Neymiş ki?



 Hasret deyince hep aklıma komşunun  kızı gelir, hiç konuşmazdı , hasret nedir diye soran öğretmenime suskunluktur deyişim ondandı yoksa o yaşta hasreti ne bilirim...
 Sevdiğine  kavuşamamak mıdır acıtan canı, yoksa sevdiğine ulaşamamak mı, akıbetini bilememek mi yakar en çok canı yoksa kara toprakta olduğunu bilmek mi rahatlatır canı 
yeri belli diye?
 Hıııhh ! Eyvahhh! siyah kuğu tüm karamsarlığıyla gelmiş  kaçın dediğinizi duyar gibiyim:).


Genes: convenient tokens of our time

My post today, perhaps typically cranky, was triggered by an essay at Aeon about the influence that the film Still Alice has had on thinking about Alzheimer's Disease (AD). As the piece puts it, AD is presented in the film as a genetic disease with a simply predictable doom-like known genetic cause.  The authors argue that the movie is more than entertainment.  It's a portrayal that raises an important ethical issue, because it is very misleading to leave the impression that AD is a predictable genetic disease.  That's because a clear genetic causation, and thus the simple 'we can test for it' representation, applies only to a small fraction of AD.  The film badly misrepresents the overall reality of this awful form of the disease (a good treatment of Alzheimer's disease and its history is Margaret Lock's thoughtful The Alzheimer Conundrum, 2013, Princeton Press).

While focusing on AD, the Aeon piece makes strong statements about our obsession with genes, in ways that we think can be readily generalized.  In a nutshell, genes have become the convenient tokens of our time.

Symboling is a key to making us 'human'
If there is any one thing that most distinguishes our human species from others, it may be the use of language as a symbolic way to perceive the world and communicate to others.  Symboling has long been said by anthropologists to be an important key to our evolution and the development of culture, itself based on language.

Symbol and metaphor are used not just to represent the world and to communicate about it, but also to sort out our social structure and our relationships with each other and the world.  Language is largely the manipulation or invocation of symbols.  In a species that understands future events and generalities, like death and sex, in abstract terms, the symbols of language can be reassuring or starkly threatening.  We can use them to soothe ourselves or to manipulate others, and they can also be used in the societal dance around who has power, influence, and resources.

Symbols represent a perception of reality, but a symbol is not in itself reality.  It is our filter, on or around which we base our interactions and even our material lives.  And, science is as thoroughly influenced by symbols as any other human endeavor.

Science is, like religion, a part of our culture that purports to lead us to understand and generalize about the world, but because science is itself a cultural endeavor, it is also part and parcel of the hierarchy and empire building we do in general, part of a cultural machinery that includes self-promotion, and mutually reinforcing service industries including news media, and even scientific journals themselves.

The current or even growing pressures to maintain factory-like 'productivity' in terms of grants coming in and papers going out is largely at odds with the fundamental purpose of science (as opposed to 'technology').  Unlike designing a better product, in the important, leading-edge areas of science, we don't know where we're going.  That is indeed the reason that it is science.  Exploring the unknown is what really good science is about.  That's not naturally an assembly-line process, because the latter depends on using known facts.  However, our society is increasingly forcing science to be like a factory, with a rather short-term kind of fiscal accountability.

Our culture, like any culture, creates symbols to use as tokens as we go about our lives.  Tokens are reassuring or explanatory symbols, and we naturally use them in the manipulations for various resources that culture is often about.  Nowadays, a central token is the gene.

DNA; Wikipedia

Genes as symbols
Genes are proffered as the irrefutable ubiquitous cause of things, the salvation, the explanation, in ways rather similar to the way God and miracles are proffered by religion.  Genes conveniently lead to manipulation by technology, and technology sells in our industrial culture. Genes are specific rather than vague, are enumerable, can be seen as real core 'data' to explain the world.  Genes are widely used as ultimate blameworthy causes, responsible for disease which comes to be defined as what happens when genes go 'wrong'.  Being literally unseen, like angels, genes can take on an aura of pervasive power and mystery.  The incantation by scientists is that if we can only be enabled to find them we can even cure them (with CRISPR or some other promised panacea), exorcising their evil. All of this invocation of fundamental causal tokens is particulate enough to be marketable for grants and research proposals, great for publishing in journals and for news media to gawk at in wonder. Genes provide impressively mysterious tokens for scientists to promise almost to create miracles by manipulating.  Genes stand for life's Book of Truth, much as sacred texts have traditionally done and, for many, still do.

Genes provide fundamental symbolic tokens in theories of life--its essence, its evolution, of human behavior, of good and evil traits, of atoms of causation from which everything follows. They lurk in the background, responsible for all good and evil.  So in our age in human history, it is not surprising that reports of finding genes 'for' this or that have unbelievable explanatory panache.  It's not a trivial aspect of this symbolic role that people (including scientists) have to take others' word for what they claim as insights.

This token does, of course, have underlying reality
We're in the age of science, so that it is only to be expected that we'll have tokens relevant to this endeavor.  That we have our symbols around which to build other aspects of our culture doesn't mean that the biology of genes is being made up out of whole cloth.  Unlike religion, where things can be 'verified' only by claims of communication with God, genes can of course, at least in principle, be checked and claims tested.  Genes obviously do have major and fundamental roles in life.  If that isn't true, we are really misperceiving fundamentals of our existence.  So, even when complexities of causation are daunting, we can claim and blame what we want on genes and in a sense be correct at least at some level.  That enhances and endorses the token value of genes.

Genes do have great sticking power.  The Aeon piece about AD is just one of countless daily examples.  A fraction of cases of AD are so closely associated with the presence of some known variants in a couple of genes, that true causation--whatever the mechanism--seems an entirely plausible explanation.  Likewise, there are hundreds or thousands of disorders that seem clearly to be inherited and as the result of malfunction of one or two specific genes.  The cultural extension of this in our society that we are stressing here is the extension of these clearly causative findings to the idea that causation can be enumerated in convenient ways mainly by peoples' inherited genomes and that other aspects of biological causation are often treated as being rather superficial or incidental.  That in a sense is typical of deeply held cultural icons or tokens.

The problem with genes as tokens is that they are invoked generally or generically in the competition for cultural resources, material and symbolic.  Personally, we think there are issues, genetic issues in fact, that deserve greater investment, rather than just the easier to invoke bigger-is-better approach. They include a much more intense attack on those many traits that we already know without any serious doubt are tractably genetic--due to one or only a couple of genes, and therefore which real genetic therapy might treat or prevent effectively.  By contrast, most traits even if they are affected by genetic variation as all traits must be, are predominantly due to environmental or chance causative factors.  We have ways to avoid many diseases that don't require genetic approaches, but as vague entities they're perfect subjects for invoking the gene token, and policy in the industrial world clearly shows this.

Some progress does of course occur because of genetically-based research, but the promise far outpaces the reality of genetic cures.  But genes are the material tokens that keep the motor running far beyond the actual level of progress.  They effectively reflect our time--our molecular, computer, technological culture imagery, our love of scale, size and the material grandeur they generate.

Every culture, every generation has its tokens and belief systems.  Genes are among ours.  They're never perfect.  People seek hope, and what velvet robes and gilded cathedrals and mosques provide for many, whereas the humming laboratories do for a growing number of others.

Tokens, symbols and metaphors: they drive much of what people do, even in science.

A real curiosity!


 I love trawling around Antique Fairs looking for 'treasure', and every so often you come across something TRULY unique. I recently found on a table surrounded by stamp albums and postcards a rather ordinary old shoe box with what at first I thought was a game of battleships. As I delved deeper into the box I discovered that there were literally hundreds of these little paper ships, all hand-drawn, then hand-painted, and meticulously cut out to form 3-dimensional models. I wouldn't be surprised if they were all drawn to scale as well, such is the detail.
Whoever created these models, and I think we can assume it was a man, was obviously a pretty good artist ( a few of the ships have been painted on previously used paper, as above) and he was passionate about the naval fleets of the world. On the back of each drawing is not only the name and country of origin of the ship, but other interesting details such as how many guns, the size, when and where it was built, if it was destroyed in warfare etc.
 The mind almost boggles at just how long this collection must have taken to produce.
There are a few galleon type ships but the vast majority are naval gun boats, not just of the British naval fleet of the last century, but also the naval fleets of Russia, Germany, Sweden, USA, Japan, Spain, France.........!!! 
 'USS New Jersey'. Battleship (2nd line). 14,948 tons. Four 12", eight 8", twelve 6", thirty-six small guns. Speed: 19 knots. Completed 1906.

'Jean Bart'. French battleship. 22,189 tons. Twelve 12", twenty-two 5.5" guns. Four 3" AA guns. Speed: 22 knots. Completed 1913. Served in French Mediterranean fleet 1914-18, and twice torpedoed. Reconstructed and appearance altered, 1928-9.

 
'Ausonia'. Cunard White Star Line. 14,000 tons. 15 knots. Built 1925. 
(Just to give you an idea of scale; the above ship measures 13 cms)

  I mulled over in my mind quite what I was going to do with this collection, and how to best present it for sale. And what I came up with was a background of printed sea chart into which I have cut appropriate length slots. Each ship can then be displayed in an upright position by easing it into the slot, but can still be removed to read the information written on the reverse. This way I have not used any glue and preserved them just as they are.
I am presenting them in groups of 5 from whichever national fleet they come from. Here are three British ones. They are on sale in the shop now and I shall also be bringing them to my next fair on the 18th June at Cowdray Park, West Sussex (see side bar). 
I hope you have all passed a pleasant bank Holiday and the sun shone for you! xxx

Cancer moonshot and slow-learners

Motivated by Vice President Biden's son's death at an early age from cancer, President Obama recently announced a new health initiative which he's calling the cancer 'moonshot'.  This is like a second Nixonian 'war' on cancer but using a seemingly more benign metaphor (though cancer is so awful that treating it as a 'war' seems apt in that sense). Last week the NYTimes printed an op-ed piece that pointed out one of the major issues and illusions belied by the rhetoric of the new attack on cancer, as with the old:  Curing one cancer may extend a person's life, but it also increases his or her chances of a second cancer, since risks of cancer rise with age.

Cancers 'compete' with each other for our lives
The op-ed's main point is that the more earlier onset cancers we cure, the more late onset, less tractable tumors we'll see.  In that sense, cancers 'compete' with each other for our lives.  The first occurrence would get us unless the medical establishment stops it, thus opening the door for some subsequent Rogue Cell to generate a new tumor at some later time in the person's life.  It is entirely right and appropriate in every way to point this out, but the issues are subtle (though not at all secret).

First, the risk of some cancers slows with age.  Under normal environmental conditions, cancers increase in frequency with age because they are generally due to the accumulation of multiple mutations of various sorts, so that the more cell-years of exposure the more mutations that will arise.  At some point, one of our billions of cells acquires a set of mutational changes that lead it to stop obeying the rules of restraint in form and cell-division that are appropriate for the normal function of its particular tissue. A tumor is a combination of exposure to mutagens and mutations that occur simply by DNA replication errors--totally chance events--when cells divide.  As the tumor grows it acquires further mutations that lead it to spread or resist chemotherapy etc.

This is important but the reasons are subtle.  The attack on cells by lifestyle-related mutagens like radiation or chemicals in the environment becomes reduced in intensity as people age and simplify their lives, slowing down a lot of exposures to these risk factors. However, cell division rates, the times when mutations arise, themselves slow down, so the rate of accumulation of new mutations, whether they be by chance or by exposures, slows.  This decrease in the increase of risk with age at least tempers the caution that curing cancers in adults will leave them alive for many years and hence at risk for at least some many more cancers (though surely it will make them vulnerable to some!)


Apollo 11, first rocket to land humans on the moon; Wikipedia

Competing causes: more to the story, but nothing at all new
There's an important issue not mentioned in the article, but that is much more important in an indirect way.  This is an issue the authors of the op-ed didn't think about or for some reason didn't mention or perhaps because they are specialists they just weren't aware of.  But it's not at all secret, and indeed is something we ourselves studied for many years, and we've blogged about here before: anything that reduces early onset diseases increases the number of late onset diseases.  So, curing cancer early on (which is what the op-ed was about) increases risk for every later-onset disease, not just cancer.  In the same way as we've noted before, reducing heart disease or auto accident rates or snake bite deaths will increase dementia, heart disease, diabetes, and cancer--all other later-onset diseases--simply because more people will live to be at risk.  This is the Catch-22 of biomedical intervention.

In this sense all the marketing rhetoric about 'precision' genomic medicine is playing a game with the public, and the game is for money--research money among other things.  There's no cure for mortality or the reality of aging.  Whether due to genetic variants or lifestyle, we are at increasing risk for the panoply of diseases as we age, simply because exposure durations increase.  And every victory of medicine at earlier ages is a defeat for late-age experience.  Even were we to suppose that massive CRISPRization could cure every disease as it arose, and people's functions didn't diminish with age, the world would be so massively overpopulated as to make ghastly science fiction movies seem like Bugs Bunny cartoons.

But the conundrum is that because of the obvious and understandable fact that nobody wants major early onset diseases, it seems wholly reasonable to attack them with all the research and therapeutic vigor at our disposal. The earlier and more severe, the greater the gain in satisfactory life-years that will be made.  But the huge investment that NIH and their universities clients make in genomics and you-name-it related to late-age diseases is almost sure to backfire in these ways.  Cancer is but one example.

People should be aware of these things.  The statistical aspects of competing causes have long been part of demographic and public health theory.  Even early in the computer era many leading demographers were working on the quantitative implications of competing causes of death and disease, and similar points were very clear at the time.  The relevance to cancer, as outlined above, was also obvious.  I know this first-hand, because I was involved in this myself early in my career.  It was an important part of theorizing, superficial as well as thoughtful, about the nature of aging and species-specific lifespan, and much else.  The hard realities of competing causes have been part of the actuarial field since, well, more or less since the actuarial field began.  It is a sober lesson that apparently nobody wants to hear.  So it should not be written about as if it were a surprise, or a new discovery or realization.  Instead, the question--and it is in every way a fair question--should be why we cannot digest this lesson.  Is it because of our normal human frailty wishful thinking about death and disease, or because it is not convenient for the biomedical industries to recognize this sober reality front and center?

It's hard to accept mortality and that life is finite.  Some people want to live as long as possible, no matter the state of their health, and will reach for any life-raft at any age when we're ill.  But a growing number are signing Do Not Resuscitate documents, and the hospice movement, to aid those with terminal conditions who want to die in peace rather than wired to a hospital bed, continues to grow.  None of us wants a society like that in Anthony Trollope's 1881 dystopic novel The Fixed Period, where at age 67 everyone is given a nice comfortable exit--at least that was the policy until it hit too close to home for those who legislated it.  But we don't want uncomforable, slow deaths, either.

The problem of competing causes is a serious but subtle one, but health policy should reflect the realities of life, and of death.  I wouldn't bet on it, however, because there is nothing to suggest that humans as a collective electorate are ready or able to face up to the facts, when golden promises are being made by legislators, bureaucrats, pharmas, and so on.  But, science and scientists should be devoted to truth, even when truth isn't convenient to their interests or for the public to hear.

Bir Bakış: Emine Bektaşi





⭐ 24 Kasım doğumlu bir öğretmen ama çalışmıyor. Yaşını yazmıyor çünkü her yıl değişiyormuş. 

⭐ Bir bölüm okumuş ama üniversitelere doyamamış. (Kocatepe, Uludağ, Kocaeli) Bu yüzden yollara aşina. 

⭐ Zamanında resim ve müzikle ilgilenmiş. Çizimleri, kemanı, neyi, erbaneleri var. Farsça öğrenimini tamamlamak üzere. Hintçe'ye göz kırpıyor. Öğrenip ne yapacak kendi de bilmiyor. 

⭐ Hayvanları pek seviyor. Okul yıllarında kuş, balık, su kaplumbağası, tavşan, ördek beslemiş. Şimdi burnunuzdan öper bir siyam kedisi var. 

⭐ Toprağı, rüzgarı, serin havayı seviyor çünkü Erzurumli. 

⭐ Lezzetli yemekler, kahve, kitap okumak, müzik dinlemek, güzel bir yüzü seyretmek ona haz veriyor. 

⭐ Venedik maskelerini seviyor. Bir gün giderse en şaşaalısından alacak. 

⭐ Türkiye ve Amerika'yı geziyor. Türkiye haritasını tamamlamak üzere. Amerika'da ise pek çok şehir gezdi. Kadim kültüre sahip doğu ülkelerini görmeyi de çok istiyor. 

⭐ Bize Hollywood değil, Bollywood lazım diyor. Doğulu ya, doğu seviyor. 

⭐ Konuşkan, eğlenceli, kapısı her daim dostlarla muhabbete açık. Zaafları da pek fazla. Aahh ahh... Hayatı, bunları aşma ve kâmil insanlığa ulaşma çabası olarak görüyor. 

⭐  Eleştiriye kırılmıyor çünkü en önce kendi kendini eleştiriyor, millete bir şey kalmıyor. 

⭐  Her insan gibi onun da içinde bir âlem gizli... Ve her insan gibi onu da anlatmaya kelimeler yetmiyor... 







May Days

A huge thank you to everyone who bought from me at the recent Decorative Living Fair up in Kent; it was a most enjoyable fair! Perhaps I shall meet some of you again if you come down to Cornwall for your summer holidays.....

 It's time I took you on a tour of the shop again.....
 Spring flowers and sunshine!



 New porcelain vessels by Rebecca Harvey, and recycled glass bead bracelets,




 new Liberty fabrics and old fabric bundles,

 and one of Wendy's handmade dolls. the hair is pure Wensleydale sheep's wool - just gorgeous!
Happy Bank Holiday weekend everyone!

The Sea Garden will be open daily 1-5pm
26th May - 5th June

SEN UMUT ETMEYE DEVAM ET

İlk defa  2009 yılında tamamen tesadüfen (Bebek girişinin önünden geçiyorduk ) fark ettiğimiz kapısından  içeriği dalmak suretiyle gördüğüm bir okuldu Boğaziçi üniversitesi.  Üniversiteye dair hayalleri olan liseli genç insanlardık. Ziyaretimiz çok ünlü birini görüp fotoğraf çektirme isteğine benzer bir istek yaratmıştı hepimizde. Birçok köşesinde fotoğraf çektirip hayaller kurduk.
 Sonra zaman geçti ve hepimiz başka başka okulların kapısından, kendi hayatımıza daldık paldır küldür.  Ben de Bilgi Üniversitesine başladım , bir çocukluk dolusu hayalle. 11 Mayıs günü gerçekleşen 13.Radyo Boğaziçi Müzik Ödülleri töreninin ardından düşünürken aklıma ilk gelen şey o ilk Boğaziçi deneyimim oldu.
 Aradan geçen 7 senede bir sürü şey değişmişti. Biz hala öğrenci olsak da ödül alan ‘’Joytürk Akustik’’ekibi  olarak davetliydik. Güler yüzlü şahane kadın ve erkek öğrenciler bizi kapıda karşıladılar ve bizler için -ödül alan davetliler için- hazırlanılmış kulis dedikleri alana yönlendirdiler.Yıllar sonra yeniden Boğaziçi Üniversitesinde ama bu sefer  yaptığı iş ödüllendirilmiş bir ekibin bir parçasıydım, akustik bir programın nasıl çekildiğini biliyordum ve belki 7 sene önce yolda karşılaştığımda heyecanlandırıp fotoğraf çektirmek isteyebileceğim tanınmış kişilerle aynı taraftaydım. İşimizi biz de iyi yapmıştık ve ödüllendirilecektik.
  Ödül töreni tam bize söylenildiği saatte başladı. Hiçbir aksaklık olmadan kimseyi sıkmadan tertemiz bir akışta devam etti. Okan Bayülgen konuşması ile ödül töreninin organizasyonunda çalışan öğrencileri tebrik etti. -Tam bu noktada bir kulis bilgisi vereyim hemen, başka ödül törenleri Radyo Boğaziçi gibi ‘’cool’’ geçmiyormuş, ben henüz diğerlerini görmedim ama Okan Bayülgenin yalancısıyım, ödüllendirmelerde çok adil olunduğunu da söyledi‘’ -  Birçok sanatçı ile birlikteydik ama Nükhet Duru ile aynı sahnede olmak da ayrıca heyecan vericiydi benim için. Düşünsenize Türkiye popüler müziğinin çok büyük bir kısmına ve birçok değişime tanıklık etmiş bir isim ile yeni medyanın geliştiği günümüzde internet müzik kanallarında yayınlanan videolar çeken biz öğrenciler  aynı sahnede ödül aldık. Umut vericiydi bence hepimiz için. Neden olmasın ki değil mi ?
  Öğrencilerle ortak yürütülen ve profesyonel bir iş olan ‘’Joytürk Akustik’’  sınavlarla ölçülemeyecek bir tecrübe hepimiz için. Her hafta profesyonel yaşama bir adım daha yaklaştıran ama  amatör heyecanımızın hep devam ettiği bir ders aynı zamanda.
Başta söylemiştim Bilgi’ye  koca bir  çocukluk dolusu hayalimle girdim diye, şimdi yetişkinlik dolusu hayalle mezun olmaya hazırlanıyorum.
 Organizasyonundan, katılımcılarına kadar son derece kaliteli bir ödül töreninin ardından o hayallerime bir yenisi eklendi.

  Bir gün çok severek okuduğum bölümümün düzenleyeceği Televizyon ödüllerinde görüşürüz belki de kim bilir :)

Another look at 'complexity'

A fascinating and clear description of one contemporary problem of sciences involved in 'complexity' can be found in an excellent discussion of how brains work, in yesterday's Aeon Magazine essay ("The Empty Brain," by Robert Epstein).  Or rather, of how brains don't work.  Despite the ubiquity of the metaphor, brains are not computers.  Newborn babies, Epstein says, are born with brains that can learn, respond to the environment and change as they grow.
But here is what we are not born with: information, data, rules, software, knowledge, lexicons, representations, algorithms, programs, models, memories, images, processors, subroutines, encoders, decoders, symbols, or buffers – design elements that allow digital computers to behave somewhat intelligently. Not only are we not born with such things, we also don’t develop them – ever.
We are absolutely unqualified to discuss or even comment on the details or the neurobiology discussed.  Indeed, even the author himself doesn't provide any sort of explanation of how brains actually work, using general hand-waving terms that are almost tautologically true, as when he says that experiences 'change' the brains.  This involves countless neural connections (it must, since what else is there in the brain that is relevant?), and would be entirely different in two different people.

In dismissing the computer metaphor as a fad based on current culture, which seems like a very apt critique, he substitutes vague reasons without giving a better explanation.  So, if we don't somehow 'store' an image of things in some 'place' in the brain, somehow we obviously do retain abilities to recall it.  If the data-processing imagery is misleading, what else could there be?

We have no idea!  But one important thing is that this essay reveals is that the problem of understanding multiple-component phenomena is a general one.  The issues with the brain seem essentially the same as the issues in genomics, that we write about all the time, in which causation of the 'same' trait in different people is not due to the same causal factors (and we are struggling to figure out what they are in the first place).

A human brain, but what is it?  Wikipedia

In some fields like physics, chemistry, and cosmology, each item of a given kind, like an electron or a field or photon or mass is identical and their interactions replicable (if current understanding is correct).  Complexities like the interactions or curves of motion among many galaxies each with many stars, planets, and interstellar material and energy, the computational and mathematical details are far too intricate and extensive for simple solutions.  So one has to break the pattern down into subsets and simulate them on a computer.  This seems to work well, however, and the reason is that the laws of behavior in physics apply equally to every object or component.

Biology is comprised of molecules and at their level of course the same must be true.  But at anything close to the level of our needs for understanding, replicability is often very weak, except in the general sense that each person is 'more or less' alike in its physiology, neural structures, and so on. But at the level of underlying causation, we know that we're generally each different, often in ways that are important.  This applies to normal development, health and even to behavior.  Evolution works by screening differences, because that's how new species and adaptations and so on arise.  So it is difference that is fundamental to us, and part of that is that each individual with the 'same' trait has it for different reasons.  They may be nearly the same or very different--we have no a priori way to know, no general theory that is of much use in predicting, and we should stop pouring resources into projects to nibble away at tiny details, a convenient distraction from the hard thinking that we should be doing (as well as addressing many clearly tractable problems in genetics and behavior, where causal factors are strong, and well-known).

What are the issues?
There are several issues here and it's important to ask how we might think about them.  Our current scientific legacy has us trying to identify fundamental causal units, and then to show how they 'add up' to produce the trait we are interested in.  Add up means they act independently and each may, in a given individual, have its own particular strength (for example, variants at multiple contributing genes, with each person carrying a unique set of variants, and the variants having some specifiable independent effect).  When one speaks of 'interactions' in this context, what is usually meant is that (usually) two factors combine beyond just adding up.  The classical example within a given gene is 'dominance', in which the effect of the Aa genotype is not just the sum of the A and the a effects.  Statistical methods allow for two-way interactions in roughly this way, by including terms like zAXB (some quantitative coefficient times the A and the B state in the individual), assuming that this is the same in every A-B instance (z is constant).

This is very generic (not based on any theory of how these factors interact), but for general inference that they do act in relevant ways, it seems fine.  Theories of causality invoke such patterns as paths of factor interaction, but they almost always assume various clearly relevant simplifications:  that interactions are only pair-wise, that there is no looping (the presence of A and B set up the effect, but A and B don't keep interacting in ways that might change that and there's no feedback from other factors), that the size of effects are fixed rather than being different in each individual context.

For discovery purposes this may be fine in many multivariate situations, and that's what the statistical package industry is about. But the assumptions may not be accurate and/or the number and complexity of interactions too great to be usefully inferred in practical data--too many interactions for achievable sample sizes, their parameters being affected by unmeasured variables, their individual effects too small to reach statistical 'significance' but in aggregate accounting for the bulk of effects, and so on.

These are not newly discovered issues, but often they can only be found by looking under the rug, where they've been conveniently swept because our statistical industry doesn't and cannot adequately deal with them.  This is not a fault of the statistics except in the sense that they are not modeling things accurately enough, and in really complex situations, which seem to be the rule rather than the exception, it is simply not an appropriate way to make inferences.

We need, or should seek, something different.  But what?
Finding better approaches is not easy, because we don't know what form they should take.  Can we just tweak what we have, or are we asking the wrong sorts of questions for the methods we know about?  Are our notions of causality somehow fundamentally inadequate?  We don't know the answers.  But what we now do have is a knowledge of the causal landscape that we face.  It tells us that enumerative approaches are what we know how to do, but what we also know are not an optimal way to achieve understanding.  The Aeon essay describes yet another such situation, so we know that we face the same sort of problem, which we call 'complexity' as a not very helpful catchword, in many areas.  Modern science has shown this to us.  Now we need to use appropriate science to figure it out.

Hint Filmi: Fan



 Öncelikle Shahrukh Khan hayranı olmadığımı belirteyim azizim. En azından üç büyük Khan krallığında Aamir Khan ve Salman Khan'dan sonra gelir bende. 

  İşte ne bileyim, bir Benim Adım Khan filmini öyle dolu dolu izledim,  bir de Fan'ı. Dur filmi anlatacağım, bir içimi dökeyim de. 

   Bu ademin en son Swades'ini izlemiştim, oflaya puflaya. Veer Zaara'yı sonlara doğru, Jab Tak Hai Jaan'ı yarıda, Om Shanti Om'u da  çeyrekte bırakmıştım. Devdas'a ne oldu hatırlamıyorum. (Enee Aishwarya Rai vardı onda, gitti gül gibi film). 

    Bende mi sorun var acep? Neyse olur öyle şeyler. Zamana bırakmıştım, iyi de etmişim. Bir Fan geldi, tekrar heyecanlara saldı beni. Çok beğendim, büyük bir zevkle izledim!


  Aryan, Hindistan'ın meşhur aktörü. Gaurav ise ona çok benzeyen, hayranı olan, hayır bu hafif kalır,  manyağı olan bir genç. (Bu arada Gaurav da Shahrukh'un kendisiymiş, her çekim öncesi 4 saatlik bir makyaj harikası). 

   Sanatçıların benzerleri yarışmasında ödül alıyor ve  ödülünü  Aryan'a sunmak, fotoğraf çektirmek, abi ben sana hayranım, bir imza be güzel abim demek için Delhi'ye yola çıkıyor.


   Aryan'la görüşebiliyor mu peki?  
Görüşmek ne kelime, adamın burnundan getiriyor, ünlü olduğuna pişman ediyor. 

 Aryan'ın "Benim hayatım, benim zamanım. Neden sana beş saniyesini vereyim ki?" cümlesiyle Gaurav'da film kopuyor. 
(Ne kadden zalım bir Aryan)
    Vay sen misin bunu diyen! Şimdiye kadar ben senin peşinden koştum. Bundan sonra sen benim peşimden koşacaksın! 
  Filmin bütün aksiyonu burda başlıyor. Sözünün eri Gaurav, Aryan'ın ününü dibinden sıyırıyor, hafakanlara gark ediyor.


  Heyecanı, koşturması bitmeyen bir film ama ben yer yer duygulandım, acıdım Gaurav'a. Özellikle son sahnelerde. Aryan'a ise hep kızdım. Bir özür dile, razı çocuk. Yok... Soykası batasıca hoşşik.

 Peki savaşa dönüşen bu oyunu kim kazanıyor? Aksiyonun bittiği dramatik nokta burası... İkisi de kaybediyor.



  Hulâsa-i kelam film özetle diyor ki, biz fanlar olmadan siz ünlüler bir hiçsiniz! 

Doğru söz vesselam... ❤










What do rising mortality rates tell us?

When I was a student at a school of public health in the late '70s, the focus was on chronic disease. This was when the health and disease establishment was full of the hubris of thinking they'd conquered infectious disease in the industrialized world, and that it was now heart disease, cancer and stroke that they had to figure out how to control.  Even genetics at the time was confined to a few 'Mendelian' (single gene) diseases, mainly rare and pediatric, and few even of these genes had been identified.

My field was Population Studies -- basically the demography of who gets sick and why, often with an emphasis on "SES" or socioeconomic status.  That is, the effect of education, income and occupation on health and disease.  My Master's thesis was on socioeconomic differentials in infant mortality, and my dissertation was a piece of a large study of the causes of death in the whole population of Laredo, Texas over 150 years, with a focus on cancers.  Death rates in the US, and the industrialized world in general were decreasing, even if ethnic and economic differentials in mortality persisted.

So, I was especially interested in the latest episode of the BBC Radio 4 program The Inquiry, "What's killing white American women?" Used to increasing life expectancy in all segments of the population for decades, when researchers noted that mortality rates were actually rising among lower educated, middle-aged American women, they paid close attention.

A study published in PNAS in the fall of 2015 by two economists was the first to note that mortality in this segment of the population, among men and women, was rising enough to affect morality rates among middle-aged white Americans in general.  Mortality among African American non-Hispanics and Hispanics continued to fall.  If death rates had remained at 1998 rates or continued to decline among white Americans who hadn't more than a high school education in this age group, half a million deaths would have been avoided, which is more, says the study, than died in the AIDS epidemic through the middle of 2015.

What's going on?  The authors write, "Concurrent declines in self-reported health, mental health, and ability to work, increased reports of pain, and deteriorating measures of liver function all point to increasing midlife distress."  But how does this lead to death?  The most significant causes of mortality are "drug and alcohol poisonings, suicide, and chronic liver diseases and cirrhosis."  Causes associated with pain and distress.


Source: The New York Times

The Inquiry radio program examines in more detail why this group of Americans, and women in particularly, are suffering disproportionately.  Women, they say, have been turning to riskier behaviors, drinking, drug addiction and smoking, at a higher rate than men.  And, half of the increase in mortality is due to drugs, including prescription drugs, opioids in particular.  Here they zero in on the history of opiod use during the last 10 years, a history that shows in stark relief that the effect of economic pressures on health and disease aren't due only to the income or occupation of the target or study population.

Opioids, prescribed as painkillers for the relief of moderate to severe pain, have been in clinical use since the early 1900's.  Until the late 1990's they were used only very briefly after major surgery or for patients with terminal illnesses, because the risk of addiction or overdose was considered too great for others.  In the 1990's, however, Purdue Pharma, the maker of the pain killer Oxycontin, began to lobby heavily for expanded use.  They convinced the powers-that-be that chronic pain was a widespread and serious enough problem that opioids should and could be safely used by far more patients than traditionally accepted.  (See this story for a description of how advertising and clever salesmanship pushed Oxycontin onto center stage.)

Purdue lobbying lead to pain being classified as a 'vital sign', which is why any time you go into your doctor's office now you're asked whether you're suffering any pain.  Hospital funding became partially dependent on screening for and reducing pain scores in their patients.

Ten to twelve million Americans now take opioids chronically for pain.  Between 1999 and 2014, 250,000 Americans died of opioid overdose.  According to The Inquiry, that's more than the number killed in motor vehicle accident or by guns.  And it goes a long way toward explaining rising mortality rates among working-class middle-aged Americans.  And note that the rising mortality rate has nothing to do with genes.  It's basically the unforeseen consequences of greed.

Opioids are money-makers themselves, of course (see this Forbes story about the family behind Purdue Pharma, headlined "The OxyContin Clan: The $14 Billion Newcomer to Forbes 2015 List of Richest U.S. Families;" the drug has earned Purdue $35 billion since 1995) but pharmaceutical companies also make money selling drugs to treat the side effects of opioids; nausea, vomiting, drowsiness, constipation, and more.  Purdue just lost its fight against allowing generic versions of Oxycontin on the market, which means both that cheaper versions of the drug will be available, and that other pharmaceutical companies will have a vested interest in expanding its use.  Indeed, Purdue just won approval for use of the drug in 11-17 year olds.

In a rather perverse way, race plays a role in this epidemic, too, in this case a (statistically) protective one even though it has its roots in racial stereotyping.  Many physicians are less willing to prescribe opioids for African American or Hispanic patients because they fear the patient will become addicted, or that he or she will sell the drugs on the street.

"Social epidemiology" is a fairly new branch of the field, and it's based on the idea that there are social determinants of health beyond the usual individual-level measures of income, education and occupation.  Beyond socioeconomic status, to determinants measurable on the population-level instead; location, availability of healthy foods, medical care, child care, jobs, pollution levels, levels of neighborhood violence, and much more.

Obviously the opioid story reminds us that profit motive is another factor that needs to be added to the causal mix.  Big Tobacco already taught us that profit can readily trump public health, and it's true of Big Pharma and opioids as well.  Having insinuated themselves into hospitals, clinics and doctors' offices, Big Pharma may have relieved a lot of pain, but at great cost to public health.

Darwin the Newtonian. Part V. A spectrum, not a dogma

Our previous installments on genetic drift (a form of chance) vs natural selection (a deterministic force-like phenomenon) and the degree to which evolution is due to each (part 1 here) lead to a few questions that we thought we'd address to end this series.

First, there is no sense in which we are suggesting that complex traits arise out of nowhere, by 'chance' alone.  There is no sense in which we are suggesting that screening for viability or utility does not occur as a regular part of evolution.  But we are asking what the nature of that screening is, and what a basically deterministic, Newtonian view of natural selection, that is we believe widely if often tacitly held, implies and how accurate it may be.

It's also important here to point out something that is obvious.  The dynamics of evolution from both trait and genome level comprise a spectrum of processes, not a single one that should be taken as dogma.  A spectrum means that there is a range of relative roles of what can be viewed as determinism and chance that the two are not as distinct as may seem, and that even identifying, much less proving what is going on in a given situation is often dicey.  Some instances of strong selection, like some of chance seem reasonably clear and those concepts are apt.  But much, perhaps most, of evolution is a more subtle mix of phenomena and that is what we are concerned with.

Secondly, we have discussed our view of natural selection before, in various ways.  In particular, we cite our series on what we called the 'mythology' of selection, a term we used to be provocative in the sense of hopefully stimulating readers to think about what many seem to take for granted.  Yes, we're repeating ourselves some, but think the issues are important and our ideas haven't been refuted in any serious way so we think they're worth repeating.

A friend and former collaborator took exception to our assumption that people still believe that what we see today is what was the case in the past.  He felt we were setting up a straw man. The answer is somewhat subjective, but we believe that if you read many, many descriptions of current function and their evolution, you'll see that they are often if not usually just equated de facto with being 'adaptations', and that means that doing what they do now came about because it was favored by the force of selection in the past.  We think it's not a straw man at all, but a description of what is being said by many people much of the time: very superficial, dogmatic assumptions both of determinative selection and that we can infer the functional reason.

Of course everyone acknowledges that earlier states had their own functions and today's came from earlier, and that functions change (bat wings used to be forelegs, e.g.), but the idea is that bat flight is here because the way bats fly was selected for.  One common metaphor going back to an article by Lewontin and Gould is that evolution works via 'spandrels', traits evolved for one purpose or incidentally part of some adaptation, that are then usable by evolution to serve some new function. Yes, evolution works through changing traits, but how often are they 'steps' in this sense or is the process more like a rather erratic escalator, if we need a metaphor?

There are ways for adaptive traits to arise that have nothing to do with Darwinian competition for limited resources, and are perfectly compatible with a materialist view.  Organismal selection occurs when organisms who 'like' a particular part of their environment, tend to hang out there.  They'll meet and mate with others who are there as well.  If the choice has to do with their traits--ability to function at high altitude, or whatever--then over time this trait will become more common in this niche compared to their peers elsewhere, and eventually mating barriers may arise, and a new species with what appears to be a selected adaptation. But no differential reproduction is required--no natural selection.  It's natural assortment instead.

All aspects of our structure and function depend on interaction among molecules.  If two molecules must interact for some function to occur, then mutant versions may not serve that purpose and the organism may perish. This would seem most important during embryonic development.  An individual with incompatible molecular interactions (due to genetic mutation) would simply not survive.  This leaves the population with those whose molecules do interact, but there is no competition involved--no natural selection.  It's natural screening instead.

Natural selection of the good ol' Darwinian kind can occur, leading to complex adaptations in just the way Darwin said 150+ years ago.  But if the trait is the result of very many genes, the individual variants that contribute may be invisible to selection, and hence come and go essentially by chance. This is what we have called phenogenetic drift.  Do you doubt that?  If so, then why is it that most complex traits that are mapped can take on similar values in individuals with very different genotypes?  This is, if anything, the main bottom line finding of countless very large and extensive mapping studies, in humans and even bacteria.  This is basically what Andreas Wagner's work, that we referred to earlier in the series, is about.   It rather obviously implies that which of equivalent variants proliferates is the result of chance.  There's nothing non-Darwinian about this.  It's just what you'd expect instead.

We'd expect this because the many factors with which any species must deal will challenge each of its biological systems. That means many screening factors (better we think than calling them selection 'pressures' as would usually be done).  Most of these are affected by multiple genes.  Genes vary within a population.  If any given factor's effects were too strong, it would threaten the species' existence.  At least, most must be relatively weak at any given time, even if persisting over very long time periods.  Multiple traits, multiple contributing genes in this situation means that relative to any one trait or gene, the screening must be rather weak.  That in turn means that chance affects which variant proliferates.  There's nothing non-Darwinian about this.  It's essentially why he stressed the glacial slowness of evolution.

There is, however, the obvious fact that known functional parts of DNA are far less variable than regions with no known function.  This can be, and usually is assumed to be, the expected evidence of Darwinian natural selection.  But factors like organismal dispersion or functional (embryonic) adequacy can account for at least some of this.  Longer-standing genes and genetic systems would be expected to be more entrenched because they can acquire fewer differences before they won't work with other elements in the organism.  This is at least compatible with the view we've expressed, and there could be some ways of testing the explanation.

This view means we need not worry about whether a variant is 'truly' neutral in the face of environmental screening.  We could even agree that there's no testable sense in which a variant evolves by 'pure' chance. Even very tiny differences in real function can evolve in a way that is statistically 'neutral'.  Again, this can be the case even if the trait to which such variants contribute is subject to clear natural or other forms of selection.

This view is also wholly compatible with the findings of GWAS, the evidence that every trait is affected by genetic variation to some extent, the fact that organisms are adapted to their environment in many ways and the fact that prediction based on genotyping is often a problematic false promise.  And because this is a spectrum, randomly generated by mutation, some variants and or traits they affect will be very harmful or helpful--and will look like strong, force-like natural selection.  These variants and traits led to Mendel, and led to the default if often tacit assumption that natural selection is the force that explains everything in life.

Further, it is important for all the same sorts of reasons that the shape of the spectrum--the relative amount of a given level of complexity--is not based on any distribution we know of and hence is not predictable, generally because it is the result of a long history of random and local context and contingencies, of various unknown strength and frequency (about the past, we can estimate a distribution but that doesn't mean we understand any real underlying probabilistic process that caused what we see).  This is interesting, because many aspects of genetic variation (and of the tree of life) can be fitted to a reasonable extent to various probability distributions (see Gene Koonin's paper or his book The Logic of Chance).  But these really aren't causal parametric 'laws' in the usual sense, but descriptions after the fact without rigorous causal characteristics.  Generally, prediction of the future will be weak and problematic.

In the view of life we've presented, evolution will have characteristics that are weak or unpredictable directional tendencies, and the same for genetic specificities (and hence predictive power). It is the trait that is in a sense predictable, not the effects of individual genes.

We think this view of evolution is compatible with the observed facts but not with many of the simplified ideas that are driving life sciences at present.

Our viewpoint is that the swarm of factors environmental and genomic means that chance is a major component even of functional adaptations, in the biodesic paths of life.

Çifte Şelale ve Ana Ocağı



  Hani demiştim bir vakit, bazen günlerce dışarı çıkmıyorum, bazen de yollar mesken oluyor diye. 
(Misal şurda  bahsi geçmişmiş Gezegenin Yol Halleri)
 Bir süredir evde temizlik terapisi yapıyordum. Bu terapinin özelliği, klasik temizlikle beraber kapı, cam, duvar silerek nirvanaya ulaşmayı amaçlıyorsunuz. (Olmayor, olmayor! Ne kadar şirin göstermeye çalışsam da hayır, manyaklık bu.)
  Çok şükür evcek yunduk, paklandık. Nirvanaya ulaşamasam da Yalova'da Çifte Şelale varmış, orayı gözüme kestirdim. Düştük yola...


  Kıvrımlı ve bol ağaçlı yollarda, güzel manzaralar eşliğinde önce arabalı bir yolculuk. 




   Sonra yokuşlardan yürüme devam ettik. Hayır yürüme değil tırmanma. Malum sporcu bir millet değiliz. O yüzden yol boyu nefes nefese kalan insanlar görmek mümkün. (Biri de ben.)  


  Nemli toprağın ve yosunlu kayaların kokusu... Anlatılmaz bir şey. (Beni ancak demir eksikliği olanlar anlar.) 
Ba hele geldi mi gohusu?


  Çifte Şelale, önce kısa ama gürül gürül olanı karşılıyor sizi. Sonra daha yüksekten dökülen, göleti olan. Suyu çok soğuk ve deli. Başı kalabalık. 


  Gündelik telaşelerin unutulduğu, tertemiz, yalıtılmış bir bölge. Yorulduk ama değdi. 




  Malum pazar anneler günü idi. (Her gün onların gerçi. Bütün güzel günler.) Bir ana ocağı sergüzeşti yapalım, mübareklerden hayır dua alalım da sırtımız yere gelmesin mülahazasıyla ver elini Bursa.


    Bahçe özlemiyle olmamış şeftali yemeler, duta dalmalar, çilekleri yarı pembiş toplamalar, yavru ördeklerin peşinden koşmalar, ne kadar çiçek böcük varsa resmini çekmeler... Ve en güzeli sevgi dolu, sıcacık ana baba sohbetleri... (Allah başımızdan eksik etmesin.)


































⭐ 

 Velhasıl masal gibi birkaç gün geçirdik, manevi bir tecdid ile saadete gark olduk, hafsalamız tazelendi...


E o zaman aşk ile,
elhamdülillahi alâ külli hâl... ❤


⭐ 














Rare Disease Day and the promises of personalized medicine

O ur daughter Ellen wrote the post that I republish below 3 years ago, and we've reposted it in commemoration of Rare Disease Day, Febru...