Philosophy of Genetics

How many genes does it take to create life?

How many genes does it take to create life? Mycoplasma genitalium bacteria has 485 genes, and this is the fewest for any free-living organism. But 103 of its genes can be individually removed without killing it, so 382 genes seem to be essential for life.

At the J. Craig Venter Institute, scientists are assembling those 382 genes from scratch to synthesize new organisms. Their hope is to insert additional genes along the way, to generate useful bi-products.  Synthetic bacteria with added genes could become "trillion dollar organisms". For example, large vats of "enhanced" bacterium could produce bio-fuels (or any other organic product), and launch entirely new industries.

1000 Genomes Project

An international research consortium has announced it will sequence the complete DNA of 1,000 people.  The goal is to "catalog [DNA] variants that are present at 1 percent or greater frequency in the human population". The project will focus not only on mapping single-letter differences in DNA, but also "structural variants" such as DNA rearrangements, deletions or duplications of segments.

According to ScienceDaily: "It is important to understand the small fraction of genetic material that varies among people because it can help explain individual differences in susceptibility to disease, response to drugs or reaction to environmental factors."

Life on a chip

According to an article in the journal Cell, scientists have devised a computer simulation of single-celled organisms named "Halobacterium salinarum NRC-1". The model accurately predicts the activity of Halobacterium's 2,400 genes, in silico.

In all living cells, genes are constantly switched on and off by so-called "transcription factors" (the Halobacterium has 72 of them). When a gene is active, it acts as a micro-scale protein factory. The resulting proteins are then used by the cell as building materials, signaling devices, and new transcription factors.

The computer model accurately simulated the behavior of roughly 80 percent of the Halobacterium's gene regulatory and functional interrelationships (called "networks" or "pathways"). The Halobacterium cell is genetically hard-wired to respond to 9 external environmental factors (EFs).

Gene activity in the Halobacterium cell is highly interconnected. (Like pressing a bag of marbles with your finger, you don't know where it will bulge out, since all the pieces are connected.) By perturbing one or more genes (perhaps by a change in the environment), scientists can test how well their computer simulation of the cell is working.

Yet, 38 percent of the Halobacterium's genes seem to do little or nothing.  That may be because scientists have yet to explore other gene regulatory mechanisms (small RNAs, epigenetic modifications, post-translational modifications, metabolite-based feedback) in their computer simulation.

Effects of variations in your DNA

If you like Wikipedia, you'll love the new SNPedia, which lists the effects of variations in your DNA (known as SNPs). Want to know what gene variants you have? Subscribe to 23andme.com. For the intrepid, you can also try the new Personal Genome Explorer.

Companion Tests

It used to be that Pharmaceutical companies wouldn't touch a drug unless they could make billions of dollars selling it.  The economics of drug development (expensive R&D, and Sales & Marketing costs) required blockbuster sales.  This led the companies to cancel many of their internal drug discovery programs when it became clear the drugs would only make $400 million or so, not covering the high development costs.

However, the science is rapidly changing, requiring a new business model.  So-called "biomarkers" used during drug development can now be developed into diagnostic tests ("companion tests"), to determine which patients best respond to drug treatment.  Since only a fraction of patients will pass the companion test, the total revenue from drug sales may now only be in the millions, not billions, of dollars.  The days of blockbuster drug sales are over.

So the economics of drug development must drive changes to the drug companies.  Sales forces will be reorganized along therapeutic lines, and there will be more differentiated drugs to understand, market and sell.

The R&D process itself must change.  The most expensive aspect of R&D, human clinical trials, will require substantial innovation in their design (early results, adaptive trials, microdosing) to save costs.  Only then will it become cost-effective to develop more, lower-margin drugs (with associated "companion tests") at a faster pace.

Tackling racism

Many have been forced to grapple with the issue of race and genetics after James Watson – the co-discoverer of DNA's double helix – recently made some racist remarks.

The 79-year-old geneticist said he was “inherently gloomy about the prospect of Africa” because “all our social policies are based on the fact that their intelligence is the same as ours - whereas all the testing says not really.". He said he hoped that everyone was equal, but countered that “people who have to deal with black employees find this not true”.

William Saletan (writing in Slate) is to be congratulated for tackling this issue head-on, bravely and correctly.  Most commentators (including the shameful New York Times) prefer to be inoffensive and politically correct, rather than accurate.

I would go further than Saletan, and argue that any racial classification is wrong.  Any demographic questionnaire asking whether you're White, Black or Hispanic should be outlawed.  By identifying yourself with a racial group, you're simply asking to be stereotyped.

According to Nature Genetics:

the use of race as a proxy is inhibiting scientists from doing their job of separating and identifying the real environmental and genetic causes of disease

Every racial group has a slightly different distribution of gene variants (i.e. genes for white skin, genes for intelligence, etc).  By saying "I am White" you're really saying "I'm assuming I have the gene variants that are most representative of my race".  You're setting yourself apart.  The problem is, you may or may not have those specific genes.

Everyone has the same rights, regardless of race.  Everyone is morally equal.  By identifying with a race – by discriminating based on "group genes" – we muddy and degrade our moral equality.

A modest proposal for Big Pharma

Drug companies have serious problems these days.  The FDA is not approving their drugs, especially when viable alternatives or generic versions exist.  Moreover, when drug companies publish their data on new drugs, scientists around the world often find fault with the clinical results, either for legitimate or self-serving reasons.

So what's Big Pharma to do?

First, Big Pharma should focus less on hawking drugs, and more on promoting a healthy lifestyle and comprehensive health maintenance.  Specifically, they could bundle (and sell) everything from healthy food and drink, to vitamins, exercise videos, workout clothes (and sometimes treatments), as part of an overall health management program.  Instead of passively watching us consume "high-fructose corn syrup" laden drinks, and then cynically providing drugs to treat the resulting diabetes, Big Pharma could instead sponsor celebrities to educate the public on the evils of such sweeteners, and promote suggestions for a more healthy lifestyle.

Second, Big Pharma needs to be more candid and open about the risk/rewards/tradeoffs of drugs, instead of trying to downplay side-effects in a shortsighted effort to sell as many drugs as possible.  For example, if a drug helps treat diabetes, but increases risk of heart attack, don't encourage people to take your drugs if they have the genetic proclivity for heart disease or other risk factors.  Propose alternate (non-drug) treatments or sell those folks something else (your consumer division's heart-friendly breakfast cereal, perhaps?).

Third, with the advent of personal genetic testing, consumers will have information on which genetic variants and disease susceptibilities they have.  Big Pharma should be ahead of this train, not under it.  Acquire a company like 23andme or Navigenics (people will soon be addicted to these sorts of information resources online).  Make it part of your marketing – your own DNA.  Make the case for consumers that certain gene variants may require active management, in the case that they increase the risk of arthritis or diabetes or Alzheimer’s, etc.  Educate consumers on how to manage the disease (with your non-drug products, of needed).  You should be about promoting overall health, not just selling drugs.

Finally, Big Pharma has to move beyond using "chemicals" as treatments for disease (a drug is basically a chemical).  That approach is played out.  Even biological therapeutics (using proteins, antibodies, and vaccines instead of drugs) may have limited appeal (since they may prove difficult to deliver to the right target in the body)  Until genetic enhancement becomes a reality, Big Pharma should develop multi-faceted treatment options that may involve highly localized changes to gene regulation.  Basically, think out of the box, and move away from chemicals as treatments.

That would go a long way toward restoring public confidence – and profitability – to the industry.

Birth control pills make women less attractive

A recent scientific paper describes how exotic dancers who take birth control pills earn less money than those who don't.  According to a summary in the Economist magazine:

The average earnings per shift of [dancers] who were ovulating was $335. During menstruation (when they were infertile) that dropped to $185—about what women on the Pill made throughout the [entire] month.

In other words, men are more attracted to ovulating women, and pay them more... attention, as it were.

The Problem with Drug Discovery

Why are pharmaceutical companies struggling to discover new drugs?

Current drugs affect “feedback loops” and pathways in the body.  For example, diabetes drugs "target" the PPARy receptor, which decreases insulin resistence, decreases leptin levels, which increases appetite…

Current drugs also target the body’s signaling infrastructure (like hormones and neurotransmitters), as well as the channels that allow molecules like glucose to flow across cell membranes.  In some cases, cancer and viral diseases (like HIV) can be modulated and controlled, since they are rapidly dividing and have a short lifecycle that can be interrupted with drugs.

In other words, drugs can affect the body to the degree that the body was designed to be affected, by leaving exposed "targets" to be exploited.  Every hormone must have its receptor, as every general must have his troops, ready for action when the signal is given. That signal-to-receptor communication can be affected by drugs.  Unfortunately, many of these easy targets and control points have already been exploited by existing drugs. 

It's true that there are 5,000 proteins in the extracellular space, and these could potentially become new therapeutic targets in the future.  Current drugs only target around 200-300 known targets, so this seems like a large opportunity.

However, it’s difficult to deliver drugs to those targets. Since drugs are usually taken orally and must survive the arduous journey through stomach acid and absorption through the gut into the bloodstream, they are limited to being small molecules.  And because the blood circulates through the liver and kidneys and the rest of the body, current drugs often have toxicity issues and side-effects.  Sometimes, a drug's target – often a specific protein – serves multiple purposes throughout the body, so affecting one target will affect them all.  Obviously, finding alternative drug delivery strategies will be important. 

Also, finding alternative therapeutics like proteins, antibodies and vaccines (instead of using small molecules) will become increasingly important.  The hope is that these therapeutics can be tailor-made to affect specific targets in the body – in specific locations – and not cause all the side-effects.

Another issue has to do with human development.  What can be affected by drugs after we're grown?  Since the human body is mostly developed at an early age, it’s difficult to change our disease proclivities (or personality tendencies), since these are already manifest into our physical form.  Can you give someone a personality overhaul with a drug (from depressive to optimist)?  Not except in certain extreme cases.  Since our brains are mostly developed at a young age, only small interventions are possible (from depressive personality to non-depressive, but not to optimist).

Another big issue is how human genetic variation affects our response to drugs.

So clearly the path forward is some sort of intervention prior to development – in other words, at the time of conception – otherwise it’s too difficult to change or modulate the trait or disease.  This would involve a major education campaign for the public, to get them thinking about diseases – and enhancement – in a new ways.

Dusty old volumes from our Genetic Library

It seems that the process of evolution makes good use of old knowledge, stored away in our DNA library.  A new study shows how ancient DNA fragments (which are really just encapsulated knowledge from the pre-historic past) can be revived and applied, to design new forms of life, through changes to the genetic regulatory system.

Apologies for my lack of posts recently.  I'm writing a novel, based on this blog!  Should have something to show for it in the next month or two.