28 September, 2015

Cosmecuticals to come: Asian flush cured.

With recent news that yet another new method for performing in vivo gene editing has been discovered the landscape of possibilities looms beyond just the superficial.

"Asian flush" is the term used to describe a condition that effects a large population of people of Asian descent which is a genetic mutation that prevents proper processing of one of the caustic by products of alcohol ingestion. This leads to an inflammatory response in the system which leads to dilated blood vessels and the "flushed" appearance.

Aside from this superficial result it also means that generally Asians with this mutation need to be very careful with the amount of alcohol they are ingesting as they don't process it as efficiently as those without the mutation.

Enter gene editing:

The gene mutation is well known so this would be an ideal 'low hanging fruit' target for an edit. A targeted Asian Flush cure could be effected with a germ line edit or a temporary one could be effected with a non germ line mutation. Obviously the latter provides a continuous line of business but the former ends up over time eliminating the mutation from the population should many people with it seek to have it dealt with.

Imagine 50 dollars a pop for a treatment for a quarter of the over billion people in China....and this is just one of thousands of little annoying mutations that we now can theoretically can edit out of existence once these gene editing technologies; Cas9 / Cpf1 / AAV and what ever new methods will be discovered are put to work on humans. The time is now...the "base nucleotide" rush has begun.

26 September, 2015

New Gene Editing tool: Crispr-Cpf1

new paper  published this week describes another bacteria associated system for gene editing, the CrispR-Cpf1 system.

As I've been covering this space for over a decade now and predicted in 2009 that gene editing would soon be a major innovation of the next 10 years you should be familiar with the progenitor systems discovered since that time. Zinc fingers, TALENS, AAV and CrispR-Cas9 via various articles of mine over the years.

Cpf1 appears to have complementary functionality to Cas9 but performs some things that Cas9 does not, allowing it possibly to be more "specific" in its ability to accurately target edits. Some of these advantages are indicated in the paper but this article is more about the fact that find new systems should be an expectation.

From an evolutionary perspective the fact that living processes under go cycles of change and growth requires that at some point they have detailed and accurate abilities to edit genetic information in various ways...either to repair faulty regions or to silence regions in order for engaging developmental change over time. So though there are several discovered systems at this moment in time there may be many more yet to be discovered with novel abilities to specify edits...this will mean that the coming age of gene editing will consist of harnessing these variably effective tools to perform desired in vivo modifications.

This is a good thing as with the discovery of these early systems patent battles have erupted between researchers which have the chance of marring wide application of some systems by gene hackers....this would be bad for Cosmecuticals which I've explained is a net good for humanity over time if we guide their development.

So more systems means more potentially patent free ways to make edits which liberates creativity in the type of edits and who can perform them. There is still much to be concerned about however as this technology has the power to make monsters (literally) but better to have this power working in the light rather than in the shadow.

23 September, 2015

Gene Editing for Cosmecutical purposes must trump all efforts to ban the technology.

The early rush to ban such use is going to fall by the wayside very quickly as governments realize that banning the technology for human use domestically will only put their people at a huge disadvantage going forward.

As I have been explaining at my blog for years and explained in my chapter of The Future of Business

:CrispR Cas9 will make all sorts new industries possible that are focused on genetic modification of superficial (phenotype) traits that are "low hanging fruit" modifications. It heralds the "cosmecutical" industry as I like to call it. I've written on this subject for quite some time having prognosticated its emergence going back a decade.

Research teams all over the world are probably already at work (bolstered by entrepreneurs and business people who have come across these ideas) will require a few months to years of focused research identifying the important gene networks, characterizing their variation and then will strike "gold" in the form of gene editing mods to switch individual network pathways to desired output forms either somatically (which isn't permanent nor does it transfer to progeny) or germ line (which is both).

The existing industry for cosmetics will flower with these new non invasive and extremely safe future means of effecting things like skin color change, hair color change, hair texture change and eye color change. Taken together I've researched that this industry is at least a trillion dollar potential.

Beyond the money however I see it as mans final domination of much of the source of xenophobia in human society. It is based on identification of apparent physical difference and creating arbitrary distinctions of ability, merit and association from them...what happens when technology can truly turn a black person white or a white person black?

All sorts of awakenings happen in the social landscape. The coming together of humans of shared experience which the internet started, the web accelerated and mobile web kicked into high gear...will be boosted yet again when superficial markers become totally and completely a fashion choice...an accessory to wear and take off ...not a symbol of identity to fight and kill and oppress over.
The dawn of the age of Neopolitan people:

http://sent2null.blogspot.com/2015/06/neopolitan-people-and-rachel-dolezal.html The obfuscation, if not end of skin based privileges and the attendant evils that they have created and maintain in many parts of the world is nigh using such technology and for that alone it may be worth all the risks.
For me this is the greatest power in the unleashing of such technologies and why it is CRITICAL we let it happen no matter what short term consequences result ....and be sure some will, teams will make mistakes in their characterizing of various pathways....teams will not produce guide RNA that are specific enough in their identification of extant pathways and result in undesired modifications. If testing (likely in animal models) is not fully performed, these may impact the deployment of the technology in the first nations to go live with human tests; so it is important that during this research process that it is: a) visible to regulation and b) complete to cover as many edge cases as possible.

Making such modifications illegal makes both a) impossible and b) unlikely (up to the ethical fiat of the "gene kiddies" running basement biolabs who would other wise be trying). So early embrace and control and guidance is the only rational choice for any government.

11 August, 2015

Bioethics of Gene editing, an analysis of some concerns as addressed by Steven Pinker

Steven Pinker provides some details regarding his view that banning gene editing technology outright is naive in this interview. I some times agree with what Pinker states on various issues and on this one a particular area of my research focus he does get the general reality correct in my view (that bans are naive at this point) however he's a philosopher and not a Scientist and thus has made a few errors that I will point out here.

First, the idea that crispr is prone to significant errors is false. The early versions of the technology produced by Doudna's team in late 2012 were but even then they were significantly less likely to induce errors than prior methods (zinc fingers and TALENS).

Since then far more advanced methods have emerged that are virtually perfect in make single gene modifications consistently, keep in mind that a large part of the accuracy is involved in ensuring the a sufficiently unique guide RNA is utilized to zero in on a given gene and induce a change...there is no reason to supposed that an arbitrarily long and unique guide RNA can't be utilized to target a change over a desired region. Technical issues exist in packing these longer guide RNA's with the complex machinery and vectoring them but those are hard to do's not impossible to do's, if we throw the will and money at the problem it will surely be able to go away...or at least go away to such a degree that people are willing to pay the necessary money to overcome any inherent risk. A paper by George Church et al described some of the issues with the then current process, some of which have since been alleviated or mitigated:

Our current pharmacy business is thriving and it operates on exactly this kind of risk profile calculus....every time you take an aspirin depending on who you are you risk dying from a stroke or having some cross effect with a drug you have been taking.

Second, with regard to "designer" babies, his description of psychological traits as being extremely difficult to modulate is very on point...such things as we saw in "GATACA" where intelligence was directly modulated in a general way are unlikely how ever it can be modulate with much more gene specific changes that effect general intelligence for example changes that may control rate of neurogenesis (which are likely to be just a few genes over thousands) or changes that control memory formation by regulating certain key neurotransmitters....sure lots of testing needs to happen on these but we have an extant body of living people already expressing a full landscape of interactions of genes.

I've described some of this in hypothetical stories on the technology going back to 2008:

Understanding what we can do will come from looking at what nature IN us is already doing with no problem and simply replicating those patterns at earlier stages of development in target individuals.

Also, there are a bunch of designer baby changes that have nothing to do with enhancement but simply eliminate dangerous traits, for example susceptibilities to all types of genetic diseases have many well known genetic factors that can be singled out and edited with little reason for concern. Again, using the corpus of expression in living people to identify extant interactions is a great guide to avoid willy nilly changes ....and so having a rapidly improving ability to perform whole genome sequencing as well as characterizing patterns in those massive data sets to identify such patterns is a very good thing to be happening now.

Third, all the difficulties many in the bioethicist camp that feel a delay on research to germ line editing should be placed ignore the fact that many phenotype associated genetic changes can be made very few to no side effects at all. These would be the types that would be included in what I've termed cosmecutical changes.

http://sent2null.blogspot.com/2015/06/cosmecuticals-trigger-to-injection-of.html In my chapter of the book "The Future of Business" I provide a break down of some of the potential opportunities that loom in pursing development of phenotype targeted gene editing. The industry has a potential to be a trillion dollar industry inside of 20 years time. Coupled with it's relative ease to implement and safety compared to other gene line modifications as well as the potential social gains it makes a very big and obvious goal to advanced humanity along several lines that is worth the small risks. http://fob.fastfuturepublishing.com/

Changes in this camp include edits to genes associated with the expression of melanin in the skin , eyes and hair...these would induce visible modulation of expression of skin types, hair color and eye color. I explain the social ramifications of such change in a few posts over the years but the advantage to society of the elimination of "race" as a fixed identifying element in the human family should be an obvious thing that we WANT to do and do as soon as we can. The age of "neopolitan people" as I've called it is important for us to mollify a great deal of the causes of xenophobia that exist in the world which are due to ignorance and fear based on differences in apparent morphology in phenotype.

Moreover, from the ethical perspective these changes are less ominous and also more potentially lucrative as targets to any researchers who are looking to take advantage of the technology...particularly in light of all the hubbub concerning modification to the germ line.

Finally such changes don't have to apply to the germ line at all, an advanced version of crispr used to precisely target and edit genes associated with skin color could confer temporary effects approximating a really long but genetically modified tan (but one where you can tan darker or lighter)...even that could be marketable and would likely have a demand space for it being done.

04 August, 2015

Altruism an emergent quality of having big brains, not directly gene driven.

Thus apparently altruism is a purely socially emergent phenomena and one that is not gene driven.

Why is this *not* surprising?

In some of my musings on altruism, morality (which I posit emerges from it) and later the ability for religions to form....the definition of altruism stems from one underlying reality of social organisms:

The competition for limited resources necessitates in closely living organisms of the same type a response heuristic to the resources various states of supply under demand. 

Here from 2012 I put a line under it:

"If a particular resource or resources is required for our survival and we are the only agent in the environment that can gain value from the resource we have no inherent desire to be altruistic, this may seem trivial but it is not...our altruism is not an absolute characteristic of our make up but rather an emergent quality of moral expression that ONLY becomes extant when others that also value that resource are present and subject to the same constraints."


It's all about the math, game theory.

In social organisms two responses to this can emerge cooperation or conflict....but they appear on a spectrum both across animal societies and also within those societies as resource variation dynamically varies.

Variation of this presentation to conflict or cooperation though depends on the individuals of these group of related members ability to *remember* and to understand the time cost average advantage of hoarding. Where hoarding is understood the signal for cooperation is stronger in fact made extant....particularly when individual variation in ability is also present and noted.

Ant (and other insect societies) present a very basic display of the opposite pole. Ants have barely any memory and use chemical signalling to govern the cooperation heuristic....right signal = friend, wrong signal = enemy.

Also as their memory is basically non existent they don't engage in individual hoarding and also don't recognize variation among their own group, nor do they engage retribution for hoarding like behavior (can't if they have a short memory)....so *apparent* cooperation in their society emerges purely from the dynamics of following the chemicals which are already inherently a genetic inheritance of the society.

This is key...as it means if true, that if one tests for methods to remove altruism in ant colonies one should NOT find a loss of genes as altruism in ant society is defined in a different way from altruism in societies of animals with a) visible individual variation (skills we can see and judge for utilization) and b) memory of time cost advantage of hoarding. c) fear of retribution (linked intimately to having memory).

So how did the researchers enable the "loss of altruism" is the next question. From the article:

"Testing this "novel gene" hypothesis is difficult given that all ants are social. However, not all ants make workers. Some ants are "workerless social parasites" whose queens exploit the worker force of other species by invading and setting up shop in their colonies. The authors took advantage of the unusual biology of these ants that have lost their worker caste to determine if worker genes really exist.

The research team, led by Chris R. Smith (Earlham College) and Alexander (Sasha) Mikheyev (Okinawa Institute of Science and Technology), sequenced and compared the genomes of six ants (3 hosts and 3 workerless social parasites) and looked for evidence that genes that are typically over expressed in the worker caste would degenerate through time when workers are no longer produced. Instead of finding degeneration in "worker" genes, they found that there are no "worker" genes and the majority of the protein coding genome is maintained in species that stopped producing workers even after one million years. Their research is online early in the journal Molecular Biology and Evolution."

:So there it is, essentially what we call altruism in ants really is antruism...unique to ants (and other chemical driven social animals) and only analogically similar to altruism in higher animals which have a strong resource driven drive to modulate behavior along a cooperate to conflict pole because they have deep individual memories. 

This makes sense as from an evolutionary perspective it leads to an ability for a group of related individuals to take radical survival departures that may cause internal conflict but still enable survival of at least some (the greedy and ruthless) individuals of the society on the conflict pole but with high risk to achieve (as such individuals need to watch their back all the time). On the cooperation pole it leads to increased survival on average as individual variation is leveraged to benefit over all ability to utilize available resources with low risk of attack.

Over all possible survival challenges this variation in potential response is a lot more dynamic to change than what exists in ant society where such response variation can't exist....a colony of ants will expend themselves to extinction attacking a foe or pursuing a food source. They survive as one and die as one...this seems honorable but it is foolish if what you want to do is propagate your species genes.

A major example of this success in human society include our technology...which emerge when individual variation is recognized and harnessed and then shared across groupings.

Where it not for language we'd still be disparate bands of cautious lineages.

Where it not for agriculture such lineage groupings would stay small in size.

Where it not for machinery and the harnessing of metals we'd still be living in mud huts instead of dispersed across the globe having used our technology to span continents and thus radically improve our survival ability to local conflict or environmental chaos breaking out.

So it turns out altruism arises not as a specific gene driven innovation but as an emergent one that arises as our individual ability to have long memories that can *chose to* hoard limited resources  while navigating the consequences from others exists. Some could quibble here and say it is still genetic but by accident of those features in the animals in question, that is a way of seeing it but I think it over looks the critical importance of memory as a key enabler...thus exists in us but appears only as a simulation (which we thus anthropomorphize in ants and other insects).

Note the connection between altruism and morality described in that earlier article, where altruism is the ability to chose to cooperate by memory baring agents. Morality is the fabric of possible ways of cooperating given a given extant situation of need of resources....they are intimately related. As indicated in the earlier articles thought experiment where there are no others to deal with morality has no meaning , no means of application thus it is bound at the hip to altruism being possible in the first place.

25 July, 2015

The share economy: The Disintermediation trap

Yet another darling of the so called share economy has called it quits, home services startup homejoy has announced they will be shutting down operations.


This gets to a truth about the marketplace disinter-mediation that is all the rage these days a concept that is core to the very reason I started working on the AgilEntity framework back in 2001. I realized then that technology enabling the removal of various types of middle men coupled with the elimination of mobility requirements for getting work done would lead to a much more flexible workforce.

After I'd built the framework I teased these ideas in an email from 2006 which I later transcribed into a blog post on the coming "telepresent workforce".


In this post I predicted a future of offices as flexible work locations (what we see has emerged in the form of co-working office startups) but more change will come as companies become fully distributed in nature, allowing their existing employees to work more flexibly...particularly as knowledge work continues to eat up the majority of jobs in the workforce.

Earlier this year I followed up on that posting and predict a future of interesting upheaval of the real estate market in large cities where telepresent workers free from having to commute to offices leave companies without reason to keep tall buildings on their books. This will lead to a drop in real estate prices that will allow conversion of many of these buildings to living apartments and condominiums.


This change will be precipitated by businesses that are leveraging fully action oriented workflow based foundations that allow leveraging fully emancipated workers who almost never need to come to any physical "office" to do their work.

Still for the companies that have emerged to use technology to disintermediate exchange between a provider and a potential customer in the physical or virtual world a danger remains, the disintermediation trap is this danger and homejoy has fallen right into it.

"Homejoy cofounder and CEO Adora Cheung told Re/code that the “deciding factor” was the four lawsuits it faced from cleaners who claimed they were misclassified as independent contractors. That’s likely true — the liabilities and legal costs associated with the suits were no joke. But there’s more to Homejoy’s demise: its customer acquisition model simply didn’t pencil out, former employees and industry sources said.

Former employees tell FORBES that Cheung and the startup pushed relentlessly for high growth numbers instead of fixing its poor retention rates, which persisted both because Homejoy relied too heavily on deal sites like Groupon for new customers and failed to improve its core service because it couldn’t train its independent contractor cleaners."

 The problem with retention rates for any business in the space of marketplace disintermediation will be quite present since as a thin layer middle man the digital service is no longer needed once it has connected customers with working agents who they find are good for recurrent business.

This is why taskrabbit is having a hard time.

This is why elance, 99designs and many other such companies are going to have a tougher time than they expect.

Services that parsel out sub tasks are likely to do better as the creation of a rapport doesn't return a benefit to the client in the same way it does for services that require humans to be mobile ...for example, amazon's mechanical turk.

Uber interestingly is mostly isolated from this effect since Uber drivers do not become married by service to their customers as there is a high level of randomness involved in how customers use the service and place is a dynamic dimension that is static for the other types of services (the customer and the taskrabbits/elance have fixed locations they live from and once they establish a rapport what need for taskrabbit?)

This is why at WorkNetz (​ in stealth) the focus has been on harnessing a companies *existing* employee base first to emancipate them in critical ways that can radically improve business performance. (Contracting reach out from this basis is enabled easily)

Emancipating an existing workforce has several key advantages:

1) Company technical and process dna stays locked up, existing workflows aren't automatically leaked into a random contractor soup. Preventing the regression to the mean with other companies providing similar services that also use disintermediation technology.

2) Cultural dna stays locked up...a big part of where people work is working with others that feel the same about things that they do, that exists already in many companies and switching over to all contractors as employees loses a great deal of that character giving no contractor any feeling of place or loyalty.

3)  the service doesn't have to deal with the legal problems of contractors attrition since by default all your workers are already de facto employees, you are just leveraging the services provided by worknetz to maximize the value landscape you can derive from them while also "emancipating" them of the restriction of hegemony of time** and place that plague traditional employees forced to commute to specific places at specific times to be magically productive.

It is clear why the AgilEntity framework  which implements the action oriented workflow paradigm developed by 2005,  is the perfect middle ground for market place disintermediate based businesses....it also explains why it was important to create a generalized solution for workflow management that worked on any type of vertical...not a purpose built disintermediating tool as all the above were designed to be....that focus enabled them to build services relatively quickly but left them horribly vulnerable to the dynamism of the customer base indicated above under a new contractor heavy business model.

The 34 slides give the 10,000 foot view in a few minutes:


Marketplace disintermediation official symbol

My rendition of a logo to symbolize generalized systems for market place disinter -mediating the execution of actions between agents engaged as buyer and seller in that marketplace.

On the left ingress and egress action requests and commitment signals by agents requesting they be performed. Those who need. (Say the person hailing a ride via Uber)

On the right ingress and egress action requests and commitment signals by those that can satisfy the request of the agents. Those who are the providers. (Say the drivers cruising around looking for fairs).

The center symbolically indicates the logic that is leveraged to enable matching of agents on either side (blue half circle meets red half circle) in order to enable a transaction.

The AgilEntity framework is a system that does this for any type of marketplace exchange that is modeled into the system leveraging the Action Oriented Workflow paradigm's statistical learning algorithms to perform efficient real time routing from and to the "best available" agents, however "best" is defined in the model of the type being exchanged making it the ONLY general solution available by design when I started work on the framework in 2001...an "Uber for everything".

Uber does this for cab rides only, Taskrabbit does this for chores and errands, Elance does this for small consulting jobs for development...etc.

Any marketplace engages the same heuristic. I've been meaning to create a graphic to encapsulate the concept for general use so here it is....if you want to represent the concept of market place disintermediation (or the "share economy") feel free to use this image.

I added a few .png versions of the image at various sizes to a google drive folder here, feel free to grab, use in slides and presentations and share the folder images. Marketplace Disinter-mediation symbol cache on google drive: