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All Sport Is Unfair, According to Geneticist. Is That True?

Author: 
Theral Timpson

Yesterday a court ruled that the South African running sensation Caster Semenya must take medication to lower her level of testosterone to compete in certain women only running events such as the 400 and 800 meters.

Some are calling the ruling discrimination against a certain athlete or against transgener or intersex athletes.  Some say the ruling is necessary to keep the sport fair.  It’s a worthy debate.  

What I find particularly useful about the debate is what it tells us about how our colleagues in the science community are thinking.

Geneticist and media personality Adam Rutherford tweeted:

The assumption behind this tweet is that fairness is a quality that is determined by biology.   Let’s say for just a moment that we went with this assumption.  How would we determine its validity?  How would we get into the position to determine it?  Let’s say we could devise a “great scale” where one could measure all the molecules of each individual person.  Or would it be a scanner?  Would it be a sequencer?  What would it be?  Would it be an HPLC instrument or all of the above?  Would it help to have Craig Venter on hand?  How would we measure each and every molecule of each top athlete and compare them with each other?  Where is—or who is—this biological deity which can see through us and determine our biological “fitness” to compete?  

Furthermore, are we able to reduce all competitive qualities to molecules?

In other words, this debate over sports fairness is another iteration of the biology reductionism debate.  It appears (I'm in the middle of two of his books about humans and their genetic makeup) Rutherford is a reductionist.  For him, it looks like all of biology can be explained by physics.  And every athlete’s performance can be explained by molecules.  All sports by the science of biology.

And many in his following agree.  One of them, a Martin Waring, tweeted: 

"Michael Phelps shouldn’t haven’t been allowed to compete at swimming as his size 14 feet and flexible ankles gave him an unfair advantage.   He also had unnatural arm reach.”

Phelps achievement has been reduced here to physical biological qualities.  There is no acknowledgment of any of Phelps’s perserverance, his skill, his determination, his work ethic.  No.  He is the sum total of his bodily parts.

Is there anything more to competitive sport than measurements and parts?  It's like saying the great Chicago Bulls team from the 90's that brought home six championships that decade was just a combination of their feet, legs, hands, reach, and jump height!  What about skilll, strategy, an amazing coach who went on to do some magic with the LA Lakers--and, let's ask about the big one, what about imagination?!  Has there ever been a great performance without a dynamic, creative imagination at work?

To the question about fairness being a quality that is determined by biology,  let me offer some alternatives there as well.  Fairness might also be created by the agreement of the players to compete.  When a group of young kids come together in the street for a pick-up game of soccer, is it not a fair game?  They immediately and intuitively size each other up and agree to a game.  The agreement itself generates the fairness.  If they see that one is older, bigger, “out of their league” they will automatically exclude this person.  Fairness may also be created from the very rules of a game.  While it may be true that life is unfair, sport is our way of creating a temporary “fair” space.  

In Semenya's case the issue of fairness will be decided by the community, just as it is in the pick-up soccer game on the street, and the sport will go on.

The drive by biologists to reduce competitive drive and success in sports (or music or other pursuits) to smaller ingredients is admittedly vigorous and complex.  But it is not only complex in the way they seem to suggest:  we just don’t have enough machines and data and PhDs yet to figure it out.  

You can have machines and biological data stacked to the moon.  This will never get you more than so far.

Where I Agree and Disagree with Precision Medicine’s Chief Critic, Michael Joyner

Author: 
Theral Timpson

Precision Medicine is more than a narrative, a story.  Hundreds of thousands of patients take drugs every day that are precision medicine drugs.  Thousands of women have been tested for BRCA genes and thousands of others diagnosed with lung cancer tested for EGFR mutations.  This has been more than a story for them.  It has saved their lives.  From rare disease diagnoses and therapies to the entire field of non-invasive prenatal testing, genomics has revolutionized medicine. 

In addition, millions of consumers are ordering personal genetic tests.  Some of these tests are reuniting families.  Some, it is true, are merely providing holiday entertainment.  And often it is more Halloween fright than Christmas cheer, for many of these tests are scaring the crap out of people.

Still, there are enough disappointments with the genomic revolution that the skeptics may easily earn their keep.     I’ve encountered several of these critics in my time hosting a podcast on the subject, but perhaps none as strong and relentless as Michael Joyner, a physician and researcher from the Mayo Clinic who joined us on the show last week.   

Whereas many of the others have tended to be arm chair critics--mostly journalists--Joyner is actively working on just the kinds of studies he thinks we should be doing rather than pursuing genomics, namely:  physiology and behavioral modeling.   This is no small feat in an age when the NIH is dominated by the genomic approach  And I might add, in an age when the Mayo Clinic is also generally an adherent of precision medicine as well.  (In order to do our interview, Joyner and I had to agree to say that his comments were not representative of Mayo’s institutional views.)

Joyner also stands out in that he is not a libertarian fantasist, one of the so called “free thinkers” who says the government should not be in the business of healthcare and that the NIH shouldn’t be funding any science.  They naively argue the market will take care of it all.  Joyner advocates for a dramatically increased NIH budget.  And though he waffled on the percentage of the budget he thought should go to basic science (it kept going up during our interview), he did agree that we should keep funding basic science.

I have quoted Joyner often on the program to keep the “hype factor” in check.  He has been a reliable go-to voice on Twitter against genetic determinism and the steady stream of papers that seem to find a gene for absolutely everything.  Joyner is right.  The simple genotype to phenotype causal connection that was anticipated before sequencing the human genome by many geneticists has simply not panned out.  I could cite study after study here and put in footnote after footnote, but you know what I’m talking about.  And besides, I don't do footnotes.  I don't have enough titles after my name for that. 

So things got more complicated than we thought for the common diseases.  We have to look at many genes.  Will polygenic risk scores pan out?  Maybe.  There is some genuine excitement there.  Euan Ashley and Josh Knowles out of Stanford say genetic risk predicts future cardio disease better than traditional risk factors.  They are not for population screening, but they do say that it’s time to incorporate genetic risk scores into clinical practice.  If it’s helpful and available, why not use it?

But maybe we have to keep working at it too.

Here’s my two points of contention with Joyner.

Number one.  Who gets to say when we throw our hands up in the air and give up on the reductive genomic approach that we've inherited from generations of biologists?

Number two.  What is the alternative?

It is a very bold position to say, OK, we tried, and now it’s time to give up.   At least Joyner has made a solid philosophical argument.  He reasons that there is no simple causal relationship of genotype to phenotype because the body uses redundancy.  One system or pathway fills in for another broken system or pathway to get the ultimate job done.  And that ultimate job is making sure the phenotype happens.  It was the phenotype that was selected for with evolution, not the genotype.  Therefore, it’s useless studying the genotype because biology will come up with constant new tricks to get to the phenotype.  There is nothing usefully predictable underneath the phenotype.  It is a black box under the phenotype.

But hey, with so much resources going into genomics, somebody oughta question it.   I’d like to see the NIH’s response.

Joyner does have an alternative to offer.  He thinks we should be pursuing more policy changes to impact healthcare.  For example, he said “it’s known that if we raised the cigarette tax nationally by a dollar a pack, it would increase lifespan by one year.”  He also points to the historical fact that we improved sanitation long before we knew what germs were.  Joyner wasn’t specific on how new policies would happen.  I challenged him, “you don’t do this at the NIH.”  He said, no, but you can model this kind of thing.  So he advocates doing behavior model studies and policy changes based on these studies.  This sounds to me like a heavy socialist government.    It turns out that far from being a libertarian, Joyner is a socialist.

This is in the direction of Bloomberg’s sugar tax.  I’m against it.  Actually California did impose a $2/pack tax on cigarettes last year.  There is no data in yet, but no matter the data how do you justify a majority imposing a health tax on a minority?  I understand banning smoking in public places because it impacts the health of others.  But how can society penalize someone for living unhealthy themselves?  In Notes from the Underground, Dostoevsky talks about just this thing, man’s need to be irrational at times, to be “unhealthy” if he chooses, to smoke a cigarette.  Will I also have to give up wine and will the police come knocking to make sure I have exercised my one hour a day under Joyner's proposals?

Finally, I’ll bring up another writer from the past, David Hume, the Scottish philosopher who got many of the empiricists going.  He’s known for Hume’s Law, the idea that you cannot get an “ought” from an “is.”  This is the famous problem that it is not obvious how one goes from descriptive statements to prescriptive ones.  Many philosophers since Hume have attempted to solve this problem, also called the fact/value dichotomy, notably Hilary Putnam in a famous economics lecture.

I think it is a blaring distinction that is inherent and not easy to explain away.  Remember back in gradeschool being presented with simple math problems such as 2 + 2.  Math was very straight forward.  You could come up with the right answer.  Then remember those questions in literature, such as what did the main character in the story do wrong?  I hated literature for this reason.  You could answer anything and be right.  Or you could answer what you deduced and be wrong.

So far we have been filling in the “is” of biology.  The facts.  The human genome is there.  One can download it.  One can get one’s own genome sequenced today and print it out.  It will be a fact.  What you do with it is something else.   Even if there is a “finding of clinical significance,” what you “ought” to do is something else entirely.  Joyner is for more exercise and and better diet.  I think most people already know they "ought" to do this.  The history of science has been about establishing the facts.  Getting them down on paper.  It’s the first step.  At one point science had to figure out how we weigh ourselves.  It was the BRCA testing of diet and exercise.  

Joyner is a physician.  It is true that science is not medicine, medicine is not science.  And medicine has its own history.  But the history of medicine has gone best when it has been based on science.

There is one question that Precision Medicine hasn't answered well.  Modern medicine in general hasn't fared any better.   That is, what is health?  For the last three years lifespan in America has gone down as the biomedical gurus have pipetted and typed furiously away.  The number one reason lifespan has gone down in America is because of suicide.  People don't want to live.  Oops.  Where do you look in the genome for that?  There is a limitation to genomic science, genomic medicine--it's true.  But the answer is not in socialism.  And while we must ask the bigger question of what is health, we must go on asking what is going on in human biology.  

What are the facts?

When Joyner says that Collins, Varmus, and others predicted this and that in the 90's for genomic science, we must not get hung up on exactly the words they used but instead look at their vision.  I think most biologists do.

 

 

Race Is No More Real than Dragons. Doesn't Anyone Read History and Philosophy These Days?

Author: 
Theral Timpson

Spoiler alert:  Race was discovered years ago.  

To be bogus.

Yet for some reason the race to discover race is back in full swing.  We're all waiting to exhale!   Will scientists discover that race is genetic after all?  That it's real?

The question is as relentless as the talk of a wall.   Just as the New Year’s fireworks were fizzling out, the race and genetics question exploded again when PBS chose to start 2019 with a show on Jim Watson, co-discoverer of the double helix and an unabashed racist to the end.  Or should we use the fashionable new parlance?  He’s just a racial realist.

As New York Times science correspondent, Amy Harmon, has shown, a new wave of racism is spreading--this time from the educated, the scientifically literate.  The white nationalists of our time are using genetic science to bolster their claims of racial purity.

Racial purity? 

First of all, let's applaud the milk chugging crowd on their decision to read some science.  But have they really thought this through?  If we all originally came from Africa, wouldn't that mean we all started with dark skin?  Wouldn’t racial purity mean dark people are the pure ones?  

It’s nothing new that racists use science.  Earlier in the 20th century, before the arrival of genetics, it was arguments about brain size or the fitness to work outdoors--you name it.  (For some reason penis size is rarely mentioned.)

What I found interesting about Amy’s pieces last year and her recent interview here was that she was reflecting a certain anxiety that scientists need to do something about this racism.   She talks about a high schooler who was working on a project who required assistance debunking racism, but he couldn’t find a scientist to help him.  Where were the geneticists?   Why were they not fulfilling their moral obligation?  Where were the scientific racism police?

And in fact, in an unusual move, the American Society for Human Genetics (ASHG) issued a public statement saying that "the study of human genetics challenges the concept of different human races."  Though the statement is brief, the studies which it cites are thorough and considerable.  One study in Nature Genetics titled, Conceptualizing Human Variation says the following, "The finding that the demographic group called 'African American' has a higher prevalence of prostate cancer, obesity and hypertension is not to be denied. This does not mean, however, that this is a 'racial' phenomenon, as disease is probably due to gene-environment interaction and not linked to the physical traits assumed to covary with this population. This group has heterogeneous ancestral continental origins, predominantly West African and West Central African. They are heterogeneous in their African origins also." 

Despite this blanket statement, Amy said that individual scientists have told her several things.  Responding to racists wasn’t their job.  They aren’t comfortable going out to the lay public talking on this topic.  And also they don’t know yet, that they are still “discovering the answer.”

Here there is a big disconnect among scientists.  ASHG issues a statement saying race is not genetic.  And yet there are many scientists out there--it’s obvious on Twitter--who feel that it is settled science that race is genetic or that we still are in the process of discovering it or haven’t discovered the answer yet.    

Furthermore, a Pulitzer prize winning science journalist for the New York Times is feeling the heat as well.  What was the title of one of her pieces . . . "Could Somebody Please Debunk This?: Writing About Science When Even the Scientists Are Nervous."

So what are we to think?  Why is this still an open question?  

Are scientists who study average genetic differences correlated to the way people self-identify racially for traits related to intelligence racist,  whereas scientists who study these differences for disease traits not racist?  

Is the term race scientifically meaningless, as ASHG claims?  

Is the term race changing in meaning, or is it already fixed?  

Are scientists promoting racism with the way they frame their studies, and if so, do they need to change this? 

In this blog I'd like to point the Mendelspod community to some fundamental scholarship on race that includes some science, yes, but also some philosophy and history. 

Is race a natural kind?  

The concept of a natural kind is one used by philosophers that has to do, obviously, with the natural world.  And second, it has to do with something which has exclusive or inalterable properties.   Water is a natural kind.  Tiger is a natural kind.   All tigers have properties which are unique to tigers (we now know they are gene sequences) and which no other animals have.   (There is brilliant work on whether species are a natural kind, but I'm not going to delve into that now.)  Gold is a natural kind.  Gold has a chemical makeup which silver does not.  

Most of the work on whether race is a natural kind has famously been done by Stephen Jay Gould and by Luigi Cavalli-Sforza who just passed away last year.   I like a more recent article by Chuck Tate and Diego Audette from Loyola University, Chicago (2001) who draw from Gould and Cavalli-Sforza but also update it with the most recent work at that time from Craig Venter and the Human Genome Project.  

Is race natural?  It appears so.  When I first went to the country of Vietnam, no matter which town I went to, I was followed by a group of children who wanted to look at me and touch me.   Those children saw with their natural eyes my natural height, the natural color of my hair, eyes, and skin, and they wanted to touch it.   

But, are there exclusive inalterable properties between races? 

As Tate and Audette show, there has been a history going back to the eighteenth century of attempts to classify race scientifically.  First it was done based on geographic origin.  It didn't take long for that theory to fail.   Then there was the theory of temperament: you know, levels of the four humors--blood, phlegm, choler and black bile.  Yes, if we lived at the time of the American Revolution, the white nationalists of the day would have been arguing their racism based on black bile.  (Not a comforting thought, considering that our founders would have been included in this category!)  

Fast forward to the present day and those who claim that race is a natural kind are in two camps.  The first argue that there are genes which are exclusive to one race which are not found in other races.  According to geneticists and Darwin’s Theory of Natural Selection, there is no reason to believe this is true.  In fact, the 1% difference that exists between humans is found as much between members of the same race as between races.   In one interview here on the program, a leading geneticist said there has been more genetic difference found between two populations living on either side of the same river in central Africa than between one of those populations and Northern Europeans.  

The second theory that race is a natural kind has adapted to the recent evidence that there is a continuum of genetic characteristics across races.  It holds that geopgraphically isolated populations have differed in distinguishable traits.   But this new theory runs into problems as well.  For example, North America is a geographical area with its own population.  Is there a North American race?  This new continuum theory also posits the idea that race is based on physical characteristics.  But how are you going to average out the physical characteristics of the North American population?  Even using the current common racial divisions as “black” and “white”, there are the same diversity of physical traits in whites as in blacks.   And no one has ever solved the problem of grey, except perhaps in an erotic bestseller.

Many jump to other terms such as ancestry, which has become a popular surrogate for race in the age of personal genomics.   But Tate and Audette show that ancestry is just a repeat of the old “geographical” argument.    The difference between human DNA is irrespective of geographic location or supposed race.   Furthermore, the term ancestry has other cultural connotations.

Tate and Audette used the work of geneticists to show that race cannot be a natural kind.   But now having used their paper (out of many possible papers) to make this argument, I want to go beyond the scientific argument!

We live in a culture where everything must have its scientific explanation, and we are expecting race to as well.   Is science always the ultimate arbiter?  There are many examples where we have given up explaining through scientific discovery terms our ancestors might have thought to be real.   Black bile, for example, and the four humors.   Or how about Sagittarius.  For a long time many believed astrology was real.   But it is not a natural kind nor do we ever expect it to become one.  Or how about dragon, demon or ghost

Now let me make it harder.  How about the term weed?   This is something that we see in nature, that we can can touch, taste, and smell.   We can make scientific observations and discoveries about weeds.  Yet we know that weed is not a scientific term.  Plant, yes.  Weed, no.  We would trust a gardener to be more informative on the topic of weeds than a biologist.

The term race is the vestige of a vernacular of our ancestors trying to make sense of the natural world and at the same time imposing a hierarchy of values on that world.  One of the purposes of classifying the natural world into kinds is to imprint our own arrangement.  Once we name a species and insert it into the taxonomy, we know where it exists in the pecking order.  And the impulse was no different for the Middle Age Europeans who developed the concept of the English word race.  However, despite all the efforts over the years, the term has never linked to any reality other than one made up by us.

That folks are going to college is great.  That they pick up some science is fabulous.  Why not add some philosophy and history as well? 

Scientists are not magicians.  That's the whole point.  They will never be able to rid the world of racists, who unfortunately grow like weeds.  But scientists can separate out their anxieties and stop jumping at the first calls of racism.  Perhaps they would benefit from some history and philosophy too.  

Perhaps this would help them cease worrying that they will accidentally "discover" race or magically turn it into a natural kind and thereby disadvantage certain populations.  Race is a term like weed or dragon or black bile.  It is more man-kind, more language-kind than nature-kind.  And that is racial realism.  Wasn't this a lesson of the 20th century?  Why are we forgetting it?  Is it the result of over STEM-ification of the 21st century? 

No Redemption in "Decoding Watson"

Author: 
Theral Timpson

It’s been the question of the week.  What to do with Jim Watson’s legacy?  On the one hand, he's been a brilliant scientist who made no small contribution to biology.  On the other, he's an outright racist.  And as we found out from a new PBS production this week, Watson is remaining a racist to the end.     Should PBS have even spent their resources on such a show, given a platform to the man?  Will this now bolster the new wave of racists who are using science for their projects of racial purity?  And can a scientist who was apparently so brilliant and open really be so closed off and pig-headed, or as one cancer biologist on the program asks, can these two sides exist mutually compatible in the same mind?

“He stands for critical, radical thought.  And how he could go back to an old-rooted notion that has nothing to do with critical thinking . . . I really don’t know," says CSHL cancer researcher, Lloyd Trotman.

A highly edited episode of television is no substitute for taking a walk with a man, or having a conversation in person to get to know him.  But this new PBS "American Masters" production, Decoding Watson, (couldn’t the makers have been more creative with the title and not stolen Craig Venter’s?) is as close as most of us who do not know Watson personally will ever come to him.  And most likely the last view of him at the end of his life. So what can it tell us?

Let’s deal with the juxtaposition question first.   History is stacked with the brilliant minds who do terrible things.  Watson himself brings up Jefferson in the film.  A few others that quickly come to mind are Wagner, Picasso and Polanski.  Most recently we have the example of Bill Cosby.  There is nothing built in to the human wiring that atomatically connects brilliance with nobleness of spirit.

On Twitter, the comparison of Watson to Shakespeare’s King Lear has been made.  I just saw the new production of Lear on Amazon Prime, and the comparison, I believe, misses the mark by a mile, but it can be instructive.  Whereas Lear did fall from the highest pinnacle to the lowest--the obvious moment of connection between our two tragic heroes is there at Lear’s “my kingdom for a horse” and Watson’s selling off his Nobel for cash.  But the similarity ends there.

Once Lear sees that he is out on the streets, he goes through what we now call the five states of grief--denial, anger, (lots of anger), bargaining, depression, and acceptance.    After crying out every tear along with the heavens in a mighty storm, he allows himself to go into a kind of madness.  But is it madness?  Or is it a liberation from his identity as a king?  Lear is happy for the first time in the play.  He dances and sings and finds a friend to care for in Mad Tom, a beggar, another feigning madness to escape his own identity.  Lear has found a way out of his former character flaws of arrogance and willful ignorance that he was unable to shake earlier in the play and which cost him his entire kingdom, men, and the coat off his back.  Though he is a beggar in the street, he is now happy and free and full of acceptance.  And he is willing to learn.

Lear must still face his sins.  He must still meet up again with his daughters.  Those who betrayed him, and Cordelia who loved him.  He must come out of his freeing madness and take on his old identity again.  Can he do it without taking on his old arrogance and anger?  Has he learned?  Has he been redeemed?

Yes.

It is Shakespeare, after all.

In the PBS play about Watson, we see no redemption.  Save for a few moments we hear about Jim and his son Rufus (it would have been great to hear more), we are stuck the entire time in arrogance and denial.

Real life can have redemptive endings.  Remember the David Frost interviews with Richard Nixon?  Frost prepared carefully to corner Nixon, and Nixon prepared carefully to do everything right to corner Frost back.  Their people negotiated over everything.  The money, the place, the times, the lighting, the handkerchiefs.  But in the end, there was something in Nixon which needed Frost (and, of course, Frost needed Nixon), something in Nixon begging Frost to ask him that question, that question which would allow Nixon to apologize, in his way, to the American people.  Nixon wanted, needed redemption.

PBS’s Decoding Watson is really a Frost/Nixon interview (granted on a smaller scale). The climax is where, for the only time in the film, we hear the director, Mark Mannucci, ask a question, thee question.  And we hear thee answer, the disappointing answer.  It is a play, a tv show, an interview to offer redemption.  But there was nothing in Watson that wanted it.

Rather Watson compares himself to Galileo, who was imprisoned for his unpopular scientific ideas.   For Watson, being stripped of his title and made a pariah was not enough to trigger a deconstruction like that of Lear.  He has chosen the route of the martyr rather than shed his arrogance and learn.

This is unfortunate, for Jim Watson, scientist extraordinaire, co-discoverer of the double-helix, will continue to give scientific cover to generations of racists.

It is the inherent risk in making this kind of end-of-life offer-for-redemption film.  And it is no doubt why the makers of the film fill the first half with lots of safe, warm and fuzzy history which we already know and which has been done over and over.

I’ve always thought that Frost sensed from Nixon that Nixon wanted to talk.  If the makers of this PBS show knew that Watson was unrepentant, why did they take the chance on a failed redemptive film?    

If they think there is a debate to be had over whether race is cultural or biological, that is a different kind of film.

Gene and Tonic Predictions for 2019

Author: 
The Editors

Oops.  We still had some champaign around.  Our look to the year ahead.

2019

January 6th  The best selling non-fiction book on Amazon over the holidays has some strong mature genetics related material in it.   The second chapter of  Advice for Generation Z  is entitled,  “Don’t Take that Cyanide Pill Just Yet: Genetic Tests Are for Fun, Not for Real.”

February 12th  The Oxford English Dictionary adds “Crispred babies” to the lexicon.

“We went back and forth on whether to all caps Crispr or not, and this is what we’ve chosen, but we did feel it was time," said one of the committee at the venerable institution which ultimately decides the way things are and were and will be.

“I was very happy to see that the word was included in this year’s dictionary,” said Roxy Nibo-Ducleic, a geneticist interviewed outside King’s College, Cambridge, UK. “I saw tweet after tweet denying the thing in China actually ever happened, and I’m just proud of the OED for being genetic-editing realists in a world that is increasingly leaning toward these pro-hacking idealistic subjectivist Tweetcakes!  They really get the concept of editing over there in Oxford, and we can appreciate that."

March 4th Biotech journalist, mountaineer, and climbing guide, Luke Timmerman of the Timmerman Report, writes that he has felt all along that the Cancer Moonshot should literally be a trip to the moon.   He adds that he is in talks with SpaceX and several biotech adventure capital firms.

March 6th Geisinger Health System announces a program to refund people for their unhealthy genes. Those with healthy genes will have to pay into the system.  Critics say it’s a scheme of genetic fortune redistribution.

April 28th STAT News announces that they will hire all of the remaining biotech journalists not already on their staff.

April 29th STAT News’ parent company, The Boston Globe, is bought.

April 30th The STAT News division is axed.

May 29th Just in time for summer blockbuster movie season, 23andMe announces the 4D experience. Moviegoers will have access to new 4D glasses, complementary of the leading genetic testing company.  The glasses will come prepackaged with a special CheekSneakTM, or removable stick, to swab their cheek for DNA. This they can hand back to an usher at the end of the film, and in a few days, voila, they will find out whether their genes liked the film they saw.  Most importantly, the company says, moviegoers will now have data-driven scientific confirmation of whether they have seen a great film, a good film, a mediocre film, or a bad film.  And furthermore, thanks to the fact that we fortunately live in the age of AI, if their friends and family connect over the 23andMe website, they too can have a little science involved in the statistical probablility of whether they should go see the film.   

"It's really very revolutionary, scientific, and in every way modern, cool, AI friendly, gluten-free and non-invasive," says a 23andMe spokesperson.

"What if there is some kissing before the swabbing?  Does this affect the results?"  asks a reporter from TechCrunch?  "And does it keep it gluten-free?"

"We recommend swab then kiss, swab then kiss.  It's all on the directions for the CheekSneakTM."

June 29th At a press conference, the Illumina family announces the birth of NovaSequelTM, a rather soon first child from a marriage a long time in the making.  It is said there is no length the baby will not go to eat.

An Illumina spokesperson has this to say, “The grandparents from the Sequel side of the family are determined to see the child raised according to certain longstanding traditions.  This side of the family likes to take their time and invest a lot into each sequence of experiences."  

A grandparent from the Nova side of the family spoke for herself.  "This is not my first rodeo.  I seek short bold wins.  The Nova’s don’t anticipate the marriage to the Sequels will do anything to disturb years of the Nova dynasty."

August 3rd FDA Commissioner Gottlieb jumps up and down in his office. He has just downloaded a new app which will keep track of President Trump’s tweets and let him know when the president has tweeted more tweets than him in a day so that he can then outtweet his boss. 

August 18th Another Chinese scientist Crisprs some more babies. Again it is argued there is no unmet medical need, but some argue that maybe there is.  Again the science is unclear. But here too, there is division among the experts. Again there is widespread condemnation. But a little less.  And again the scientist is taken into state custody, but this time into a five star hotel. 

A leading American scientist is caught on recording saying, “This is not fair. The Chinese have given up god, and it puts us on an unlevel playing field.”

September 16th Bowing to Silicon Valley pressure, biotech CEO, Ethan Perlstein, hires a personal training guru.

The next day he resurrects his old meth lab.

October 2nd Another Chinese scientist Crisprs some more babies.

November 17th The NIH’s All of Us Research Program announces the real beginning of the beginning of a new beginning.

December 8th Just in time for Christmas, a new genetic testing company, InHisImage, releases a new app giving polygenic risk scores for children you haven’t yet had.

A spokesman for the company says this, “We just thought if people could see the chances their future kids might have of having disesase, this would bond them to those future kids and make them more likely to embrace the calling to be parents."

A Few Notes on Tomorrow's Holiday Special with Sci-Fi Writer Kim Stanley Robinson on the Gene Edited Baby Story

Author: 
Theral Timpson

It was the headline of the decade in genomics. Humans had monkeyed with their own gene pool.

When Chinese scientist He Jiankui came to the podium at the 2nd International Summit on Human Genome Editing in Hong Kong last month, journalist Kevin Davies, author of “The $1,000 Genome” wrote that he hadn’t seen as much press coverage of a genomics event since the announcement of the sequencing of the human genome. Genomics journalists have been in a tailspin.

Not to mention genomics podcasters.

Who could we have on the program here at Mendelspod to talk about such a story?

A scientist?

You mean another voice in the chorus of condemnation? Hasn’t STAT News just about croaked out every crier?

A journalist?

The Times’ Carl Zimmer reminded us of the history of three parent babies. Should we ask on the Genome Whisperer?

How about Antonio Banderas who dragged up the villainous story from the shadows that Sunday evening? Will it be Twitter's own Zorro?

“This story is getting more sci-fi every minute. Michael Crichton couldn’t have made this stuff up.” tweeted Eric Topol of the Scripps Institute when he learned the most outlandish part of the story--that He Jiankui’s PR person was co-author on a scientific paper with Jiankui. (Because that's never happened before in science. Gasp!!!!)

Dr. Topol is right though.  This is a story for the sci-fi writers. But which one? Michael Crichton, the king of gene editing gone wrong didn't bother hanging around long enough to see it working in humans. Like so many sci-fi writers today, he wrote for the kid in us, not the adult.

Who could we talk to that could be a grownup about this? Who could imagine the designer baby story gone right? What if He Jiankui had done a better job? Surely it will be soon someday. And again. And again. Where are we headed? NIH Director Francis Collins says we cannot alter the "essence of humanity." What does that even mean? Is this a Christian view of the genome or a Darwinian view? Who will challenge this thinking? Should we challenge this thinking?

Calling all utopian science fiction writers!!

“Hello Stan, is that you?”

“Hello, Theral, yes it is.”



“Hi, are you out in your garden at your writing desk? Is your Ursula Le Guin rock there next to you?”

“Well, Theral, actually, there was construction on the street. So I’m inside this morning. But, yes, my Ursula K. Le Guin rock is out still out there next to my writing chair.”

It’s Kim Stanley Robinson, author of the Mars Trilogy and such recent novels as New York 2140 and Red Moon. He’s agreed to talk with me for the gene-editing story, and I’m stoked. A sci-fi writer is the one for this interview. Stan will be able to “fly.”

You see, through all the shock, condemnation, and stuttering over the past month about the rogue Chinese scientist, He Jiankui, I’m quite convinced I’ve detected that at least half of the scientists out there are, if not overtly, then secretly thrilled. Have we passed a threshold? Have we crossed a red line? They know that we've come up to what has been a wall called "designer babies" and now, rather than turning back as always before, we're writing on that wall.

One scientist who went through the motions of showing over Twitter that He Jiankui’s own data showed that his experiment failed also ran some fancy statistics showing (scientists are big "show offs") that this mutation had a 15% chance of appearing as a de novo or inherited mutation naturally.

Now how does the utopian sci-fi writer see the designer baby story unfolding?

Well, we were ready for a ride, but we weren't quite ready for this.

Coming tomorrow . . . .

George Church Has a Point. Do With the Messenger What You Will, Lulu and Nana Are Here.

Author: 
Theral Timpson

When we first encounter Frankenstein in Mary Shelley’s classic, the scientist has lost all his friends, his wife, his meaning in life because of his science. Now he is frozen half to death out on the sea ice chasing his creation of “gigantic stature” toward the North Pole. It’s the only thing he knows to do. Monster and creator, they are locked in an obsessive battle of existence, creation and loss, birth and death. They both know one thing surely. They have known it all along. There is no going back.

Not actually reading the book until some years ago, I always thought that Frankenstein was the monster. In fact, Frankenstein is the name of the scientist. The author invites a parallel confusion throughout the tale between the scientist and his creation. We are constantly made to wonder who is the stranger one. The “monster” at times sounds quite human: tender, impressionable and rational.

This past week we heard of a scientist “going rogue” in Southern China editing a gene--the germline--of two actual new humans, or as we science journalists so bluntly put it, creating “the world’s first CRISPRed babies.” Yet the way he went about it has led us all to condemn the scientist as stranger than the science. His rebellion has allowed us to hide our fear of this fantastic and utterly terrifying technology behind our outrage.

A few days on, are we still in denial?

There’s no question that He Jiankui has done some improper medicine and some questionable science with some pretty good technology. I say improper medicine, but not ineffective medicine because if it didn't work (think of stem cell clinics in Mexico) then there wouldn't be much reaction. It's precisely because we think it worked that we are so afraid. And the reaction from around the genomics community has been swift: a combination of bewilderment, shock, rage, condemnation and wonder since we read Antonio Regalado's piece in Tech Review on Sunday. “Wait a minute . . this is not what it was supposed to look like.” Even though it's not what we might have envisioned, it is the headline for which we were all waiting. We might want to attack the messenger, but the message is still here.

It certainly was surreal as we watched He Jiankui announce this biggest of all medical breakthroughs from a Youtube video. Breaking with standard ethical protocols, he seemed to be making it up as he went along. An app would have done a better informed consent. "Families need this technology," he argued directly like a populist politician might on Twitter, and he was “willing to take the criticism for them.”

Was he so young and naive that he did not know it would be more than just criticism? Did he not know he would lose everything, his life as he knew it? Or will he?

It became even stranger as we saw him on center stage at the International Summit on Human Genome Editing in Hong Kong led by the Nobel laureate, David Baltimore. There He Jiankui sat, defiant, his name tag dangling, a debilitating constant sniff betraying his fear: the modern Frankenstein facing the flash of a thousand cameras.

Maybe I had been right all those years. Frankenstein was indeed the monster after all. This young man had been created by the peers who now sat around him in judgement, questioning his every word, his every move. This was the trial of He Jiankui. He had become the creation, the monster. Did they know he was theirs?

What will the modern world do with the monster today?

After He Jiankui's personal appeal and before the inquisition, the Nobel laureate stood, the leader, the arbiter, looking at the floor--before anyone asked their questions--with his words of judgement, reflecting what the whole world felt: horror. “Irresponsible.”

Condemned.

"I feel strangely satisfied," tweeted Antonio Regalado.

“It’s dangerous, unethical, and represents a perilous new moment in human history,” said O. Carter Snead, a former presidential adviser on bioethics.

The full title of Mary Shelley’s book is Frankenstein, or The Modern Prometheus.

Prometheus was a trickster who went against the authority of the gods to give fire to humans. For this the Gods sentenced him to eternal torment. He was bound to a rock and pecked each day by a giant vulture who fed on his liver which was eaten only to grow back each day and eaten again.

Poor Jiankui.

His work is "justified,” says George Church of Harvard. “The genie is out of the bottle now.”

Promotheus was also remembered for his intelligence and for championing mankind.

He Jiankui has held fire, and there is something about fire, there is something about technology which burns through the hands of its creators. It must be controlled to be of use because it can enflame whole villages. Exhibit A: Facebook. Zuckerberg was not similarly condemned or shut down after his trial for what many are calling a humanitarian crisis that dwarfs the gene editing of two babies. This is not the crossing of the Rubicon as we have heard this week. That was a military, a political move. There was no new technology in Caesar's hands. This is that burst, that spark of the human mind, that tinkering that led to the first IVF baby.

Right now is the time to feel the shock, the condemnation, the wonder at the strangeness. But tomorrow we have to decide what to do with this story.

“This story is getting more sci-fi every minute. Michael Crichton couldn’t have made this stuff up,” tweeted Eric Topol of the Scripps.

Then Dr. Topol sent in an OpEd to the New York Times to explain to the public, to make his case that it is too early, that it is too risky. I admire Dr. Topol for reaching out to the public as a researcher and a doctor, for swiftly getting ahead of the story. However his opinion piece (or pick any one of a number of others from the head of the NIH to the FDA) is heavy handed and risks condemning the very technology which I know he is very excited about, the potential for genomic medicine to eradicate disease and ease human suffering.

I've seen a quote floating around by one of the inventors of the CRISPR technology, Jennifer Doudna, that her greatest fear is "waking up one morning and reading about the first CRISPR baby, and having that create a public backlash where people ban or regulators shut this down."

What story will we tell our friends and family? And I have to say that none of my friends or family have known about it until I told them.

If this story is not true, "it would be a pretty bald-faced fraud,” Hank Greely of Stanford told the Atlantic. “If it is true, I’m disappointed.”

Disappointment is a kind word. A parental feeling.

What do you feel? How will you frame this to your family and friends? Is it science fiction? Is He Jiankui a Frankenstein who will forever be chasing his monster? Or is he the monster created by others? Will those others now turn on him? Should this all be shut down, or is this one small step for man, and one giant leap for mankind?

Whatever story we choose, there are now two new characters that we must add: Lulu and Nana. I hope the world will be kind to them, that they will not end up lonely, isolated, and desirous of running away to the North Pole. They are no more strange than He Jiankui, or than the scientists who tamed this bacteria and archaea based tool suite CRISPR/Cas9, no more strange than you or me.

Genomics and the 2018 Election

Author: 
Theral Timpson

The last two years have had us on edge.  It had scientists marching in the street.  That was unprecedented.

So what does last week’s election mean for the genomics community?

Scientists can focus on science

A friend of mine put it this way, “When Obama was in office, I realized I’d been like a cat, relaxed and having my nap in the afternoon. When Trump was elected, I felt like a mouse, always on edge.”

There are studies showing (did we need studies for this?) that relaxed states are better for focus and creativity.  The Libertarians have been supportive of Trump and his doctrine of rolling back regulations and “draining the swamp” of professional governmenteers, saying this is good for innovation.   The opposing argument is that when we’re all wondering if the basic things that we’re used to counting on--our drinking water, basic education, respect for the planet and its limited resources--are all going to go to hell, we might not be innovat-ering at our optimal pace.  Not to mention such things as the funding of the NIH, which Trump proposed to cut by one fifth.

The stock market took a quick sigh of relief, and so too have a lot of scientists.  Something tells me even the data is happier this week.  Single HPLC peaks are showing beautifully.

Still, let’s agree too, that scientists--that we all--have become more aware of the precariousness of the fundamental values of the enlightenment, like reason and science: this has been a good outcome of the past two years.  And let's celebrate the fact that we can say now, “the past two years” with some knowledge that the next two will be different.    

Scientists have become more civically engaged.  Some even ran for office.  It was laudable.  At the same time it was horribly unfortunate that professors of science who had spent a lifetime, or half a lifetime, developing their minds in a special discipline and contributing to a body of research and to a community in pursuit of big fundamental questions of biology would have to go to Washington and fight for the basic right to be able to do such research.

John Adams wrote:

“The science of government it is my duty to study, more than all other sciences; the arts of legislation and administration and negotiation ought to take the place of, indeed exclude, in a manner, all other arts. I must study politics and war, that our sons may have liberty to study mathematics and philosophy. Our sons ought to study mathematics and philosophy, geography, natural history and naval architecture, navigation, commerce and agriculture in order to give their children a right to study painting, poetry, music, architecture, statuary, tapestry and porcelain.”

I wonder where he would have put evolutionary biology.

DTC Testing

Speaking of cats, some say there is one cat that came out of the bag with Trump’s election that won’t be going back in with this recent election.  DTC testing is having a heyday, and most of the thought leaders in our field think that now that Pandora’s box is open, it won’t be shut, even if a Democratic president is elected in 2020.

For years the FDA kept a tight lid on DTC testing.  Those days are over with the Trump administration.  I’ve just today seen the new Helix ad promising folks "100 times more data on important health and lifestyle information”.    Black Friday is upon us.   Last year, DTC tests were competing with the InstaPot on Amazon at this time of year.

What’s the problem with genetic testing going DTC without FDA oversight?  I encourage everyone to listen to Laura Hercher’s recent podcast with Matt Fender over at the Beagle Has Landed.  What struck me most about this interview was that Matt represents the next generation, one that is growing up with DTC testing as a part of life and assuming that the tests mean something.  Afterall, it’s our DNA.  Isn’t there ample scientific data connecting our genes with disease?  Matt went through terrible anxiety before he got to a doctor and a genetic counselor and did some confirmation testing with a clinical company which confirmed that he had nothing to worry about.

As I say, the clinical community has accepted this shift on DTC testing, and are now moving on, albeit with advice and caveats.   In a recent Mendelpsod interview with Daryl Pritchard of the Personalized Medicine Coalition, this was the warning he gave to anyone and all:

If you get a DTC test, don’t belive anything it says until you go to your doctor or unless it's approved by the FDA. 

Ummm . . . O . . . K . . .

But I'm not ok with it, and disagree with most others on this.  I think the cat has to go back in the bag.  And will when the first big scandal breaks, such as a woman getting a BRCA test from 23andMe that she thought was the real thing only to find out it wasn't.  She sues 23andMe.  And she sues the FDA when she hears how it could have been done right and is done right in some countries.  Why are we playing around with this?

Race and Genetics

Race was a big topic in the election, driven, as we all know, by the president himself. Amy Harmon wrote a piece in the New York Times that provoked the committee at ASHG to issue a statement on race and genetics.  No doubt the topic will die down somewhat now, but I think it’s an important conversation, and I plan to write more about it.   And whether scientists continue to run for office or not, they can always speak out more in public on the question of race and genetics.

Why is race not genetic?

We’ve heard on this program many times from geneticists how certain diseases are correlated with certain racial groups.   African American women have a higher rate of abnormal BRCA1 or BRCA2 genes.  Ashkenazy Jews have known for years they should be tested for the cystic fibrosis CTFR gene because of studies showing it runs higher in their population.  (There I go, conflating "population" with "race."  Come on, geneticists.  Work with me here, and quit dodging the question.)

That white nationalists in this country are now using studies such as these and other studies not always on the topic of health and disease to promote their despicable project of racial purity is abhorrent, and it needs to be answered in direct easy-to-understand language.  I’m talking about language one would use in the bar or at the barbershop.  We all have family.  What language are you going to use at the Thanksgiving table, for instance?

So, Uncle Bill, you’re reading science now?  What else have you learned--could you pass the candied yams?  Did you come across that article about the planet heating up as well?

Have you also read the science showing that the ancestry of all white Europeans goes back to Africa?  At what point did the Homo Sapiens who had walked out of Africa into Euorpe become pure? 6,000 years ago?  2,000?   When was the cut off?  And how do you define pure?

We also have to face the fact that Trump’s election and the populist movements around the world have exposed “some bone,” have caused many of us to face our own epistemic realities.  Whence science?  Whence truth and fact?   What is science?  Is there a special scientific method that spearates science from other knowledge gathering disciplines, such as cooking or gardening?   We all know the troubling statistic that a majority of biomedical research cannot be reproduced.   This soul searching journey will go on even after what's his name . . .that one guy . . . Melania's husband . . is gone from the White House, one way or another.

Illumina Concedes on Long Reads, Buys PacBio

Author: 
Theral Timpson

At 1:02 pm today, there was a tremor in the world of genomics as it was announced that the two leaders in the field of sequencing have become one company. Goliath has opted to pick David up and put him on his shoulders. Upon first reaction, I'd say three things. 1. High quality long reads are the future of sequencing. Disrupting a standard carried for years in the drive toward the $1,000 genome of quantity over quality, PacBio stepped in and raised the bar for the technology of DNA sequencing. As Evan Eichler of UW put it to me in an interview once, "when long reads are just twice the price of short reads, short reads are dead."

 

2. Why now? Roche had a major deal with PacBio which ended this past year. Were the Illumina folks in the hallway when the Roche people closed the door and headed to the airport? This is Illumina’s biggest purchase ever, but they have the money. Did it take this long for Illumina to recognize the value of PacBio's long reads? Is PacBio facing some limitations with their technology, made more urgent with Oxford Nanopore appearing closer in the rearview mirror?

 

3. Is this good for science and medicine? Since Mike Hunkapillar took over at PacBio, the company has slowly and methodically built up the business based on this niche of high quality long reads. I remember the first interview I did with Mike back in 2014. I brought up Illumina. He quickly said, “oh you mean short reads...” He said it so diminishingly as he sat there at his desk in his plain red shirt looking down at the floor, then directly back up at me. At the time Illumina seemed absolutely unstoppable. And PacBio’s stock was at its lowest. Their instruments were way behind schedule, not doing what they were supposed to do, and having a terrible problem with errors.

 

My first reaction was, what a cocky guy. My second reaction was, what are short reads? It was the first I’d heard of the distinction. PacBio then went around the world educating one scientist after the other on the possibilities of their long read technology. And they demonstrated that their errors were random, and that with deep enough sequencing, the error rate could potentially be not a problem at all. Then scientists came to PacBio educating them on the possibilities of their long read technology. At that time we had a bioinformatician on the program by the name of Gene Myers, the same guy who worked for Craig Venter in the Celera days and wrote the Blast algorithm. Gene said he loved the PacBio long reads and was getting 100% accuracy! This was not what I was hearing from the critics of PacBio down in San Diego. It was painstaking work for PacBio when the whole world was buying up Illumina machines without a second thought. Soon scientists were collaborating with PacBio on very new and innovative projects such as exploring areas of the genome that had never been characterized, going back to the days of the Human Genome Project. A whole new field of structural variation blossomed and began to have meaningful impact on cancer and neurodegenerative disease. The folks at PacBio were having fun. There has been an atmosphere over there akin to a university institute. They have published and co-published thousands of papers. It’s been a unique company. Now let's move south. Illumina is more than just a company today. They are an ecosystem. I was just in San Diego at the Jay Flatley Innovation Center. Up here in the Bay Area they set up the world’s first genomics incubator. They got FDA approval of the first clinical next gen sequencing diagnostic test. Illumina is an ethos, and that ethos is boldness. They have kept an aggressive timeline in coming out with new products, and they have conquered new markets. They spun out a company called Grail for heaven's sake. It’s mission? To detect cancer before we have it. Illumina has also driven personal genomics. Years ago they began offering to sequence anyone's genome. They spun out the direct-to-consumer company, Helix. It seems DNA just can't replicate itself fast enough for this bold company. Here's my question: Will that boldness nurture or knock over PacBio’s methodical scientific collaboration laboratory? We’ve talked about the elephant in the room. And the monkey. We must mention the mouse. This year Oxford Nanopore, who Illumina divested it’s shares of a couple years ago, sequenced a whole human genome on their pocket sized synthesizer. The read lengths were much longer than PacBio’s read lengths. The scientists I listen to tell me that in the coming head-to head between PacBio and Nanopore, PacBio had nowhere to go with their technology, that Nanopore wins out on throughput and, already, on price. Is this a surrender on PacBio's part? Will Illumina be able to take the Sequel and advance it? And will we soon hear that Illumina will be buying Nanopore? Remember that Illumina's current technology, the tech that made them who they are was picked up in a buyout. That was Clive Brown's technology, who is the technologist at Oxford Nanopore. He already lost one instrument to Illumina, and I've heard he’s sworn never again. As I write this, I can't help but see that the engine of Illumina's boldness has been built on the assumption that gathering all this data about all the DNA in our whole world will mean a whole lot to a whole lot of people. (I'll never forget one bioinformatician on a panel in a very chic setting in San Francisco one night saying, "we're just sequencing for sequencing sake!") Some of it is very important. BRCA data mean a lot to many. New structural variants can mean a lot to some patients. Understanding how life works will go into our biology text books. Don't get me wrong. But the pace of sequencing should somewhat match the pace of our making sense of the data, the pace of our understanding. PacBio and their scientific partners have been pretty good at that.



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