Quick intro into what ALS (Amyotrophic Lateral Sclerosis) is:

ALS is a neurological disease of unknown origin characterized by a selective degeneration and death of upper and lower motor neurons, initiating in mid adult life and almost invariably progressing to paralysis and death over a 1-5 year time. The majority of patients afflicted with ALS seem to have it in non-familial form.

About 95% of ALS patients are sporadic, whereas 5% are familial. In this group, approximately 15% are caused by mutations in the SOD1 gene (on chromosome 21)

Biological causation behind ALS disease:

Several potential mechanisms of motor neuron degeneration in ALS have been proposed. These include:

- the involvement of environmental and genetic factors

- autoimmune phenomena

- increased oxidative stress

- glutamate toxicity

- protein aggregation

- mitochondrial dysfunction

- cytoskeletal abnormalities

- impairment of axonal transport

- pro-apoptotic alterations

- Both Neurons and surrounding Glial cells are affected

However the cause of ALS is still unclear and the only current approved medication,  Rilutek (riluzole) only extends average survival time by 2-3 months. So what are the most promising future targets for therapeutic development based on our latest understanding of ALS?

Promising potential treatment targets for ALS

• Glutamate toxicity – increasing neuronal reuptake or reducing Glutamate in the brain and cerebral spinal fluid (due to implication in Neuronal cell death) seems to be a promsing avenue and several potential therapeutics could assist. Cephalosporins and memantin have been tested and show some promise
• SOD1 familial – 15% of cases and a mutation in this gene is assumed to increase oxidative stress damage. One potential therapeutic, Edaravone is a free-radical scavenger is which has been shown to significantly reduce the loss of function in motor neurons (currently in PhIII testing). Anti-Sense SOD1 also significantly reduced decline in mouse SOD1 models.
• Apoptosis and ALS - Transcriptional dysfunction has been implicated in the pathogenesis of many neurodegenerative diseases including ALS. Valproic acid inhibits apoptosis, promising in SOD1 mice but not effective at doses used in epileptics in humans (perhaps its worth trying higher doses in humans?). Tauroursodeoxycholic Acid (TUDCA) may have also have an effect on ALS disease progression.
• Inflammation – may be a secondary response in ALS, inflammatory cascades contribute to neuronal cell death, Celastol a potent anti-inflammatory and antioxidant, showed improved motor function in humans.
• Neurotrophic factors -  involved in the regulation of neuronal survival and differentiation and in maintaining neuronal structural integrity. In SOD1 G93 mice treatment with insulin-like growth factor (IGF)-1 or glial-cell-line-derived neurotrophic factor (GDNF) have beneficial effects on survival and motorneurons morphology, overexpression or administration of VEGF protects motor neurons from degeneration and prolongs mice survival
• Autophagy – reduced autophagy linked to neurodegeneration, therapeutics like Lithium may have an effect on increasing neuronal autophagy and have a neuroprotective effect but human clinical results are mixed.
• Neuronal Stem Cell replacement – Ultimately, neurodegeneration results in neuronal cell apoptosis and one potentially promising therapeutic option is neuronal stem cell replacement, several companies are currently working on neuronal stem cell replacement therapies (Neuralstem, Brainstorms and others) and promising results have been seen in mouse models but none yet reported in humans.

It's important to note that most pre-clinical pharmacological studies failed to translate to ALS patients most likely due to the limitations of ALS mouse models, which carry the same mutation and are relatively homogenous, while ALS patients are genetically homogenous and only a small percentage have familial ALS. After a review of the literature, it seems there are several promising pathways to target for effective therapeutic development, however this has to be guided by both an understanding of the potential genetic variability in different forms of ALS and the disease stage in patients effected by ALS.

The talks are now online and my specific talk focused both on the developing medical technologies (regenerative medicine, 3D bioprinters and targeted therapies) as well as the emerging commercial realities (a move away from small molecule blockbusters and the emergence of the E7 block of countries as healthcare powerhouses). If you're interested, please feel free to check it out here (my talk starts at 1.35) and share your thoughts below!

There were of course a fantastic array of speakers on various future forward topics which included:

Session 1, Re-Imagining Humans: Mind, Media and Methods

Session 2, Radically Increasing the Human Healthspan

Session 3, Redefining Intelligence: Artificial Intelligence, Intelligence Enhancement and Substrate-Independent Minds

Session 4, Business and Economy in the Era of Radical Technomorphosis

Humanity + is an organization built and run by technologists and entrepreneurs to help continuing to push the bounderies of science and technology. If you'd like to find out more, please feel free to swing by the H+ website.

While, that controversy seems unlikely to get resolved any time soon, at least one piece of that puzzle has become clearer. Researcher's at the Salk Institute have discovered a major key to how human and other animal cells age, shortening of the protective tips of the chromosomes (where a cells DNA is held) causes damage to the structure of the chromosome itself, Chromatin which is made of a combination of DNA and Histones) is damaged by the production of defective histones which increase with the shortening of the chromosome end caps (telomeres).

Not only is this an extremely important finding but it may also have future potential in the development of treatments to reverse, at least partially, cellular aging in humans as the Salk institute scientists were partially able to reverse this cellular damage in the laboratory! Does this mean we'll soon have therapeutics to reverse the aging process, not likely. However, I wouldn't bet against a Robert Heinlein type anti-aging clinic sometime in the future... a sci fi nerd can hope ;)

The emerging virtual biotech model,which some Angel and VC investors are now funding, so far seems a very lean and resource effective model. Virtual biotech's nowadays are actually being built with very small teams that outsource as much as possible to reduce any overhead costs. Typically from my experience these teams can be as small as one full time CEO with a fully part time/consultant executive team through to a more classical 5-10 person full time team. The aim of many of these virtual biotechs is getting to signal with their lead therapeutic, this means getting some proof concept or proof mechanism data that their drug works either in humans or animals to help raise the next financing round. So far in this tighter financing environment this model has proved to be one of the more successful strategies for founding new biotech companies, as can be seen with the Flexion Biotech deal with Pfizer. The flip side of this is that a lack of signal in a lead molecule can also be more lethal set back both to a new therapeutic and virtual biotech.

I personally wouldn't be surprised if this push to innovate both in biotech business models and how clinical development is done doesn't result in a more cash and resource effective strategy for bringing new therapeutics to the market and brings in higher returns for biotech investors.

Within the Burrell report they looked at seed, series A and B rounds which increased 43% over the same quarter last year. The information below provides an overview of the number of deals and also the percentage increase or decrease of these deals.

Disclosed deals in Biotech     Q1 2009     Q1 2010

Seed, A-B rounds     28     40     42.90%

C and later rounds     12     10     -16.70%

More good news for early stage biotech's

There's also additional good news for early-stage biotech's in regards to the upcoming R&D tax credit which the U.S. Treasury is pushing forward which will for the first time be providing grants in exchange for R&D tax credits. This tax credit was actually as a result, somewhat surprisingly of the highly unpopular patient protection and affordable care act which was signed by Pres. Obama on March 23, 2010.

The legislation allows biotech's to claim a non-refundable credit for 50% of their qualified investment costs and covered projects for the 2009 and 2010 tax years. The Therapeutic tax credit differentiates itself from previous R&D tax credits for the first time in that cash burning biotech's can request this tax credit as a grant in efforts to effectively recoup their original investment (up to 50%). The Treasury Department expects to release applications a little later on in the year. Qualification criteria are included in the link attached. This is a very promising development for fledgling biotech's, especially as it shows that the current administration is thinking about the importance and value of the innovation in the biotechnology industry!

• Scott Thacher, CEO of Orphagen
• Richard Lin, CEO of Explora Biolabs
• Gonul Velicebi, CEO of CalciMedica
• Jiwu Wang, President and Ceo of Allele Biotech
• Douglas Lappi, President/CSO of Advanced Targeting systems

What seems to really connect with Dr. Watson's statement is that our most cutting edge cancer therapeutics are often based on ancient hypothesises or assumptions.

Angiogenesis

Take Angiogenesis as an example(the need for tumors to create their own blood supply to sustain themselves), this mechanism of action was proposed by Dr. Judah Folkman back in the early 70's and after much resistance in the scientific community accepted decades later. As a result of Dr. Folkman's work and the the development of drugs that choked off the creation of new blood supplies to cancer cells our latest generation of Cancer therapeutics have emerged (Erbitux, Herceptin, Velcade and Tarceva). One seemingly important point here should be the glacial pace of Cancer development over the last couple of decades and our need to innovate out of this deadly lethargic pace of innovation.

Understanding how to differentiate between cancers

The good news is that biotech's and pharma companies are heavily investing in new experimental therapies (arguably the number 1 target for therapeutic development) through the use of newer genomic technologies and an increased understanding of how to really separate out different variations of cancer. Herceptin (Trastuzumab) only works well for certain types of breast cancer, typically on those breast cancers that over express HER2 but when it's appropriately used it can have a substantial effect, further reducing relapse risk in some women by 50%.

Future Cancer treatments

Increasingly, there's a consensus that not only do cancers have to be specifically targeted based on their specific genomic mutations (which can be a daunting task based on the latest findings of 23,000 mutations in a sequenced lung cancer cell)  but it seems likely that cancers will also have to be treated with a combination of therapeutics to reduce the risk of resistance developing (a similar concept to treating bacterial infections). As a result many current studies are ongoing to identify effective combination therapies and over time will likely be a combination of better and better biologic therapies (protein, RNAi and cellular) as well as through the use of targeted radiotherapy and surgery. 

One key entrepreneur and venture investor that I’ve followed over the last decade or so has been Guy Kawasaki, if for no other reason that he provides salient words of wisdom but in a very entertaining format to budding entrepreneurs and has been doing since the early days of Apple computers.

In one of his articles, Guy talked through some of the finer points of “The Art of the Start” and I highly recommend reading his original article. I’ve simmered down some of his key points and connected it to some of the lessons I’ve learned and observed in the biotech industry.

1. Early Cash flow is king – Not Profits! : This is a tough one for us in the land of biotech start ups as it’s often touted that it takes 7-12 years to develop a therapeutic and anywhere between $800M-$1BN USD to get a therapeutic drug approved by the FDA. Statistically, this may be true (and I wouldn’t want to doubt Tuft University’s numbers in aggregate) but the reality of it is that a really solid platform technology with proof of concept data (even in vitro) could be enough to raise, angel, venture or even grant funding and I have known of Biotech entrepreneurs in the past that have been able to raise substantial sums (in the millions) of even non-diluting grant funding from the government and non-profits. Other interesting models are starting a service business (even if only temporarily) or in the medical device/tools space it may be possible to start selling/partnering your technologies sooner to jump start a positive cash flow.
2. Bottom up forecasting is the way to go!: market segmentation is a class that’s taught in business schools globally and can also lead to some pretty confused thinking for first time entrepreneurs if you listen too much to your B-School Prof theories on assessing essentially established markets and apply that rational to tiny or non-existent  but rapidly developing markets. It doesn’t really matter if the market for your particular drug/device or service is in the billion dollar range, your market size might be limited to the 10 researchers that would be willing to try out your device in the first year in their lab or how much you can get for your first licensing deal in year 1. My advice is to see past the excel worksheet and really think about how you personally will sell your biotech product!
3. Truly understand that you’re building a scrappy start up (under staff and chose your battles): this is perhaps my favourite of Guy’s points and links in with cash being king, for a bootstrapped start up you have a precarious lack of both time and money, this means on the one hand you should buy as much off the shelf (rather than bespoke) equipment as possible but on the other hand realize that you will likely have to under staff your start up initially to gauge the true level of resource need but be careful not to fall foul of any existing rules or regulations in our highly regulated industry (OSHA being just one example)!

I’ve highlighted a few points that I felt are particularly important to bear in mind as you start up your projects/garage biotech. The catch in our industry of course is that there is a vast difference in how you’d structure your project/biotech dependent on your individual focus, be it tools, devices, diagnostics or therapeutics.

I’m always interested in finding out more about how innovative Garage biotech’s have surmounted these challenges so please feel free to get in touch or leave a comment.

Most lab scientist currently still use notebooks, strategically placed by their lab benches to track their progress but you could argue the need to manually insert each procedure would be too time consuming for a part time scientist. One method of stream lining this necessary process of tracking experimental progress by garage biotech enthusiasts is through the use of  webcam videos that can (if needed) be saved and then later modified to ensure that your work can be easily reviewed at a later date and time and also potentially be easily distributed. An excellent illustration of this technique was the Video Diaries created by Will Smith’s fictional character in the movie “I am legend” which showed the power and simplicity of tracking experiments in a video format (these webcam software programs are already widely commercially available).

I’ve included one example of a video that shows and explains how to extract DNA, pretty neat!

It's very difficult to get any sort of statistics on the number of Garage Biotech's being started or run currently by scientists or small entrepreneurs as many are hesitant to disclose their projects until they're close to completion (not unlike the Garage entrepreneurs of Silicon Valley) but anecdotally there seems to have been a rise at least in regards to resources available to this types of biotech entrepreneurs with dramatically dropping assays, used lab equipment sold on ebay and increasingly sophisticated open source bioinformatics tools.

There have also already been signs of success for some small biotech/bioinformatics start ups:

Eric Engelhard - is bioengineering a honeybee in his garage and hoping to use this technology to develop non-venom producing honey bees.

James R. Graham - was inspired while making electronic music on a half-dozen computers in his bedroom and used the algorithms that he developed to create Diction, a tool that converts the genome into a series of waveforms and locates crucial regions that are actively producing proteins utilizing the human genome which is publically available at the NIH website.

Agribiotics - an agricultural biotech start up was aquired by Nitragin for $24M and was developed by a garage biotech entrepreneur.

Spaltudaq - Johnny Stine a lone entrepreneur in Seattle and a former scientist at Icos founded a small therapeutic biotech called Spaltudaq which has been successful in setting up three partnerships to make rabbit-based antibody drugs for biotech and pharma companies. These partnerships could generate as much as $200 million, if he manages hit all of his targeted milestones (which as we know in the biotech world can be difficult).

So it seem that even though hard statistics may be hard to find in this growing niche, there's definitely growing promise!