25 September, 2009

The coming pathogenic relief impulse

The last few years have been an astounding roller coaster ride of discoveries in the areas of genetics, molecular biology, oncology and in particular our understanding of how to analyze pathogens to find highly effective, targeted methods to destroy them without invasive or dangerous side effects to the living organism. The sequencing of the human genome has opened the flood gates on investigations into the genetic causes of diseases and to the quick isolation of proteins and enzymes that by over abundance , imbalance or lack of creation lead to various pathologies.

In this post I am going to cover some of the recent discoveries and provide some analysis on how I think those discoveries will lead to accelerating benefits in the years to come.

The story of stem cells

An argument could be made that the ban of embryonic stem cell derived research in the United States by the Bush administration in 2001 forced researchers to seek other methods to investigate the power of these cells for theraputic or genetic means. The promise of cells that could be differentiated into any tissue type in the organism was too much of a lure for researchers to just let die because of bad religiously inspired policy. Programs were soon initiated to answer the question of , if embryonic cells can be differentiated forward to any type is it possible to differentiate a somatic cell back to a stem cell? The answer soon came in the landmark paper and announcement of the Yamaka team out of Japan. They successfully created stem cells from somatic skin cells, the process was dubbed iPSC and has in the short time since this first advance seen amazing further advances.

  • 2007, Japanese and American teams create iPSC's using different methods. Both methods involve gene insertion using viral vectors and were prone to oncogenic pathology.
  • late 2007, teams announce the ability to perform iPSC without use of viral vectors, removing the chance of gene insertions that change the cell line or potentially trigger cancers.
  • early 2009, team announces the ability to create iPSC using recombinant proteins.
  • mid 2009, team announces the ability to create iPSC with limited memory of previous cell state.

The importance of advanced iPSC techniques will be discussed in subsequent sections.


The harm of not normally lethal pathogens

The human race has been plagued by quite a few nasty bugs in its history. The fungal, bacterial and viral pathogens encountered from close contact with domesticated animals accelerated our susceptibility to various bugs , many mutating in lock step with our improved fitness to keep at our throats. The lethality of some of these bugs saw its greatest heights during the black death or bubonic plague of middle aged Europe. This bacteria is said to have emerged from the close proximity of humans to waste and rats that served to carry the pathogen between human and animal populations. It was deadly and killed tens of thousands over the centuries from its initial outbreaks and still kills people in parts of the world today but in reduced numbers thanks to better sanitation habits than existed in the 14th century. It can be said though that the high profile pathogenic killers like the Yersinia Pestis of the Black Death and the SmallPox virus are only the obvious contributors to reduced fitness and pathogenic attack on humans. The common cold and flu has also reaped a tally on human populations due to the high survivability of humans afflicted with these diseases but the costs of surviving are still high. Here are a few reasons why the repeated exposure to the Rhinovirus and flu virus strains can be doing significantly more damage to over all human fitness than the more lethal but infrequent afflictions by bugs like Yersinia Pestis.

  • Most people think that after suffering an infection their body fully recovers but this is not true. Many infections leave internal scar tissue which forces permanganate strains on the physical system that reduce individual fitness.
  • The process that the body performs to fight infections leads to localized swelling or inflammation, this inflammation results from the bodies defenses invading the area in order to fight the pathogen. As most wars the outcome of the battle leaves many casualties in the form of dead and dying elements of the bodies defenses and the pathogen. Inflammation can lead to elevated heart rate, blood pressure and it is implicated in increased possibility for plaque build up in the blood stream. For example studies show that the inflammatory condition of bactrial infection of the gums known as gum disease can increase the chances of developing heart disease. Repeated infections multiply this effect and lead to reduced fitness and shortened life span.
  • Though the pathogens tend not to be life threatening one thing they are is incredible productivity destroyers. A country battling an outbreak can't be productive and grow its economy. The amount of lost revenue in various countries due to simple cold infections easily numbers in the multi-billions of dollars ever year. Eliminating of the pathogens would recover a huge productivity potential for human workers that could significantly accelerate the rate at which we are discovering new things about the world.

Imagine what could be if the deletirious effects of these common pathogens could be prevented, reduced and eliminated. How would this achievement change individual fitness, average life times? It will be discussed further in a following section.


Playing the music of genes into the symphony of organs

One of the greatest achievements of man was the sequencing of the human genome in 2000. This massive effort to uncover how the DNA code encodes the proteins and enzymes of which we are made by singling out the defining genes that are transcribed to make the stuff of us required millions of hours of computer time and the hard work of dedicated scientist all over the world. Today, the sequencing of several critical "model" organisms and other organisms has been completed as well. The chimp, rat, mouse, cat, pig and nematode all are now fully sequenced and researchers are going through their maps to find all the associated genes. Since the sequencing of the human genome researchers have realized several exciting but also some what humbling truths. Prior to the sequencing effort it was believed that the DNA would be found to have a rule where each expressed enzyme or protein would have precisely one gene translation behind its formation, that "one gene produced one protein" many thought that researchers would find genes for each of the 100,000 or so proteins and enzymes in the body and be able to move on to describing and finding ways to activate or suppress expression of these genes should they be found to be missing or faulty. However this was not to be, it turns out that when the tally of genes was made the number fell well short of what was expected by 2/3's. Indeed , there are only 30,000 or so genes, this blew the idea of one gene per protein out of the water and revealed that the real story involves a complex process where genes in single action but also in unison or with variance due to local environmental changes in the cytoplasm could produce more than one protein. This makes the process of developing therapies significantly more difficult as before we can do so we need to find out the gene relationship that expresses the particular protein or proteins implicated in some pathology in the organism.

Research on the working of genes known to be instrumental in such conditions as Alzheimers' disease or Arthritis has uncovered the developmental pathways that are faulty in those conditions. Therapies to either fix the faulty pathways by repairing genes or enabling stalled enzymatic or protein actions are under development. These types of therapies will significantly change the efficacy of treatment that will be routine for pathological conditions effecting human beings. The targeting of the treatment will reduce the possibility of adverse effects on the patient and speed aleviation of the conditions. However, a more intriguing possiblity lies in what will be possible once entire developmental pathways are mapped. The genetic sequences for building a heart for example must follow specific sequences of cell division and growth as conducted by a master script of dna translations over time. Once our knowledge of the correct sequence of pathways to play to initiate and then continue this process is complete we will be able to play the music of the genes to generate entire organs, not just create a specific protein or enzyme.

The recent work that has revealed the importance of what are called "non coding regions" in the code will be critical in revealing the timings associated with the developmental pathways to enable organ growth. When these technologies are combined with the advances being made in stem cells via iPSC, there will be the ability to culture non invasively any cell type from an individual, to revert that cell to a pristine stem cell, to differentiate that stem cell into any desired target cell type and then to engage the developmental pathways for growing an organ from that cell and sit back (having provided the environment and food necessary for growth) and grow an organ in a dish. Current methods are already harvesting batches of cells of particular tissue types using various methods but they require human shaping of the cells into the structural geometries required for implantation. However, in the future the knowledge of how to grow organs will replace the shaping required with the methods today.

One must ask what will be the gains from this type of work, well imagine being able to go into your doctors office and be diagnosed for emphysema. Today the condition can only be alieviated and not cured but in the near future a culture of your cells and then triggered expression of a clump of lung stem cells generated from your cells to express the development cycle of a new growing set of lungs will be possible. As you wait your lungs will be grown to a size large enough for implantation and you will undergo surgery to have genetically identical lungs transplanted into your body with none of the chances for tissue rejection or requirements for blood match that exist today. Now take this example for any organ part and you see that simply by this replacement capability alone that humans will live much longer. Further down the line as the riddle of the causes of aging are explored we'll be able to reverse the cellular damage that accrues over a life time and thus enable fit living in individuals for arbitrarily long periods of time. Researchers have already identified the pathways and cellular machinery most implicated in age related damage during the course of a life time, methods to fix these pathways and machinery are in progress. An estimate that the majority of them will be solved by 2050 is a conservative estimate. It is safe to say that by the third quarter of this century human beings will be able to be virtually immortal. The social, economic and political ramifications of the times to come will be huge and we'll have to deal with them while trying to fight the existing battles of our damage to the environment, our ballooning population and rise in ignorance and the diminishing supply of potable water and food for all these teaming masses. The consequences of these developments will be far reaching and broad.


The end of killing for food

One of the side effects of having methods for creating specific cell types in culture or to express the complex play genes that are required to grow specific organs is that we can use non invasive methods to extract cells from a living host and then generate any desired amount of cells or organs from the genetic information in those cells using the developing techniques. This can be applied not just to human cells as the descriptive frame work for these techniques occur at the low level commonality of cell function that all prokaryote cells have in common, the machinery is ancient going back potentially a billion years and thus can be used to perform the same technique on non human tissues. This has already been doing on many model organisms but the potential to use the emerging techniques to address several critical issues of the current world industry for production of meat products. First, the need to raise living organisms like fish, sheep, chickens and pigs for the purpose of slaughter for human consumption involves moral considerations that people have mostly ignored, the possibilities of what I like to call "unkilled meat" or as some have called "invitro meat" allows us to harvest the flesh of animals without killing them. A small cell culture taken from a living member of the species can be regressed to a stem cell and then differentiated to any desired type of cell associated with human consumption. When the ability to express entire organ development pathways is realized this will lead to generation of meat products that have the identical texture and geometrical construction of the same organs taken from a slaughtered host but won't require any killing at all to procure.

The elimination of such production methods eliminates the moral issues with growing such animals in inhumane conditions for food, of slaughtering individuals that are not useful to the production process (as is done with make chicks in chicken production, see video below).
Another major disadvantage of killing animals for slaughter comes from the various by products of the industry, industrial bovine , chicken and pig production produces massive amounts of waste from these animals that is severely effecting near by ecosystems. The excess potassion and nitrogen stored in the waste is often leached into aquafers or river systems and can contribute to uncontrolled blooms of bacteria or other organisms (jelly fish) in the bodies of water that those river systems feed into. The elimination of these sources of environmental pollution from our desire to consume meat would restore balance to the ecoystem.

A final major problem with industrial production that would be solved by the clean methods of specific tissue creation in labs would be the fact that polluting bacteria would be eliminated as a production concern. This would reduce the chances first of existing bacteria evolving hardier strains as can occur in existing facilities and it would also eliminate much of the shelf life problem that attends slaughtered meat by allowing the tissues to be packed for freezing or storage with an absolute minimum of bacterial pollution, increasing dramatically the shelf life of the final product without compromising taste or texture.

Moving the industry to these methods would be a win , win situation for all involved. The animals would no longer need to be harvested and slaughtered, they could be grown and bred to provide the genetic blue prints of the desired tissues but they can then be allowed to die naturally instead of killed. The significant reduction of bacterial infestation during production would reduce the incidence of food poisoning issues that strike and kill thousands of human beings every year. The savings in medical costs for the countless more that are afflicted but do not die are also a great benefit. As well , the ability to more closely tie production to demand will ensure that the generated meat is fresher as it will not be tied to growing and harvest seasons as is the case for many of the animals grown for human consumption. This will lead to wider availability of exotic meats which no longer will suffer ecological damage from human over consumption, allowing the ecosystems which they populate to recover from any human induced unbalanced states. Ultimately, the limitless production capability tied to the short window from production to distribution will reduce prices and allow humans to consume exactly the meats they wish absent of the associated fats and other tissues that may not be desirable but are part of meats harvested using traditional means. There could be potential drawbacks to this coming age, one potential problem would be the shift in requirement for food products to sustain the artifically growing tissues and organs. The standard laboratory practice involves providing sugars and other nutrients in the growth medium, the additional reliance of the industry on such simple food sources versus the more complex grains, seeds and grasses fed to active live stock will need to be made and will likely come from an increased need for grains in particular that can be used to extract sugar, this will adversely affect the remaining industries that will have their need (such as various types of seed production) severely reduced. However, the advantage of the conversion are likely going to more than compensate for the impact that will be felt by a few existing industries that rely on the industrial meat production and harvest industry.


The visibility of molecular methods

The last year has shown the amazing power of visibility into the molecular processes that govern cell growth. The clear realization that proteins/enzymes define how the life processes of such cells proceeds by various geometric and electrochemical constraints and behaviors and the illumination of the specific proteins production by gene pathways in the organisms DNA is allowing us to create specific strategies for either enhancing or destroying functions to suit our needs. In the case of the rhino virus this has recently been demonstrated in the form of announcements to target "highly conserved" proteins deep within the membrane layers of dangerous pathogens such as the flu or rhinovirus families, by targeting inner and not just the highly mutating outer surface binding proteins researchers will be able to generate therapies that specifically disable critical life functioning apparatus in the pathogens and thus generate treatments that eliminate them far more efficiently than the inefficient "shot gun" method of discovery that had been used up to now. This promises to revolutionize and reduce both the costs associated with drug discovery and the time over which such new drugs will be available for use. The smaller set of side effects that result from the unique specificity to proteins in the invading organisms will reduce the incidence of deleterious multi-drug interactions in patients. It will also by reducing costs bring down the incredible health care costs that accompany a rapidly aging population.


New test beds to study 'cells gone wild'

One of the clinical boons of the new technologies involves how they will benefit researchers looking to reproduce existing pathologies. The ability to export cells from a diseased host and then study the origins of the pathology by watching how the developmental pathways go wrong when compared to a model cell will be incredibly instructive and illuminate faster research into existing pathologies to divine gene based therapies for them. This will be and is already baring fruit for the study of various cancers and will improve over time.


Pathogenic relief on the horizon

So aside from the advantages gained from the moral , environmental and cost issues how will these changes effect humanity? One immediate result of our being free of the inflammatory conditions associated with the "harmless" pathogens will be increased fitness throughout a normal life span, reduced incidence of the cardeovascular and internal damage done when fending off repeated infections resulting in a notable boost in average life spans. This will pathogenic relief will come in a very short time as the targeting of highly conserved proteins in the Rhinovirus and flu families that plague humanity most often have programs already under way to target and eradicate them. It is likely that the developments on this front will outpace those of more advanced developments in the quest to generate tissues in bulk in the lab either for consumption (animal based) or for therapy (human replacement). Later , once we fully understand how to play the genes correctly to to sing the song of organs, additional advances as outlined in the associated section will occur. So the first sizable return from the new understanding of pathogens is only a few years away, certainly no more than 10 years away given the accelerating pace of research in the area and the number of teams aiming to solve the problem. The successful team will be in a driving position to reap the rewards of what could be the most lucrative pharmaceutical achievement of all human history. The coming years will no doubt continue to provide astounding advances on the front of molecular biology and genetics and the excitement of these developments will continue to resonate with the public much like the development of the integrated circuit and large scale integration in the 70's by Carver Mead and others at Intel led to the acceleration of processor speeds that have made the current internet and telecommunications age possible. However, unlike the advances in semi conductors which effected machines, the biological advances will literally benefit (or be a detriment to if used nefariously ) us, will we be mature enough to wield the great powers we will have responsibly? I am optimistic that the parallel development of a global , networked humanity along with the exciting work in biology and genetics will help us keep from destroying ourselves with the power of life modification and eventually life creation that we will soon exercise routinely. I will write another post that will do more analysis of the possible bad side to developing such powerful methods it is not all Roses and we have to achieve an amazing level of maturity as a species in a short time if we are to avoid Armageddon on the scale of a Hollywood movie.

Here's to US!


References:


http://en.wikipedia.org/wiki/Induced_Pluripotent_Stem_Cell

http://www.allthingsstemcell.com/2009/06/induced-pluripotent-stem-cells-a-new-stem-cell-line-with-a-long-history/


http://en.wikipedia.org/wiki/Black_death

(Article indicating using cell tissues to grow organs)
http://www.newscientist.com/article/dn17020-bioengineering-graft-could-lay-ground-for-organ-growth.html

(An article and video showing male chicks ground alive)
http://www.huffingtonpost.com/2009/09/01/chicks-being-ground-up-al_n_273652.html

(Sir Paul Nurse talks about genetic techniques and stem cells)
http://www.charlierose.com/view/interview/1074

23 September, 2009

Demo day 1

Well here's the skinny on the first live demonstration that I gave for numeroom.com
since going live private beta on June 2. I'd been preparing for such events by lurking at a few
in the city to see how other companies were going about it and crafted my presentation
strategy for maximum effect! I had to jump through a few hoops with Rackspace
(my hosting provider) to get the servers online but the deed was done.

I got to bed nice and early in order to be well rested and was able to get about 4 or 5
hours of deep sleep before I got up early that morning restless at the day to come.
I hit the road around 5 am for my run, 6.88 miles of "meditation" that formed the
substrate for thoughts on how it would go. I reviewed my demonstration script in my
head and after the run was over and I was showered and ready for the day reviewed it
again. The hours flew by and before I knew it it was time to head out to Manhattan.
I got my laptop configured and ready and hit the road.

I arrived early as is my ken and was curious about the venue, a bar with a back room
for such presentation events. I'd never been to or pitched at such an event but
there is a first time for every thing I guess. One reason I wanted to get there
early was so that I can be the first presenter to set up the laptop on the
projectors and call dibs on "first!".

I love starting the event off and then watching the other presenters and I got
the opportunity this time. Slowly people started trickling in until about
15 minutes before the event and then a flood of people came in, I made various
introductions to people that were there, fellow presenters and the organizer and
then the count down to the big show! The total count was about 100 people packed
in the space. One bad thing about having such an event in
this bar ("SideCar" in Manhattan) was that the "divider" between the main bar room
and the presentation room was just a couple of curtains, this allowed a lot of the din
coming from the bar to intrude upon the presentations. I had to speak extra loud to keep the
viewers attention but noticed that all eyes were glued on the screen so I knew
I was getting through at least to those not situated so close to the bar!
I was introduced and went into my script, I'd memorized it so it was automatic,
I even skipped over a planned language translation demonstration without skipping
a beat, a friend in Venezuela was to play the part of a remote foreign participant
but a late start to the event and a power outage on her part put the kibosh on that!

The description of the feature seemed to be enough for the people present.
When time was called (each presenter was given ~5 minutes to do the dance)
I took several questions from the crowd. This was cool as it allowed me to
extemporaneously talk about my product. One guy asked me how my service was
different from "Google Wave" which is not the first time I've had such a question,
despite our products going about solving the business collaboration problem in very
different ways. After the Q & A, some applause and the next presenter was up to
take the spot light and I could then mingle, take and give cards and talk, talk,
talk.

I have no shortage of words when it comes to my work so the talking part was the
easiest. I made quite a few contacts that are baring dividends. Several potential
speaking engagements to talk about my tech. and woo customers and just minutes ago,
contact from a Hedge fund member for a coffee to talk a bit more about my service
(he was at the demo event apparently watching silently)

So that pretty much sums it up, I just need to get something fired up before I
totally run out of loot I am down to the dregs and
making magic happen just to keep my personal lights on (let alone the servers
at Rackspace!)

If anything, all these travails will make a really great founders story should
I succeed!

carpe diem!

07 September, 2009

cable versus phone price wars are good!

In light of the debate (or is it a conflagration?) on Health Care reform that is currently raging in the United States an instructive story comes from my experiences with the company that provides my internet / phone and cable service. Cablevision, I'd been a customer of the service for about 4 years and was fairly happy with the quality of the options being provided (though the video signals on the standard cable channels are a bit too compressed..but I digress) the bandwidth and speed of the internet connection is routinely rated as some of the best in the country and the phone service does its job, it works and the sound quality is excellent. The problem is the service that I purchased is continuously going up in price, at one point I was paying nearly $200 a month for the combined service, to some that is nothing but as an engineer I have the curse of knowledge, I am well aware of the underlying technologies required to provide the service and know that for the cable provider , providing the service becomes a diminishing cost over time as Cablevision upgrades their back end routing nodes. In particular the ready ability to arbitrarily increase bandwidth on the back end using fiber optic interconnects and DWDM technology makes bandwidth a resource that the cable companies can procure with relatively little cost. So for Cablevision the costs of providing the combined service (which also makes things significantly more efficient and cheap on their back end) actually goes down over time, yet they continue to raise their prices yearly and in fact document that in their marketing materials as if as a customer I should accept the inevitability of the price increases. NO.

As an engineer I had learned and read about the plans by the "phone company" Verizon to lay fiber optic cable directly to homes. This FTTP or fiber to the premises rollout was scheduled to come to Brooklyn in 2008 and did just that. As soon as it was available Verizon put together a very competitive package of internet/cable/phone service to match that offered by Cablevision. A marketing push eventually led to agents going door to door to sell the new service, I dealt with an agent and switched my service over from Cablevision a little over a year ago, however I hadn't done my homework to figure out how I could continue to have distributed internet access to all the computers in my home (7 machines at the moment) this caused some consternation which led to eventual cancellation and then I reverted back to Cablevision after they called and offered to boost my service and reduce my fee for a year. All of this price play would not be possible had not Verizon come out to provide the competing service, you might wonder why it was that Cablevision had such a monopoly in my area and the answer was that it was government sanctioned. The cable companies were given specific rights to provide services that the phone companies could not, but as the technologies began to merge on the back end it made no sense to separate the providers (of phone/internet versus cable/internet service) as with modern data services phone/internet/cable were all transmittable down the same pipes. The attempts by the phone companies to be given the right to compete with the cable companies was finally granted and that opened the competitive landscape and immediately allowed the consumer a choice which lowered prices.

Now, fast forward to the present day. The year worth of reduced pricing that I got from Cablevision for coming back from Verizon is about to run out and the the cable company was sure to warn me of the 31% jump in monthly pricing that was to come. As if in clairvoyant recognition, a week later Verizon began a promotion for reduced service costs on the "triple play" that significantly out performed what I was currently paying for Cable vision (before the price goes back up) I am now in the process of signing back up with Verizon to take advantage of the opportunity. Hooray for competition! If it weren't for the regulation of the competitive zones I would have been forced to swallow the price increases by Cablevision for service that I will now enjoy from Verizon for less than half the price that Cablevision would claim they have no choice in charging me. This reinforces the truth of business pricing that many people don't think about, a company sets prices not at a fair percentage above the costs required to provide that service but rather they tend to price the service at what they determine the customer will pay. This difference will always exist in the absence of competitive pressures and the only way to get rid of it is for competitors to enter the space and thus keep the previous provider "honest" in terms of charging customers costs closer to the costs of the actual service or take no revenue at all from those customers.

An interesting aspect of this ordeal is that as soon as I switch back to Verizon , Cablevision will send a hard nose salesman to try and win back my service. In order to give them the opportunity to match pricing before I switch over I called cablevision and told them of my intentions , they claimed they could do nothing since my existing promotion was coming to an end. I am curious to see if I'll get that "come back" call any way after I switch, we shall see, for now ...it is time to call Verizon and cut my data service bills in half, consumer options always force providers to charge honest pricing, yay for the customer.

02 September, 2009

numeroom.com and apriority.biz down

I was on the phone last night trying to get Rackspace to turn my service on to my customers, the site is down while I try and figure out a way to get it back restored. I apologize to any users that have been inconvenienced by this outage and hope to be back up as soon as possible.