Philosophy of Genetics

The genetic "patch"

Scientists recently corrected a genetic disease (in zebrafish) using a "genetic patch".  The disease, Menkes disease, is caused by a variant of the ATP7A gene.  "The research could lead to the prevention of up to one-fifth of birth defects in humans caused by genetic mutations," according to the authors.

"Children who have Menkes disease have seizures, extensive neurodegeneration in the gray matter of the brain, abnormal bone development and kinky, colorless hair. Most children with Menkes die before age 10, and treatment with copper is largely ineffective."

Zebrafish are used in research, because they are transparent, breed quickly, and have other qualities that lend them to understanding human disease.

Value-based healthcare

The UK government, with its nationalized healthcare program, plans to save money by rationalizing the cost of drugs.  The UK wants to establish the value of drug treatments, based on their cost-effectiveness. If a drug's benefit doesn't outweigh its cost to the payer (the government), doctors will not be allowed to prescribe the drug.

How does the UK government intend to measure a drug's value to the patient?  According to a Reuters article, the patient's quality of life gained must exceed the drug's cost:

The National Institute for Clinical Excellence (NICE) bases its assessments on "quality-adjusted life years", or QALYs, which measure a person's state of health. One QALY equals one year of perfect health, two years of half-perfect health or four years of one-quarter perfect health. As a rule of thumb, NICE reckons medicines costing more than 30,000 pounds per QALY are too expensive, though it does make exceptions.

Pharmaceutical companies can either accept the way NICE values their drugs, or fight back. Pfizer has protested NICE's recommendation that its Aricept and similar drugs be prescribed only for patients with significant symptoms of dementia.  Bristol-Myers Squibb's rheumatoid arthritis drug Orencia was knocked back by NICE as too costly.

Since the U.S. is quickly moving to a form of nationalized healthcare, it's an instructive debate.  Soon, we too will be debating the merits of drug QALY's and value-based healthcare.

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.

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.

Personalized medicine

According to a recent article in Time, the number of people who must take a drug to avoid a single adverse event (e.g. a heart attack) is called the "number needed to treat" (NNT).  For statins, the NNT is around 50 people.  In other words, for every heart attack avoided, 49 people were taking statins to no benefit, with all the potential side-effects (and cost) that entails.

Pharmacogenetics and personalized medicine are trying to change that by rationalizing who is treated.  One way to do that is by creating genetic tests, to see who responds better to certain drugs.  If the NNT were reduced to 1, that would mean everyone would receive only the drugs they needed. 

But it would also mean a 50-fold decrease in drug sales, which is why pharmaceutical companies are trying to downplay personalized medicine (or, rather, to use it to predict drug safety, but not efficacy).  Saving healthcare costs is probably what Senator Barack Obama had in mind last year, when he introduced the "Genomics and Personalized Medicine Act of 2006" that would "improve access to ... genetic tests by all populations".  That bill hasn't passed, yet, but it could revolutionize the way healthcare is administered, especially if Obama is elected president in 2008.

Drugs I'd like to see

The difference in motivational levels among people is innate.  Clearly, you spend more time doing what interests (motivates) you, and your interests differ from other people around you.  What you spend time doing (“time on task”) leads to greater ability (intelligence, analytical ability, leadership skills).  Greater ability leads to greater social rewards.  Therefore, social rewards (big paychecks, etc) are linked to our gene variants.

Because not everyone is motivated by things that lead to "success" in the modern information age, we see a fundamental genetic inequality in society.  However, even if it were possible to create drugs to remedy the problem, the FDA would never approve them, since its mandate is to focus on diseases, not human enhancement. Still, how many people take Viagra for a disease/condition (erectile dysfunction), and how many take it for enhancement?

So here is a list of drugs I’d love to see that would address some of the social inequity caused by innate differences among people, along with the "formal" disease or indication:

• Enhanced memory drugs – treats “mild cognitive impairment”
• Enhanced charisma drugs – treats “social anxiety disorder” or "diminished social affect"
• Enhanced intelligence drugs – also treats “mild cognitive impairment”
• Enhanced drive – treats “low self-esteem disorder” and “low affect”
• Anti-criminal-behavior drugs – treats “low anger threshold disorder”
• Anti-sociopathic drugs – treats “low social empathy disorder”
• Enhanced leadership ability drugs - treats “social anxiety disorder” and “low self-esteem disorder” and “low social empathy disorder”
• Enhanced spirituality drugs - treats "low affect" and depression

The Druggable Genome; or, the limit of what drugs can do

I previously discussed human development from conception to adulthood, because it’s relevant to a fundamental question – What can we change about ourselves after we're born (using drugs, or by altering our genes, etc)?

Through the process of development, we're born with two arms and two legs, and it seems nearly impossible to add another arm or leg (with drugs, or otherwise), since the differentiation of cells takes place in irreversible stages, and quite early in the process.  Those development genes are programmed to work in the context of an undeveloped body, not a fully developed one.

Still, some things can be changed after we're fully developed.  Some psychological outcomes (like depression) can be treated by drugs.  But it’s not clear that the underlying cause is treatable.  If you get depressed easily if someone dies, that tendency is deeply embedded in the developed circuitry of your brain.  Other people are less depressed in the same situation, due to their gene variants, which program their brains to be less sensitive to traumatic events.

There is some hope that stem cells could be introduced into an adult body, and re-generate cells (nerves, skin, etc).  Skin can repair itself when cut, because we all have stem cells in our skin.  So some development is possible, even after we've reached adulthood.  But unless that new development is guided differently from before (by different genes), it won’t make you a different person.

Drugs can affect us, but only to the degree that the form of the body has developed itself to be affected.  Recent debates have focused on how many targets (usually proteins expressed by genes) in the human body are druggable.  Possibly 3,000 to 5,000 targets are druggable, which is only a tiny percentage of the whole. 

Any change to our genes would require a change to the genes in each of our 100,000,000,000,000 body cells, which is certainly possible, through the introduction of HIV-like viruses, which can embed new genes inside many of our rapidly dividing cells.  But even new genes can't reverse all the previous steps of development and re-generate our brains from scratch. 

So our personality probably can't be affected by either drugs or gene treatments.  Certainly, we know of targets in the brain that allow us to mitigate conditions like depression, and we have antidepressant drugs for that.  But do targets exist to improve charisma, ambition, or desire for leadership?  I doubt it.  Does the development of the brain leave itself open, such that we may alter our basic personality with drugs?  I don't think so.  So the only time we can dramatically change things (personality, etc) is at the time of conception.

Genetic Variation and how we respond to drug treatments

Drugs don't always work for everyone.  Often, having a certain genetic variation means you won't respond to a drug.  For example, a certain breast cancer drug only works for 25% of women.  So first, a woman must take a genetic test to see if she has the specific gene variant that responds to the drug.

The PharmGKB is an integrated resource about how variation in human genes leads to variation in our response to drugs.