Fool's wisdom

It’s okay to fail they said.  Failure is the key to success.  ‘It’s the key to success!’ they screamed.  Your ears are still ringing.  That’s what they told you then, because they didn’t understand.  You hadn’t moved anywhere in months.  Do they know what it’s like?  You didn’t even have an idea where to go.  Not only did you fail, but the mistakes you kept repeating were moronic.  They weren’t ‘smart’ mistakes.  You didn’t learn from them the first time – or the second or the third, or the fourth, or the fifth. And this wasn’t a grand struggle in the face of ultimate mysteries, or something.  The things that caught you up were trivial things, which nobody else even struggles with.

Now that you know how you could have gotten out of the rut the whole time, it’s even worse.  You had all the skills to get there from day one if you’d only been thinking straight.  In the end, you solved the problem over the duration of a coffee.  Now you’re in flow again.  It’s insane to you that you could have gotten so stuck for so long that way.  Look at how efficient you are when you’re flowing.  It washes that stuck feeling away like a bad aftertaste.  In the end, that stuckness was only temporary, and it was just a step to get here, wasn’t it?  Think of the perspective you've now gained, all that wisdom.  Failure is the key to success, you realize.  You tell all of them.  

Why are they covering their ears?

Science Communication's Future

The journal Science put out a call for short essays on how science communication will look in 50 years, and my response was chosen for print. Check it out here (it's the 2nd one on the 1st page):

http://www.sciencemag.org/content/340/6128/28.full.pdf

The revolution is inside you

She was a dignified beast.  Stuffed full of coils of wire and disk drives and mysterious metal-laced innards, she occasionally emitted whirring sounds or high pitched beeps from within her thick plastic carapace.  Her husk was beige and somewhat rough, because those were the textures of that day, kind of like black and white photographs.  We had to feed her a floppy disk to get her to boot.  She only had about a thousandth of the storage space of a modern thumb drive, and the same computing power as a modern throwaway flip-phone, but we didn’t care -- she crunched our numbers for us and had a word processor.  What else could we ask of one?  My brother was one of the few, the elite, who understood how to even use her.  He was fluent in DOS.  He even taught himself back then a few of the mystical languages of programming.  Yes, my family’s first computer was a Brontosaur.  But she was a Brontosaur with some megs, and it made all the difference.  

All that wasn’t so long ago.  Who would have thought we would have smartphones and tablets with apps for every bit of our lives in our hands by the year 2013?  Computers have exploded in speed, functionality, and ubiquity since those early days.  While this explosion involved billions of programmer-hours, its most convenient metric is Moore’s law, which states that computers tend to double in computing power approximately every two years.  The trend has held since the mid 1960’s.  Bootstrapping off of those advances, we have reached an era of computerization that a generation ago, few could have possibly predicted.  

But this blog post isn’t about computers.  You see, there’s another technological explosion happening right in front of our faces, an explosion every bit as far reaching and powerful as the computer one, but one about which tremendously fewer people are aware.  I mentioned it in my last blog, but I didn’t get too deeply into it.  What I’m talking about is the explosion in Genomics.   

What is most striking is that over the last decade, genomics has been advancing at a rate even faster than Moore’s law.  How much faster?  Well, if we measure the progress of genomics by the cost at which we can determine the sequence of DNA in an organism, then nearly four times faster.  This means that while sequencing the length of DNA in a bacterium in 2001 would have cost around $20,000, today it would cost something less than a dollar.  The cost to sequence is not the whole story -- to actually assemble the genome of a whole bacterium you need to do quite a bit more sequencing and other processing, and interpreting genomes is one of the biggest challenges we face in science today -- but you can imagine what this reduction in cost has enabled.  What this all means is that what took ~3 billion dollars, 13 years, and millions of man-hours to achieve in 2001 at the pinnacle of the Human Genome Project -- sequencing a human’s genome -- is now possible in a few weeks for several thousand dollars, and will be possible for less than a $1000 price-tag within only a few years.  

The $1000-genome milestone matters, because around that price, genome sequencing starts to become relevant on an individualized basis in medicine.  To put this more clearly, this means that when you go to the doctor not too long from now, she will be able to send off a drop of your blood or skin and have your genome sequenced as a routine procedure.  In fact, even now, companies like 23andme will sequence parts of your DNA that indicate susceptibility to a plethora of diseases for just a few hundred bucks.  

Just as with the computer revolution, by the time that the genomics revolution is done, we may barely even recognize the world that we live in.    

If you were to ask a person on the street what genomics will do for them in their lifetime, they probably wouldn’t even know what you’re talking about.  They might respond like a 1950’s housewife may have responded to a question about computers, or a pre-industrial farmer to a question about gasoline.  Or perhaps they’ll think about embryonic stem cell research or human cloning and have a gut negative reaction.  Most wouldn’t think of designer bacteria that emit wonderful perfumes, genetically modified algae that may solve the majority of our energy needs, cures for pretty much any genetic disorder, or totally personalized medicine (like a more advanced version of this).  But these things are precisely what scientists think, talk, and dream about.  The field is so rife with potential and is expanding so rapidly that how it will reshape us in the future is extremely hard to predict.  But just as computers have changed our lives in ways we couldn’t have fathomed, so may genomics.  And just as with computers, although there are certainly negative consequences, the potential of genomics for our lives is one of vast improvement in quality of life and happiness.

Genomics is the study of genomes.  A genome is the collection of all DNA in a person or organism.  DNA is a long, stringy molecule that dictates all of your genes, i.e., the traits passed on to you by your parents.  The most amazing thing about DNA is that it dictates our genes using a digital code with only four basic letters -- A, T, C, and G -- which act sort of like binary code in a computer.  This makes it extremely amenable to computerized analysis, an aspect that scientists have taken tremendous advantage of.

Every person on earth has a unique genome, and to sequence a genome means to use a combination of automated physical platforms and sophisticated computational methods (often run on a huge number of computer servers) to figure out the exact series of the A’s, T’s, C’s, and G’s that make a particular person genetically unique.  Although the genome doesn’t explain a person’s every trait, it explains a great majority of them.    In 2001 when researchers published the first draft human genome, it was actually an averaged genome of several people.  Now, our technology enables us to sequence individual genomes to near completion, which may be the key to truly personalized medicine.  

Each one of your cells has a couple copies of your own personal genome (except for a few weird cell types, like red blood cells, which contain no DNA).  The fact that there’s a copy in every cell is how, for example, scientists were able to create embryonic-like stem cells out of skin cells, a technology that may both bypass many ethical issues and allow for some amazing new therapies.  Imagine regrowing a damaged organ, and having a transplant from yourself.  As we get better at understanding and manipulating genomes, we will shine guidelights into many more areas than just that.  

This was amply demonstrated in 2010 when a team led by Craig Venter created the first ever synthetic lifeform.  To do this, they synthesized from scratch the entire genome of an organism based on a string of DNA code that had been planned on a computer (mostly following the DNA plan of a natural organism, Mycoplasma mycoides), and then implanted the synthesized genome into a cell whose DNA had been removed.  The “synthetic” cell proved to be viable, replicating billions of times.  While this synthetic cell was not so different from its natural parent, the process could be repeated for much more outlandish designed genomes.  

I saw Craig Venter speak about this in Tel Aviv last year when he accepted a science award called the Dan David Prize.  During a student Q&A session, he spoke about automated evolution: creating synthetic lifeforms and then mutating, evolving, re-sequencing, analyzing, and re-designing them, and thus closing the loop between computers and biology, enabling us to build and understand bugs that do anything.  He spoke about cells in a way I had never heard before from a biologist -- as computers running DNA software that is now, with Venter’s technology, easily exchangeable between silicon machines and biological hardware.  I asked him about Ray Kurzweil’s singularity, and whether he feels his technology is driving towards it.  He smiled like a man in the know.  

Of course, such power is not without dangers.  Who should be able to wield this technology, especially if synthesizing new genomes becomes cheap enough to be commoditized?  Because of the potential damage, it is almost inconceivable to release synthetic cell technology into lay hands.  Think atomic energy.  Good bioethicists and regulators must play a role, but even there we will face difficult dilemmas.  

And the dilemmas don’t just begin with synthetic lifeforms.  There are also basic ethical questions surrounding the mere sequencing, and not even getting into the manipulating, of genomes.  Sergey Brin, the co-founder of Google, knows this well.  When his wife founded the sequencing company 23andMe, Sergey Brin was one of the first to have parts of his genome sequenced.  It turns out he has a rare mutation putting him at high risk for Parkinson’s disease.  Brin has taken a pragmatic approach, and is now doing everything he knows of that will decrease his risk.  But the lesson is obvious.  Even if you can know about all the diseases you’re at risk for, do you really want to?  Do you want potential employers to?  Your insurance provider?   

That being said, to forsake such technology because of fear of its dangers seems foolhardy.  Last century saw the atomic age and the space age and the computer age, and I believe that when we look back, we may call nowadays the genomics age.  We should proceed with caution… but we should proceed.


See my related post:
Why a black swan named Brooke Greenberg might make you immortal -- or not

Why a black swan named Brooke Greenberg might make you immortal -- or not

Back in the old days, black swans used to take their tea with purple zebras, play hopscotch with orange kangaroos, and ride the unicorn skiff down the Cadbury-cream river with yellow porcupines.  That is to say, black swans didn’t exist.  At least Europeans were certain that they didn’t until a seventeenth century Dutch explorer actually discovered one on a trip to Australia.  It turns out that in the land down under, black swans are not only possible, they’re common.  So if you happen to see an inverted swan waddling by outside of your window, don’t panic.  First off, you're probably in Australia; and secondly, you've just seen a reminder of how a single unexpected observation can topple hundreds of years worth of dogma.

I first heard the story of black swans in a talk by the Chief Scientific Officer at TEVA Pharmaceuticals, Michael Hayden, a few months ago in Jerusalem.  Hayden’s topic was not actually swans, though, but rather drug discovery.  He summed up his philosophy on finding new drugs by saying that people who display rare physiological attributes, either beneficial or harmful, may be the key to our next blockbuster medicines.  He was referring to people who experience pain excessively and also people who don’t experience pain at all, who are extremely tall, who are resistant to deadly diseases like AIDS, or people who don’t age.  Hayden called these types of people black swans because, like their namesake, they exhibit traits that we never would have expected to exist.  That is, until the day we actually encountered people who have them.  

Perhaps the idea of developing drugs by studying black swans seems like no big deal to you.  Of course we discover new drugs by studying people with rare conditions, there’s nothing new about it, right?  The answer is somewhere between “sort of” and “no.”  Actually, new drugs are typically developed either by searching for molecules that can cause a beneficial-seeming effect in cells growing in a petri dish, or by testing large collections of drug-like molecules for their ability to target a protein that is thought to be important to a disease.  These approaches are problematic because they often lead to new drugs that are dangerous in humans, have major unintended effects, or simply don’t work.  Even a drug that perfectly targets a protein we think is important can be a failure, because targeting that protein in a human may lead to effects not encountered in the cells assayed.  It is because of such an unintended effect, for example, that the hypertension drug Sildenafil became the erection drug, Viagra.  

A black swan approach would be different.  The key to Hayden’s philosophy is that if we are able to identify the cause of a black swan trait and to perfectly target it with a new drug, then we already know what the side effects of the drug will be from the get-go.  The side effects, if there are any, should be readily apparent from observing the black swans after whom the drug was fashioned.  This idea isn’t just science fiction.  I mentioned before that there are certain otherwise healthy people who simply do not experience pain.  A black swan approach to developing a new pain medicine would involve identifying the mutated protein that causes this rare trait (if such can be found), and then developing a drug that makes this protein in normal people act like the mutated one. A well-targeted drug would have a very low chance of being harmful, because we already have examples of people who have this condition permanently, yet who display no seemingly adverse side effects.  In fact this example is real.  Drug makers are now developing a new class of highly effective, non-addictive painkillers based on this no-pain trait, which may soon be changing the lives of sufferers of chronic pain. 

There is another black swan named Brooke Greenberg, who may hold the secret to aging.  

Brooke enjoys being swung around in the air, playing with her sisters, crawling on the floor, giggling, and getting attention.  Do these activities seem strange for a twenty year old?  That’s because despite being twenty, Brooke stopped developing around the age of five, and still has the mentality and physical appearance of a toddler.  Her case has baffled doctor after doctor, and has led to stupefying interviews and media appearances by her family.  It’s too early to tell if Brooke Greenberg actually holds any keys to immortality, but it certainly appears that in some aspects of aging she has either stalled or has almost done so, which provides hope.  Taking a forever-young pill may be possible in the not-so-far future. 

The key then lies in being able to figure out what’s causing Brook’s condition.  If we can determine its cause, maybe we can develop drugs that can mimic it.  But the thing about black swan traits is that up until recently, we haven’t had a reliable way to figure out what was causing them.  We could do a battery of physiological tests, take blood samples, search for abnormal proteins or tissue functions, and write case studies, but these often just led to more head scratching or a long process of biological discovery, rather than a straightforward path to a cure.  

This whole process may be on the verge of an overhaul. 

In January, 2013, in an interview alongside Brooke’s family on the prime time show “Katie,” a geneticist at Mount Sinai Hospital named Eric Schadt explained that his group has sequenced Brooke’s genome, and is in the process of analyzing it for clues about aging.  

Until very recently, sequencing an individual’s genome would have been either impossible or prohibitively expensive.  Not so anymore.  A full human genome now can be sequenced with reasonable accuracy for something around 5 thousand dollars, down from 50 thousand dollars just in 2009, and hundreds of thousands or more just a few years before that.  This opens enormous new avenues for understanding black swans like Brooke Greenberg.  Many of the differences between her genome and a “normal” one will be readily apparent, and as more people’s genomes are sequenced as references, the differences will stand out more and more clearly.  Knowing these differences is the key to then developing cures.  

Of course, knowing what’s in the genome is only a part of the whole picture.  But, as Michael Hayden pointed out in his talk, there is a hidden advantage to the black swan approach over other drug discovery methods.  This is that when dealing with a black swan trait, we have a very good hunch before we even start drug development what a well-targeted drug would have as its side effects.  

The importance of knowing the side effects of a drug from the get-go cannot be overstated.  Developing drugs is almost inconceivably expensive -- in the neighborhood of four to eleven billion dollars per drug.  The majority of this cost is from the huge number of drugs that fail during clinical trials because they’re not safe, which in turn pump up the cost of the drugs that do make it.  Although it may not seem to matter how much drug companies pay to develop drugs, it matters hugely -- lowered cost could be a game changer, making drugs cheaper for consumers, and enabling drug companies to focus on many diseases that are not now on their radars because they simply aren’t cost effective.

Black swan-based drug discovery may be the ticket to reducing drug failures because of side effects, but black swans can sometimes portend some pretty serious side effects, too.  Brooke Greenberg is no exception.  First off, it may not be so simple to isolate Brooke’s anti-aging trait from fundamental and crippling developmental abnormalities, which have kept her not in the prime of her life, but as a toddler.  Secondly, Brooke has had a smorgasbord of medical complications, including stomach ulcers, seizures, a stroke, a brain tumor, and non-uniform tissue aging, which led to her esophagus closing and her needing to eat through a feeding tube.  These are discouraging.  Yet Brooke has also recovered from many of her complications astoundingly quickly, lest we forget that her body is harboring a great many secrets.  To some of these secrets, her genome sequence may yet reveal answers. 

Brooke Greenberg was born into an exciting age, in which a confluence of technology and knowledge has given a condition like hers a tremendous potential to help others.  It’s yet unclear if her condition will enable us to attack aging, but genome sequencing gives us a leg up on any other time in history, and we have reason for optimism.  Sequencing a person’s genome now costs on the order of Lasik eye surgery, and it’ll soon be much cheaper.  The possibilities are as numerous as the traits we can see in people around us.  We’ve really only just cracked open the doorway revealed by genomics, and the next leaps in medicine, in biology, in our very culture, may be incubating even now, somewhere, in the nest of a black swan.  

The play-dough of science

When we are infants we play with things, feel things, put them in our mouths, crawl around until we bump into objects and explore and discover the properties of everything about us, and each new experience helps us build a concept of reality, which we then use as a framework for all of our subsequent behavior and our categorizations of the things we encounter.  

Infants are naturally scientific.  For example, a child’s epiphany about language—connecting the sounds people make with actual meaning—is pure science.  The child consumes many different sources of data and searches for patterns.  She’s not intentionally looking for the meaning of language, for in the beginning, she doesn’t even know to look for such a thing—she’s merely exploring and playing, and the noises made by other humans are among the many stimuli that seem interesting.  But then an awareness begins to awake in her, a new and transformative way of experiencing what she’s encountered all along.  She understands now that these—words—can have power.  Certain ones make the adults behave funnily.  She tries to speak some herself.  A struggle ensues to master the concept of speech, with extravagantly positive results.  And now finally she understands language—her mind has undergone a paradigm shift.     

What distinguishes a scientist’s work from a child’s is that the child rediscovers conceptions that are common to us, whereas a scientist tackles phenomena that are not yet comprehended by anyone.  But scientists can learn from the process of children.  Indeed it’s the scientists who take risks, who misunderstand the dogma and run crazy experiments, and who view the unknown with fresh eyes—typically young scientists—who do the most revolutionary work.  Older scientists can reject foolish notions and keep the youth focused, but they have trouble embracing the radically new.  The youth are the architects of paradigms.  

Skills are essential for science, but specific skills do not a scientist make.  The actual science comes in the play—in the use of hard skills to futz around with the sillyputty of reality, and to generate epiphanies.  This process is not about throughput, it’s about novelty; discovery; seeing the patterns that are perpendicular to the usual conception.  Although a scientist can spend tremendous effort and time doing one task with utter efficiency, the most significant science often occurs outside of the lab.  It is out there, at the beach or the cinema, that she experiences her earth shattering moment, and sees everything familiar anew. 

But I don’t mean to imply that science is a pursuit for the lazy.  A scientist must be utterly immersed in her problem if her trip to the beach is to benefit her.  The boundary of our knowledge is mercurial and amorphous, and identifying it, and then being able to find the shape of its weaknesses, requires a deep knowledge of precedent.  Although efficiency and skillfulness aren’t synonymous with good science, good science generally doesn’t emerge in the absence of these.  Epiphanies spawn from intuition and knowledge, as well as a huge dedication and effort.    

So how then do we judge progress in science?  After a paradigm shift the goodness of the science is obvious, but before then it can be murky.  While science often requires completion of roadblock tasks, ordinary definitions of productivity, such as ‘throughput’ or ‘hours of work put in’ or ‘speed,’ can lead us to stress the wrong factors.  If the solution to a scientific puzzle is West, it’s not helpful to move North, even if you do it with utter efficiency.  That being said, a scientist might need to travel North for a while to realize that West is the way.  But the best science might involve thinking and reading about the meanings of North versus West, and understanding well that distinction before ever leaving the origin.  Balancing contemplation and movement is all part of the craft.  

Nowadays, your field—whatever it is—is probably starting to feel a lot more like my description of science.  Tasks can be outsourced, but intuition cannot be.  So nurture your flexibility and creativity.  Be willing to work like a dog when it’s needed, but also make time for your passions.  Remember that your trip to the beach might provide the epiphany that will revolutionize everything.  And keep in mind that it’s not about effort—it’s about seeing your destiny like play-dough, and building the right intuition about how you must shape it.