. I'm writing this and understand that I can't find right words to express how grateful I am.I also want to tell Eric (the donar) that his donation means '"surviving" for one more PALS (for me). That this is more than a gift! That I will always be grateful to him and never forget it. I want to cry out THANK YOU FOR EVERYTHING YOU ARE DOING FOR PALS! IT'S PRICELESS! Happy Olya 29.03.2011, 17:18, "ALS GuardianAngels" <@.com>:YAY, I am so relieved! Here is the companies contact information: Respironics Inc - 6 reviews - Place page www.respironics.com - 1001 Murry Ridge Drive, Murrysville, PA - (724) 387-5200 From: olya@.ru To: @.com Subject: Re: Olya: Mission accomplished! Date: Tue, 29 Mar 2011 15:09:30 +0400 Hello Lisa, It was voltage issue (the user guide info was right). My husband bought another adapter and the bipap works with the new one. Actually, at first we used an adapter too (an American one, as we have American product and it does with the device), but the bipap didn't work with it, but Ukrainian adapter is good.Thank you, Lisa, for your help, anyway. I was really worried. But I still need the contact of a provider in case something goes wrong in future.Model ð 1003986PCA1SN:3074661My phone number +38 095 700-68-67 29.03.2011, 02:25, "ALS GuardianAngels" <@.com>;:Also, please send me the model number and serial number...any other information would be great. A detailed reply about what is happening will also be helpful. Send me your phone number again as well. From: @.com To: olya@.ru Subject: RE: Olya: Mission accomplished! Date: Mon, 28 Mar 2011 18:23:01 -0400 For now, bring it in to your doctor at your appointment...they may have some advice. I'm hoping it's not a voltage issue between US and Ukraine products...we looked into that and we were certain it wouldn't be an issue. I can look for contact info, I already called them to see where the device was originally made (needed that for Customs). I will call them tomorrow as they are closed already today. From: olya@.ru To: @.com Subject: Re: Olya: Mission accomplished! Date: Tue, 29 Mar 2011 01:59:47 +0400 Picture is attached. This is what I see on the screen, when trying start the bipap. 29.03.2011, 01:07, "ALS GuardianAngels" <@.com>;:Olya, here is the user guide: http://global.respironics.com/UserGuides/UserGuideBiPAPSynchrony.pdf Let me know if this helps or not. Otherwise, I can definitely ask the Donor if he has any suggestions. From: olya@.ru To: @.com Subject: Re: Olya: Mission accomplished! Date: Tue, 29 Mar 2011 00:51:09 +0400 Hello Lisa, We have just tried to start the bipap and failed. It does turn on, but in several seconds long alarm sound and red solid and yewllow solid turn on while system self test. I think we should adress the provider, but we don't have one. Could you advice what to do? 28.03.2011, 17:58, "ALS GuardianAngels" <@.com>;:I just received this wonderful update form Olya! Also, since Olya wished to thank the donor I included him on this message. Olya, his name is Eric Valor...and he's a wonderful man and PALS from Santa Cruz, California. Thank you all, and Olya I look forward to more updates on how you are doing! - LisaFrom: olya@.ru To: @.com Subject: Re: Need help to live with ALS Date: Mon, 28 Mar 2011 16:53:01 +0400 Hello, Lisa! I have news. I've just received the bipap and the mask. I didn't try it yet. I'm going to see a doctor tomorrow and she should do all the settings. But I'm very excited I have the bipap. I will do my best to get accustomed to it. There is a nice surprise. When I opened the box, I found a humidifier there.I can't express how grateful I am to you and Stu and the donor and to all the people who helped me to get it and of course to God, who arranged my meeting ALS GuardianAngels. I'd love to thank the donor who agreed to donate it to me. I hope you can deliver my thanks to him. I am really very very excited. I can't believe everything is done.I will write you how I am doing with the bipap. Olya

A Possible Cause

For some time it appeared that the inclusions found in the cytosol of neurons in degenerative disease were causing the disease, likely due to disruption of movement of organelles and proteins up and down the axons. But evidence is now suggesting that may not be the case. With TDP-43, it appears that depletion of it from the nucleus is the cause of disease. With SOD1, an unknown toxic gain of function is still theorized. However, a recent study reported that mutant SOD1 interacts with TDP-43 where normal SOD1 did not. Conflicting previous studies have found and not found misfolded SOD1 inclusions in the motor neuron cytoplasm of sporadic ALS patients, though a study using novel antibodies specific for denatured SOD1 reported small inclusions in all tested SALS patients. SOD1 is a highly complex protein and such are easily misfolded. Usually this is no problem as either chaperones refold the protein or intracellular autophagy destroys the errant protein. But age and stress can cause autophagy to decrease in effectiveness, possibly leaving errant proteins in the cell where they can do damage. So assuming that mutant SOD1 is present either by genetic mutation or routine misfolding not corrected or cleared by the cell, and assuming interactions between mutant SOD1 and TDP-43 where TDP-43 is depleted from the nucleus, it could be held that mutant or misfolded SOD1 causes disease through depletion of nuclear TDP-43.

Activation of the glial cells (astrocytes, microglia, etc.) is a driving force in ALS progression. Experiments where mutant SOD1 was limited solely to the glia demonstrated the ability to drive disease on their own. In the case of inherited forms of ALS where particular mutated genes produce mutated forms of proteins throughout the body it is easy to imagine disease spreading rapidly once initiated. But what drives the more common sporadic forms? A clue might be found by looking at prion disease. In fact, a recent study shows that Huntington's Disease may very well spread this way, and it may be applicable to other neurodegenerative diseases. Indeed another study found that extracellular SOD1 can induce microglia to release pro-inflammatory cytokines and free radicals which promote motorneuron damage. A more recent study showed that introduced mutant SOD1 can induce disease. The biotech company Amorfix makes antibodies against extracellular mutant SOD1 and is now in trials to use these antibodies as a vaccine against ALS.

So with mutant or misfolded SOD1 we have multiple paths for disease as well as a likely pathway for spread of disease. Each of these questions are comparatively easy to test and seemingly easy to intercept in the extracellular space. I look forward to more studies to further illuminate these questions.