Genetic Horoscope -: Genetic matching and Marriage!

My earlier post referred to healthy longevity and whether it was possible. Well that discussion shall follow, but what I am about to discuss does have a significant bearing on that too.

Most of the human race marries at some point in their life. We may not like it, fret about it, go crazy , but most of us still fall for it. Many a time, it is societal pressure and expectation to be normal that leads us to do it, at other times it is LOVE, or perhaps because one simply loves the concept of family. Whatever that means!

Although things are changing in India with girls going to job and marrying late, live-in relationships becoming more acceptable etc. It is still true that marriage is a social barometer. And ones parents are happy when they see their children "happily" married.

Like it or not the "Hidden", "Hush Hush" reason why we marry, is to propagate our kind. Which parent doesnt smile inwardly when friends claim that their children look and behave JUST LIKE you! Remember that feeling? Despite our protestations to the contrary, there IS a warm FUZZY feeling.

Asians in general, South asians more specifically and Indians to get to the point, believe in this quaint notion of arranged marriages. In my experience neither a love marriage nor an arranged marriage really pips the other in terms of success rates. In case arranged marriages last longer there are mostly factors related to inertia and society pressure and personalities involved rather than anything else. Remember that the couples involved in love marriage NEED to a priori have an adventurous temperament which later in marriage may actually be a hindrance for the relationship!

Ok, so now lets discuss genetics. Throughout human history we have indirectly used genetics. Banning consanguineous marriages to avoid birth defects, relying on gotra etc have been an important part of the Indian tradition.  My own view is that we have taken things too far with the Khap panchayats quelling what is a matter of personal liberty and turning it into an issue of tradition. Our thought needs to be evolve with times and a better understanding of science. The rates of disease /genetic defects claimed for consanguineous marriages are not THAT high! Really...If two people wanna marry, let them! 

Anyways the issue thus is that genetics has always played a part in Indian marriages. My proposal is to take it a step forward. Genetics can today reliably understand small single letter changes in the genetics code of human beings. There are many known mutations or changes can single nucleotide polymorphisms that have been identified with risks for particular diseases. In case of some mutations called autosomal recessive, if both parents are unaffected carriers of the same defect the children have a very high chance of getting the disease. Since both parents do not have the disease itself , there is no way for both parties to anticipate that their children may have ones like Cystic Fibrosis, sickle-cell disease, among others. In case of autosomal dominant only 1 defective copy from either parent suffices for the disease to occur in children. Examples are Huntington's disease, hereditary nonpolyposis colorectal cancer and several others.

This much is classical genetics, known for quite some time. The key fact is that the genetic profile of both parents plays a role in the children's likelyhood for getting these diseases! So any potential spouse that has the same defect is a strict no-no. So why aren't there many many such children. Simply because the chance that an individual will carry these mutations is low and that he/she will marry a person with the same defect is low. However why not play safe and be sure?

Now we come to modern genetics. The human genome sequence project was equivalent in effort to NASA designing and launching a space shuttle and much of the science was developed during the course of the project. So we now know the genomes of a few people. But each of us has different DNA and a unique genome. Of course most of our DNA is the same but not all of it. DNA and the genome are made up of A,T,G, C that represent particular chemicals. In some place on the genome these change mutually. So for example on Chromosome 7, at position number 222455 in some people an A may be replaced by a C etc etc. Most of these changes are not known at present and may have no significance. But some times these individual changes also called " Single Nucleotide Polymorphisms" or Snips are significantly correlated with the RISK of developing diseases. Note that we are now talking about relative risks. And unlike the classical genetic diseases mentioned earlier, there are many environmental and dietary factors that may affect the likelihood of getting the disease. But there are now quite a few known associations between cardiovascular diseases, cancer , metabolic malfunctions etc

In general some snips reduce the risk for certain diseases for the progeny in their later life and some increase it. So what's the BIG IDEA?

Well why not get a sputum sample from eligible bachelors and anaylze all known classical mutations and also Snips? Do this for many many people all over India? Yes the consumer may have to pay for it, at least partially.  So imagine now having access to a matrimonial website or perhaps  marriage counsellors in Pune, who rank all the potential spouses in terms of the best match genetically. All the matches with classical genetics related VERY HARMFUL mutations will be immediately screened out. They will not appear in the results. But the ones left will be ranked in terms of lesser risk of diseases for your babies later in life!

Note tht all your regular criteria for marriages like educational and family background, looks, nature, age, religion and caste , horoscope etc will still apply. This will be an "Add-on". If you pay beforehand, then you may search the profiles free for a year! 

What about the opposition and criticism about genetics in marriage. Let me respond to some.


1. It is illegal. The US FDA is turning the heat on direct2consumer genetic testing.


No its not illegal. In case of the FDA versus companies like 23andme and navigenics among others, they directly sell the genetic profile to consumers and a genetic counsellor can then advise them. There are significant psychological problems that can arise of one knows that there's a risk of cancer or dementia etc. Moreover the associations are preventable and do not doom anyone. However a case can still be made that most people will respond negatively to such information leading to unnecessary depression.


In our case the genetic profile is never revealed to the consumer avoiding the above problem. Our interest is only to use it to match other genetic profiles to maximize health benefits to the next generation.




2. Is the science perfect?


No. But only science has the guts to accept this. Are horoscopes reliable? Do most marriages turn out to be successful because they match? But most people do believe in them!


But in so far as genetics goes there is a huge amount that is already known. So why not use it to do the best we can and search for the best spouses?


3. What about ethics and who will have access to my data?


The personal profiles will never to revealed to the consumer or a third party unless explicit legal permission is granted. However, if the consumer opts out of paying the money necessary for the service, then the profile shall belong to the company.


4. How hard is it?


Well remember the Titanic scene in which Leonardo Di Caprio has a spitting competition? Not necessary. Just spit into a vial or similar and that is enough!

5. Is this not eugenics by another name?

Well it is eugenics if that means improving the genetic profile and thus the health of future generations. However, it does not endorse or tolerate discrimination on the basis of race or any other factor and does not seek to manipulate genes to enhance features or give your baby a fairer skin or blue eyes!

If you are in love, then this is not for you. Love is blind so it does not need such trifles :-). So what doe you think of the proposal? Think of this proposal as GENETIC HOROSCOPE MATCHING :-)

Vote yes/no at http://apps.facebook.com/opinionpolls/index.php?ref=bookmarks

SNES 1988 Batch

September 18th 2010,

It was a small but poignant reunion of my 1988 Sister Nivedita 10th std. batchmates. It really was endearing and emotional. Although guys being guys, nobody shed tears unlike some girls! Of course some of them later drowned their feelings in High Spirits! :-)

For those who know my schoold friends, checkout who's become fat, bald, old etc etc. Hmm, this is a good lead to the next topic "Ageing and living healthier longer lives than ever before..."

Open Source Drug discovery: Open Sesame or Open Pandora?

The previous post was about Dogs and Cats. Well, its important to note the pivotal role that animals like these, rats and rabbits play in Drug discovery. Animal models serve as a basis for in-vivo simulation of the efficacy and toxicity of drugs new medicines under development. So lets talk a bit about drug discovery.

We are now in a phase where it takes millions of USD to bring a drug to market. Other than the fact that  low hanging fruit are gone and more science needs to be done for discovering efficacious molecules, other problems are related to regulatory hurdles and costs of clinical trials. In a general sense, the regulatory oversight has indeed helped bring toxicity of drugs into focus. But it has also meant that garage science and garage based startups cannot realistically hope to find a cure for diseases. This is quite unlike the tech scene where the investments required in terms of infrastructure are low and ideas and teams are more important.

So its when some university or other researcher elucidates a terribly critical disease pathway and shows that some molecule can address this does he/she get sufficient funding. Even so, many such startups never are really able to bring any drugs to market. Personally I have known several companies that have potential drugs for cancer but cannot dream of bringing them to market. 

Can we, should we think of an open source model for drug discovery then? Other luninaries have certainly thought of this before me, but let me contribute my tuppence worth. Why keep something in your head if it can be blogged for posterity to bang their head about: -). Note that I have been thinking of a for-profit but open source model but it can obviously apply to a not-for-profit organizations too.

For what its worth here are my ideas about open source drug discovery , in a series of questions and answers.

Open Source Model for Discovery, Development and Distribution 

Nature of Open Source: 

Open Source, particularly the GPL V3 means no patenting or copyrighting of intellectual property, allowing physical access to data, algorithm, methods, code i.e all the constituents of the product or service to anyone who wants it , given that 

1. The entity consuming the information and product has to commit to allowing the same level of openness and access to any derivative work done on the inherited work. 

2. So long as condition 1 is observed there is no bar on commercialization  . 

Open source as a business philosophy is viable iff 

a. The consumers are divided into a few who can actually tweak the product or service and others are mostly consumers but are protected from vendor lock in due to proprietary standards and code.

b.  The product is hard enough to manufacture, distribute , improve while competing at the same time with proprietary alternatives with significantly large funding.

c. More eyeballs, more users, can help identify side-effects that are hard to spot in the development cycle.

Am I missing a few points. Perhaps..Do feel free to add to the list above. So now lets begin with the questions and answers about open source as a model for drug discovery-:

q1.Why would people share intellectual property e.g. interesting drug molecules if they stand a chance to build their own for-profit companies? 

a1. Drug discovery is not an end in itself. What matter is making a profit or money by selling the drug molecule as a finished product either to the public or licensing it to a larger company that has the distribution network to do so. 

However, most molecules that are discovered for any disease never see the light of the day as drugs. Most small companies and institutions are never able to sell their molecules for large sums to large pharma companies even after putting in enormous resources into their discovery by their modest standards. There are various economic, technical and strategic reasons for this. So no individual or entity can build investor confidence by pitching their ability at drug discovery, when the likelihood of this being licensed in a reasonable time frame for reasonable money is absent. It is only when the concept is very very novel can it pique the interest of investors. Recent example is that of a company targeting the sirtoin gene for longevity. 

(Hmm, healthy longevity is another topic I have  thought quite a bit about. But more of that in a later post.)

The true barrier to a molecule reaching the consumers is always the costs , risks and regulatory matter associated with clinical trials and not not drug discovery and development. Even after extensive research a drug can fail with economic consequence greater than a supernova imploding. The resultant black hole can suck in everything the company has invested in!

In fact a drug can be discovered for a known drug target(s) in 2-3 million USD, even lesser if novel computational approaches are used all along the discovery and development pathway. 

Open source does not mean the company open sourcing the drug discovery data cannot make money. The IT sector with companies like RedHat has demonstrated this. As the motive of profit notive is still there, along with openness, putting faith in a for-profit open source approach, may not be a very craxy idea!

q2. Won't anyone be able to copy the molecule, particularly if the animal experiments and clinical trial results are promising? 

The viral nature of the GPL permits and indeed encourages copying and tinkering, but does so provided that the fruits of derivative labour are backported to the novelty originator. Every person who makes derivatives or innovates has to pass the innovation back. In case of molecular structures there can be many potential derivatives or modifications of the original lead for optimization of certain ADMET feature or even efficacy. It is risky for an R&D institution to modify/derive a variant, use it surreptiously and sell the same. This is because clinical data or bioequivalence data has still got to be produced and approved and there can always be another variation out there that is better!

This is true even in case modifications are not made to the API structure but different formulations are produced . These formulations will still form under the gpl since they are using the API as core to the functionality, much like a software library or web service over which they apply a wrapper [formulation]. 

Production of a molecule should also be covered by the GPL as it is akin to building exactly the same software product when the complete specifications are well known. 

There are other economic and technical entry barriers to piracy of open source molecular data. It is not an easy process to setup a government and FDA recognized manufacturing facility even when the info about a drug is known and off-patent. 

Since the projects would be open source, it may get benevolent attention from government labs, NGO's and private research foundations that may contribute their data and science.

Big pharma may buy its way out of trouble by licensing rather than compete if the scale of the effort is big enough. Note that large corporations license both proprietary and open source products to hedge and manage risks.

q3. How is open source different from open science and just using open source software for an endpoint? 

a3. The open source drug discovery company will discovery, develop, validate, get regulatory approval and market a Product i.e a drug . Think of it as the linux debian project or redhat! Both models work. 

The science behind the discoveries of interesting molecules may or may not be open, the software used for drug design or experimental analysis may or may not be open source, but the final results would certainly be. Think about the human genome project, the hapmap project but now with commercial objectives.

So while the procedure used to arrive at the final product may not be open source the product will certainly be. It is of course desirable that processes and software be open source too but using closed source or commercial techniques would not be banned or frowned upon. Mostly information about assays and protocols is well known but may not be so in certain cases as with drug design software. 

q4. How will the participating entities benefit. 

Participating research institutions be it private or universities or other publicly funded institutions will be able to contribute to the science and the success of alleviating disease. The fruits of the research will not lie around in some repository for some future archaeologist to find.

Companies will not have to wait for patent expiry to start manufacturing and selling. The public will probably get access to drugs faster and cheaper. Since the information about who is producing the drug and marketing it will be public too, competition will reach and equilibrium and only those who have a clear benefit will undertake. Companies looking to profit will have early and complete access to all relevant information. 

The public will see the progress of the projects in almost real time and can choose to fund projects if they choose too, just like consumers of open source software. 

If there are bugs in proprietary software that are very serious for consumers and are well known, they get fixed, but it may or may not be the same for not so well known defects or bugs as there is less incentive to fix them. the situation is seriouser with drugs. 

Many negative animal test results are never revealed and thus lead to needless expensive clinical trials. All along the drug disovery pathway all stakeholders will always know the pros and cons for certain features and defects e.g. toxicity. Thus some of the main fears related to disclosures will not affect this model. 

This may also lead to lowering of costs of for governments whose national programs are increasing budened and who are already on a path of govt sponsored life sciences and dd research. Medicare, NHS anyone?

Governments of coutries like China, Brazil, Russia are worried about the takeover of their pharmaceutical companies by MNC's. In time there may be no competition left. Some have responded in typical fashion by starting national drug discovery programs. Russia for example. China may not be far behind as it already has a chip design program well underway.

The Indian government is keen to fund Industry-academia collaborations.

 q5. Open source software companies make money by providing support rather than selling the product itself which is generally free. Would an open source dd company do something similar. 

a5. Yes well it all depends on whom you trust to solve your product support issues, urgency of fixing or customization needed etc.

So selling a drug is akin to sell a software product. So what's a service? The service component is difficult to determine. But it could be using pharmacogenomics to recommend dosage or dispensing combinations or opening up of brick and mortar clinics for treatment. 

q6. Is the model disruptive enough? 

a6. This model for drug discovery is extremely disruptive although the NIH and EBI and other effort have already contributed substantial drug data into the public domain. Such an effort would disrupt the business as we know it. As of now it provides disincentives to eveyone concerned, the industry, consumers, government and researchers.

q7. Would there be any focus /disease areas, who would sign up? 

The company would focus on signing up and getting as many labs from both the public and private research institutes, committed to the effort. Drug disovery will only be done for validated drug targets intitially in the sense that the biology for a particular disease is known to significantly affect the phenotype although it may not be known to cure it.

Data sharing would be both within disease areas as well as between them. There are several instances where a molecules useful for one indication has been found to work for something completely different. E.g. Rogaine

This would lead to synergistic effects in an open source model as  drug targets are shared between several different pathologies. 

Basic biology labs would be welcome, but drug discovery chemistry efforts would not start till such time as drug targets are validated. 

q8. Can you elaborate on competition from large and smaller me-too viagra companies?

The critical thing about open sourcing dd is that there's less incentive for larger competitors to work on the structure since the structure and its derivatives are non-patentable. 

For copycat companies, too they can only produce the molecule if they agree to an open source license and thus all formulations and derivatives info about need to be back contributed. It provides a powerful incentive to university research groups who wish to see their work have social relevance as it otherwise would never reach the public for whom these DD efforts are made.

q9. So why aren't there many such open source efforts.

The primary reason is that there is no enforceable open source license for drug discovery. GPL v2 and 3 ARE enforceable, as evinced by lawsuits against several companies that used open source code in proprietary products. 

The second point is that as compared to software products there is a huge critical mass required for drug discovery. Someone has to take a lead and talk to all the different stakeholders and bring them to a common platform. Who's gonna bell the cats? Is there a Richard Stallman, Linux torvals out there to take the first critical step?

Can it be me? Well, there's a thought. But I would need Blair and Clinton's charisma, savvy and clout to make any headway!

Its raining Dogs and Cats

So after a rant about god, what can one write about? Well, lotsa things actually, but lets dwell on cats and dogs. Yes, lets talk about those friends of ours in lonely moments, our alter egos. They are equally at home in remote hamlets to the largest cities.

For a few days every monsoon, these beings create a ruckus at night, exactly at the moment that I am about to FINALLY fall asleep. "Mating season it is" , my all knowing Yoda wife tells me, when I can't fathom the reason for these voices from the dark  side.

Well why can't the damn Pune municipal guys pick up the strays among them? Appropriate sentiment, especially in the given frame of mind. After all there are so many strays loitering around !

Wifey and my mom being the more aware members of the society actually did call up the health authorities a coupla years back. Why can't we Indians have clean streets with no litter and no strays or any dispensation? A shining city like Singapore perhaps? Or melbourne or..New York...nah the big apple's got em too...:-)

Well, I am torn, really torn. No no, not torn to shreds by rabid dogs, but rather between my desire for a city without strays &good sleep
and
whether its really correct to call in the dog/cat squad.

Think about it from their perspective for a moment. They are stray, not by choice but by circumstance. Several pups came to this earth in some rubbish bin or in the backyard amongst the grasses of some housing society where the mother could keep them warm and safe.

They then had to live rough, get chased by mean spirited kids and then one fine day some homo sapien calls and another picks them up to be killed. Pretty much mirrors the life of human orphans and street kids doesnt it?

If a Jain or buddist monk comes to me at this moment and talks about how how one is born as a human after 1000 lives as cats, dogs and other species then it would really stoke up feelings of kindness for these  street urchins.

How you seen how the pet industry is growing in India. No wonder these mongrels feel the have and have-not divide too ! They have to scrap for every morsel while others live in fancy bungalows with special diets and what not!

And what about the health department guys who have to do the onerous task of picking and perhaps killing off these unwanted ones?  Do they and can they leave their emotions behind in the line of duty. Very hard one would imagine.

Of course we would get a good nights sleep, no longer fret over how modern India is still a place where stays wander and cause road accidents....but still is there no moral conundrum here?

Mebbe , I am going soft with age.

Well its not all gloomy for the strays though. Some can rest at fine places and get to each morsels of expensive food.

Beware, its the monsoon and its raining cats and dogs!

O mein Gott!

Yeah, here's the best ever, most original way to start the very first blog of ones life! Talk about God! Doesn't matter if it does not endear you to Heem or Herr, it may just attract enough eyeballs to make it count in the blogosphere.

The immediate urge to purge my soul of unearthly thoughts, about the One up there,came about when I read "Good to be God" by Tibor Fischer . In the book a brit guy with a failed marriage, job as a salesman and living in the dumps, goes to Miami and decides to abandon everything that made him a loser. That's small qualities like hard work, honesty etc etc. He observes the religulous (wink wink, Bill Maher) god sellers and decides to do one better. Why not be God? What follows is a very piquant narrative ...but also something that meanders too much.. so I never could get to the end of the story.

The second reason to think about the Powers that Be was the constant refrain of my wifey that I am not Religious, and that I dont participate in festivals. Well other than the fact that I am  socially compromised or socially challenged there's really no connection I can see between most festivals that are based on traditions and religions and the need for a god GOD.

If we are to think about the existence of such a being it needs to be independent of what religions tell us. It is what science has , will and can figure out. Or cannot figure out. Rather what the limits of knowledge of any kind are!

Well I have given the Powers that be a lot of thought.  It was certainly depressing for an egotist, self centred but self effacing guy like to have to give so much attention to someone else:-)

The usual soul  searching about why we all IT wallahs are well off and the poor, well poor.... and the disease stricken , orphans is all fine. Believe me, there have been enough of these to make one believe that there is only a devil if anyone out there!

But to get a feel for what GOD really means and ITS existence see talks by Bill Maher, Richard Dawkins, Christopher Hitchens and George Carlin among others.. And boy O' boy that guy George Carlin really does hit the nail. Watch him even if you don't watch the others.

God as an entity in my mind is a construct that any conscious mind , anywhere in the universe, will always come up with. "Who am I, what am I doing here?"  is but a universal constant or invariant behind all such questions and answers. Guys,guys I am NOT referring to what u think about your spouse 10+ yrs into the marriage :-).

Many people believe that the Anthropic Principle is proving to be increasingly true. The stronger version of the principle seems to indicate fine tuning of parameter.. But even if this principle were true I can't understand why it would need a super intelligence to do the fine tuning.

And what about the famous eastern philosophies that everything is Maya or the Maya Vi? These are nowadays of course reflected in Hollywood movies;. The 13th Floor, Matrix Trilogy and Inception? How do you know you are not in a DREAM..or that all we see is a simulation.

Well, there are several things known about simulations. They are generally non- deterministic, non-reversible, complexity emerges out of simple rules and emergence changes the rules of the game. Which basically means that the simulator can set the rules of the game, its dimensions but may not have the computational power to know what will happen! and control over such a system may well nigh be impossible. Yeah Yeah, I am not taking about simple systems like single fluid dynamics turbulence etc.

Anyways, so what are my personal belief's. Well I dunno. Really dunno. I don't even know if defining a God means anything. Perhaps it does. Well if the definition is an omniscient, omnipresent being then it beggars belief. What is somewhat believable is an entity that mebbe kickstarted the whole operation and then very possibly has no real control. So basically I dont mind if people think I am an atheist although my personal leaning is to <TAG> myself as an agnostic.

But let this worry about a God not deter you from doing good deeds! BTW, Carlin died of cancer and Hitchens has got it. So is it retribution?