Category Archives: Genetics

A Surprising Disappointment Derails NewLink Genetics — What’s … – Motley Fool

Roche Holdings(NASDAQOTH:RHHBY)surprisinglycut ties with NewLink Genetics (NASDAQ:NLNK)on GDC-0919 last week, and that decision puts NewLink Genetics further back behindIncyte Corporationin theraceto develop a new class of cancer-fighting drugs called IDO inhibitors.

Roche Holdings' decision is particularly disappointing because industry watchers had thought GDC-0919 would be NewLink Genetics most competitive IDO-ihibitor. Now that GDC-0919's future is in flux,investors are right to wonder what's up next for NewLink Genetics.

Indoleamine 2,3-dioxygenase (IDO) is a protein that has immunosuppressive effects, and because cancer cells can hijack it to evade detection by the immune system, drug developers think inhibiting its activity could help other cancer medications work better.

IMAGE SOURCE: GETTY IMAGES.

At the forefront of this research are NewLink Genetics and Incyte. Until now, NewLink Genetics has been developing indoximod and GDC-0919, while Incyte Corporation has been developing epacadostat.

In April,NewLink Genetics reported that the objective response rate in a 60-person phase 2 study evaluating indoximod alongside Merck & Co.'s (NYSE:MRK) Keytruda in advanced melanoma was 52%. If you include patients with stable disease, the rate increases to 72%.

Similarly, Incyte Corporation reported data from its own melanoma trial earlier this year showing patient's objective response rate to epacadostat plus Keytruda was 58%. A total of 74% had a complete response, partial response, or stable disease.

In both cases, the findings suggest each of these drugs could win FDA approval someday. Especially since theFDA approved Keytruda for use as a monotherapy in advanced melanoma patients after it delivered a 33% objective response rate.

However, it's Incyte's drug that's closer to FDA review, and that first-mover advantage, plus the similarity in results from these trials,could make it difficult for indoximod to win away market share.

Because of Incyte's lead over indoximod, industry watchers' had hoped trials evaluating GDC-0919 wouldshow it works better than epacadostat in cancers other than melanoma.Unfortunately, that doesn't appear to be the case. Last week, Roche presented data onGDC-0919 at the American Society of Clinical Oncology (ASCO) conference that was lackluster, and it appears those results were a big reason why Roche has decided to walk away from developing it any further.

Specifically, adding GDC-0919 to Roche's Tecentriq (a drug that works similarly to Keytruda) resulted in anobjective response rate of just 9% across a variety of cancers. For comparison, adding epacadostat to Keytruda resulted in objective response rates of between 30% to 35% in a variety of cancers, including non-small cell lung cancer.

NewLink Genetics hasn't licensed indoximod to anyone yet, and now that it's getting the rights to GDC-0919 back, it's got a decision to make. Developing both of these drugs concurrently would be costly, and the company probably can't afford it.

As of March 31, it has $118 million in cash on its books, but it's burning through that cash at a rate of $12 million per quarter. Cash burn is likely to increase from here given plans to start a registration ready trial of indoximod in melanoma this year. Currently, management expects it will finish 2017 with $75 million in cash, and that suggests to me that a cash crunch could be coming in 2018.

Ideally, NewLink Genetics probably wants to convince another company to share in development costs by out-licensing GDC-0919 again. However, that seems less likely given Roche's data at ASCO.

It's also possible thatNewLink Genetics would consider selling itself lock, stock, and barrel. However, finding a buyer could be unlikely too. The most logical suitors would be companies marketing PD-1 checkpoint inhibitors that they could pair up with NewLink Genetics drugs, but the two leaders in this class areBristol-Myers Squibb and Merck & Co., and they're already working with Incyte.

If licensing and M&A is off the table, then NewLink Genetics next option could be tapping equity investors for more money. However,that's not going to be easy given its crumbling share price.

NLNK data by YCharts

In the end, NewLink Genetics might have to focus on indoximod trials and hold-off on developing GDC-0919 -- at least until new data emerges that reignites its share price.

Potentially, trials evaluatingindoximod plus Abraxane and gemcitabine in pancreatic cancer could make that happen. Data from aphase 1/2 trial evaluating indoximod alongside these treatments are expected soon. Fortunately, the bar for success is set pretty low. The ojective response rate for Abraxane plus gemcitabine alone is only 23% in trials, and an interim look at adding indoximod to these drugs produced an objective response rate of 45%.

Having said that, investors might want to keep their optimism in check. Pancreatic cancer is notoriously hard to treat, and there's no guarantee that interim trial results will be confirmed.

Overall,the risks facing NewLink Genetics are big, and the stakes for its survival are higher now than they were before Roche's decision. Therefore, investors should approach this company with a big dose of caution, at least until we know for sure if indoximod's pancreatic cancer trial is a success.

Todd Campbell has no position in any stocks mentioned. His clients may have positions in the companies mentioned. The Motley Fool has no position in any of the stocks mentioned. The Motley Fool has a disclosure policy.

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A Surprising Disappointment Derails NewLink Genetics -- What's ... - Motley Fool

Seattle Genetics suspends trial of leukemia treatment after data showed higher rate of death – MarketWatch

Seattle Genetics Inc. SGEN, +0.61% said Monday that it is discontinuing the Phase 3 clinical trial of its acute myeloid leukemia treatment, SGN-CD33A, after data indicated a higher rate of deaths, including fatal infections. The company said it will suspend patient enrollment and treatment, and will closely review the data and consult with the Food and Drug Administration to determine future plans. "This is a disappointing and unexpected result for the CASCADE trial. Patient safety is our highest priority, and we will closely review the data and evaluate next steps," said Chief Executive Clay Siegall. The stock, which is still inactive in premarket trade, has rallied 22% year to date through Friday, while the iShares Nasdaq Biotechnology ETF IBB, +2.10% has climbed 10% and the S&P 500 SPX, -0.52% has gained 8.7%.

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Seattle Genetics suspends trial of leukemia treatment after data showed higher rate of death - MarketWatch

Is coffee your friend or foe? Genetics makes a difference – Seattle Times

More than half of American adults drink coffee daily. But how does that caffeine affect us, biologically? It depends on genetics.

Is morning just not morning without a steaming mug of coffee in your hand? Youre not alone, as a little more than half of American adults drink coffee daily, for the taste, the aroma, the pick-me-up or all of the above. I suspect that numbers even higher in Seattle. As an added bonus, moderate coffee consumption is linked to a number of health benefits, including reduced risk of developing type 2 diabetes. But for some people, the caffeine in even moderate amounts of coffee could have a downside.

The safe caffeine limit for healthy nonpregnant adults is 400 milligrams (mg) per day, the amount in four average 8-ounce cups of brewed coffee. The average caffeine intake in this country is about 180 mg per day, but those averages are just that average. Some people get less caffeine than that, and others get more, sometimes much more, because not all coffee is average.

For example, a 12-ounce medium roast at Starbucks has about 235 mg. Get a refill and youve exceeded your limit. Then theres the growing trend of super-high-octane coffee, with brands like Black Insomnia and Death Wish competing for the title of worlds strongest coffee and clocking in at about 700 mg of caffeine for a 12-ounce cup. While thats not optimal for anyone, for some people it might be risky the collision of genetic differences in how we metabolize caffeine with the latest generation of high-caffeine beverages may have unintended consequences.

How caffeine makes you feel is partly due to your tolerance level, but its largely due to genetics. Of greatest concern is one gene CYP1A2 that alters how caffeine affects us, but in ways we dont actually feel. Depending on which version of the CYP1A2 gene you inherited, you metabolize (break down) caffeine slow or fast. Lets look at why that matters.

For a long time, drinking more than a few cups of coffee was linked to an increased risk of heart attack. But when researchers looked closer several years ago, they found that risk was only increased among people who were slow caffeine metabolizers. For slow metabolizers, one cup per day wasnt a problem, but after that, the risk started to rise. Slow metabolizers under the age of 50 who drink four cups per day or more had quadruple the risk of having a heart attack. By contrast, fast metabolizers especially those under age 59 actually saw reduced risk of heart attack with a moderate one to three cups per day.

Four cups of coffee for one person might be the biological equivalent of one cup for someone else, just depending on how much of that caffeine sticks around in their system, said Ahmed El-Sohemy, PhD, one of the studys authors, at the 2017 Nutrition & Health conference in Phoenix in May. He said more recent studies have found similar effects for risk of pre-diabetes, hypertension and kidney disease in slow metabolizers.

El-Sohemy said that slow metabolizers dont self-regulate caffeine because they dont feel the difference. So what does this mean for you? You could get tested for the CYP1A2 gene, but insurance might not cover it. Or, you could play it safe and enjoy a moderately sized cup or two and leave it at that. You could go decaf or half-caf decaffeinated coffee contains the same health-promoting compounds, including phytonutrients, found in regular coffee. Finally, if you find you rely on coffee to get through the day, maybe its time to cultivate a more beneficial source of energy sleep!

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Is coffee your friend or foe? Genetics makes a difference - Seattle Times

Seattle Genetics ends clinical trial of leukemia drug after ‘a higher rate of deaths’ – The Seattle Times

Seattle Genetics said it is discontinuing a Phase 3 clinical trial after data showed a higher rate of deaths, including fatal infections in acute myeloid leukemia patients receiving its drug than in the studys other patients.

By Seattle Times business staff

Seattle Genetics said it is discontinuing a Phase 3 clinical trial after data showed a higher rate of deaths, including fatal infections in acute myeloid leukemia (AML) patients receiving its drug than in the studys other patients.

As a result of data it received June 16, the company said Monday, Seattle Genetics is suspending patient enrollment and treatment in all of its clinical trials on the drug, called vadastuximab talirine or SGN-CD33A. The drug was also being used in a Phase 1/2 clinical trial in myelodysplastic syndrome (MDS).

Both studies were testing the drug as a so-called front-line treatment, meaning it would be an early therapy rather than a second or third choice for patients who dont respond to initial treatment. It is pursuing similar studies in various cancers for its leading approved drug, Adcetris.

The Bothell-based company did not disclose the number of patient deaths or other details in its statement early Monday. It said it will review the data and consult with the federal Food and Drug Administration (FDA) to determine future plans for the drugs development program.

Three early-stage studies SGN-CD33A in AML patients receiving stem-cell transplants were placed on a clinical hold by the FDA in December, after what the company reported were four fatal events, but the hold was lifted in March. The study discontinued Monday was already in progress at that time.

Seattle Genetics said in December that more than 300 patients had been treated with SGN-CD33A in various clinical trials.

The Phase 3 trial discontinued Monday was a double-blind study of SGN-CD33A in combination with either of two hypomethylating agents, compared with those agents alone, in older patients with newly diagnosed AML.

Seattle Genetics has spent more than $100 million over the past five years on developing the drug, making it the companys second most expensive development program after Adcetris, it said in a regulatory filing last month.

This is a disappointing and unexpected result, said Clay Siegall, president and chief executive officer at Seattle Genetics. Patient safety is our highest priority, and we will closely review the data and evaluate next steps. AML is a devastating disease with a poor prognosis in most patients, and there is a great need for therapeutics against this disease.

Shares of Seattle Genetics opened the day down 8 percent but recovered somewhat, closing at $61.88, down $2.64 or 4.1 percent.

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Seattle Genetics ends clinical trial of leukemia drug after 'a higher rate of deaths' - The Seattle Times

Apple, PerkinElmer rise; EQT, Seattle Genetics fall – Seattle Times

NEW YORK (AP) Stocks that moved substantially or traded heavily Monday:

PerkinElmer Inc., up $4.16 to $67.73

The company, which sells testing equipment and scientific instruments, agreed to buy Euroimmun Medical Laboratory Diagnostics of Germany.

EQT Corp., down $5.26 to $53.51

The energy company agreed to buy Rice Energy for $6.7 billion in cash and stock.

Novodaq Technologies Inc., up $5.70 to $11.70

The maker of surgical technology is being acquired by Stryker Corp.

Valeant Pharmaceuticals International Inc., up 81 cents to $13.47

The company said hedge-fund manager John Paulson, its largest shareholder, will join the companys board.

U.S. Steel Corp., up 64 cents to $20.80

The Wall Street Journal reported that President Donald Trump may announce plans to curb steel imports.

Apple Inc., up $4.07 to $146.34

Technology companies posted some of the biggest gains in the market.

Hain Celestial Group Inc., down 67 cents to $33.24

The Wall Street Journal reported that the organic food company, which hasnt released financial results for more than a year, risks being delisted from the Nasdaq.

Seattle Genetics Inc., down $2.64 to $61.88

The biotechnology company discontinued a clinical trial of vadastuximab talirine in older acute myeloid leukemia patients.

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Apple, PerkinElmer rise; EQT, Seattle Genetics fall - Seattle Times

Genetics Might Be Settling The Aryan Migration Debate, But Not How Left-Liberals Believe – Swarajya

Writing in The Hindu, Tony Joseph has claimed that genetics has very sure-footedly resolved the debate about whether there was a migration of Indo-European people (Aryans) into the subcontinent around 2000-1500 BCE apparently, the unambiguous answer is yes. To anyone with a nodding acquaintance with the literature in the area, such an assertion is unfounded. Given the sheer importance of this topic to Indian history, it is necessary to challenge Josephs one-sided presentation of facts. There also seems to be much that is questionable in his very approach, and this deserves scrutiny.

Conclusions decided upon in advance?

Ironically, after saying that the dominant narrative so far that genetics had disproved Aryan immigration had not been nuanced, he abandons nuance himself.

Noting the clear slant in his article, and his quoting of Razib Khan, who was sacked as a columnist by the New York Times apparently for racist views, I got in touch with Dr Gyaneshwer Chaubey, senior scientist at the Estonian Biocentre, Tartu, and a widely-published scholar in the area. Indeed, Chaubey is a co-author with Peter Underhill (whom Joseph quotes) of the 2015 study on the R1a haplogroup that Joseph cites in his article.

To my surprise, it turned out that that Joseph had contacted Chaubey and sought his opinion for his article. Chaubey further told me he was shocked by the drift of the article that appeared eventually, and was extremely disappointed at the spin Joseph had placed on his work, and that his opinions seemed to have been selectively omitted by Joseph a fact he let Joseph know immediately after the article was published, but to no avail.

Having known Chaubeys views for some time now especially that the origin of the R1a is far from settled I was not surprised to hear this. This in itself gives the lie to Josephs claims of the unambiguous conclusions of genetics about the hypothetical Aryan immigration.

Mitochondrial DNA vs Y-chromosomal DNA

Joseph claims that we only had mitochondrial (mt-) DNA (which is inherited from the mother) analysis till recently, which failed to capture the fact that it may have been mostly Aryan males who migrated first to the subcontinent and intermarried with the native women. This, apparently, has been conclusively established by a recent avalanche of Y-chromosomal DNA (which is inherited exclusively by sons from their fathers) data, which shows a Bronze Age gene flow into the subcontinent. This remark seems to suggest an embarrassing lack of familiarity with the literature.

Also, does Joseph seriously imagine geneticists would not have envisaged the possibility of males spearheading a migration all along? The first suggestion that Y-chromosomal DNA analysis may be making a case for Indo-European immigration, and the proposal that the R1a haplogroup (M17) may be a marker for this migration, was made as early as 2001.

This was subsequently contradicted in 2006 in a seminal Y-chromosomal DNA study by a group that included Richard Villems, Toomas Kivisild and Mait Metspalu, also of the Estonian Biocentre, and among the leading authorities in this area (Kivisild has since moved to Cambridge, but Villems and Metspalu are Chaubeys current colleagues at Tartu). Villems and Kivisild were, in fact, co-authors in the 2001 paper I just mentioned, but revised their view about a migration after a fresh analysis of more extensive data.

This paper, concluded, It is not necessary, based on the current evidence, to look beyond South Asia for the origins of the paternal heritage of the majority of Indians at the time of the onset of settled agriculture. The perennial concept of people, language, and agriculture arriving to India together through the northwest corridor does not hold up to close scrutiny. Recent claims for a linkage of haplogroups J2, L, R1a, and R2 with a contemporaneous origin for the majority of the Indian castes paternal lineages from outside the subcontinent are rejected...

The dominant narrative that Joseph talks about actually stems from this study, and Im not sure he is qualified to dismiss it as a bit of a stretch. This study, which has never really been contradicted, is, in fact, published in a much more respected journal than BMC Evolutionary Biology from where Joseph cites Martin Richards paper. This is significant, as good studies in this area have generally found a place in highly-ranked journals, even if they have arrived at diverging conclusions.

Indeed, this itself would suggest there are very eminent geneticists who do not regard it as settled that the R1a may have entered the subcontinent from outside. Chaubey himself is one such, and is not very pleased that Joseph has not accurately presented the divergent views of scholars on the question, choosing, instead to present it as done and dusted.

The R1a haplogroup

There are some inherent issues in regarding the R1a as a marker for any hypothetical Indo-European migration.

Firstly, Iranian populations, who are also speakers of the Indo-Iranian family of languages like most North Indians, have very little R1a. Also, tribal groups like the Chenchus of Andhra Pradesh and the Saharias of Madhya Pradesh show anomalously high proportions of R1a. The Chenchus speak a Dravidian language, and the Saharias an Austro-Asiatic one (though they have recently adopted Indo-European languages).

They are hunter-gatherer peoples who remained stunningly isolated without admixing much with other population groups, and consequently, their lifestyles have remained startlingly unchanged for millennia, as they would have been before the start of settled agriculture.

The best that studies which argued that the R1a could be used as a marker for the hypothetical Indo-European migration could do was to simply ignore these groups as aberrations. But is that very convincing? Note that it is possible no, almost certainly the case there were many tribal communities with high proportions of R1a that, unlike the Chenchus and Saharias, were assimilated into the caste matrix over the millennia. So how correct is it to link the R1a with an Indo-European migration?

Significantly, Richards et al acknowledge Chaubeys critical advice with their manuscript. That seems like a euphemism for saying that Chaubey (and, by extension, the Tartu school) had reservations about their conclusions, which is probably why he is not a co-author. So what should one make of Josephs claim that geneticists have converged on an answer?

If Underhill expressly stated to Joseph that he has now reversed his published position that there has been no significant genetic influx to Asia from Europe, indeed specifically that he is now convinced the R1a entered the subcontinent from outside, Joseph bafflingly does not reproduce this statement in his article.

The statement Joseph actually quotes merely points out that we have better data now, but that is not the same thing. Joseph also cites his 2015 paper, in which Chaubey is a co-author, but this paper actually underscores the limits of current technology, and says their data is too preliminary to jump to conclusions about migrations and culture shifts.

The genetic data at present resolution shows that the R1a branch present in India is a cousin clade of branches present in Europe, Central Asia, Middle East and the Caucasus; it had a common ancestry with these regions which is more than 6000 years old, but to argue that the Indian R1a branch has resulted from a migration from Central Asia, it should be derived from the Central Asian branch, which is not the case, as Chaubey pointed out.

In other words, contrary to what Joseph claims, as the Y-chromosomal DNA data stands today, there is no support for a recent migration into the subcontinent.

Ancestral North Indians (ANI) and Ancestral South Indians (ASI)

Joseph continues to tilt at windmills when talking about the ANI / ASI construct of David Reich et al., who used analysis autosomal DNA, which is different from mt- and Y-chromosomal DNA.

Joseph writes, ...this theoretical structure was stretched beyond reason and was used to argue that these two groups came to India tens of thousands of years ago, long before the migration of Indo-European language speakers that is supposed to have happened only about 4,000 to 3,500 years ago.

One doesnt know what to make of this. It was geneticists including Lalji Singh and K Thangaraj who were Reichs co-authors in the paper which proposed the ANI/ASI construct who argued that the ANI and ASI are considerably more than 12,500 years old, and not the result of any recent migration.

He then goes on to quote David Reich arguing in favour of a migration from the Steppe around 2500 BCE. Once again, Joseph presents this view as the last word on the subject, although not all geneticists agree.

For instance, Partha Majumdar and co-workers have very recently come up with quite different conclusions in the journal, Human Genetics: In contrast to the more ancient ancestry in the South than in the North that has been claimed, we detected very similar coalescence times within Northern and Southern non-tribal Indian populations. A closest neighbour analysis in the phylogeny showed that Indian populations have an affinity towards Southern European populations and that the time of divergence from these populations substantially predated the Indo-European migration into India, probably reflecting ancient shared ancestry rather than the Indo-European migration, which had little effect on Indian male lineages (emphasis mine).

The Evidence From Archaeology

Since Joseph believed he was shocking those who believed genetic analysis had disproved Aryan immigration theories, I shall return the favour.

Hypotheses of migrations of Bronze Age populations into the subcontinent fall afoul of archaeological evidence. Paradoxically, as I have described earlier, bronze itself goes missing from the archaeological record for several centuries that are supposed to correspond to the settling of the Bronze Age Indo-Europeans into the subcontinent. As one of the foremost authorities in the archaeology of the Indus Valley Civilisation, Professor Jonathan Mark Kenoyer of the University of Wisconsin points out, this actually reflects a prolonged lack of contact of the subcontinent with the regions the Aryans are supposed to have entered from.

Also, geological evidence shows that the Ghaggar-Hakra river, along whose channels numerous Harappan sites have been discovered, was the River Saraswati described in the Vedas and other ancient literature; indeed, the team of geologists led by Peter D Clift which carried out the geological studies asserted that the descriptions of the Saraswati in those texts was remarkably accurate, as I wrote in an earlier article.

Such findings negate the Aryan immigration model, establish the overlap (if not identity) of the Indus Valley and Vedic cultures, and push back the dates for the composition of the Vedic and other literature considerably.

Agriculture In Subcontinent Indigenous, Autochthonous

There is clear evidence of continuous inhabitation of the Gangetic plain from the Pleistocene. It is also abundantly clear that agriculture was developed indigenously, autochthonously, based on exploiting local resources, at multiple centres on the subcontinent the Saraswati-Indus region, the Gangetic plain, Eastern, Central and Peninsular India in a natural progression from a hunting-gathering lifestyle to a sedentary one, with no external stimulus, but with strong interaction between various regions of the subcontinent themselves right from the earliest Neolithic.

The myth that the founding of agriculture, whether in the Indus Valley or elsewhere in the subcontinent, is owed to migrations from West Asia (the so-called Fertile Crescent) is not supported by archaeological evidence.

Based on current evidence, whether genetic or archaeological, Josephs conclusion that, ...we are a multi-source civilization, not a single-source one, drawing its cultural impulses, its tradition and practices from a variety of lineages and migration histories, is quite simply totally wrong.

One cannot impressed by Josephs quoting of a blogger with a very questionable history like Razib Khan, while selectively omitting the comments of a known scholar in the area like Dr Gyaneshwer Chaubey after having sought them himself.

Can one be sure he has not interviewed other scholars, but left out their views from his article as they didnt suit his pre-determined agenda or just didnt interview scholars he felt held such views?

Joseph and others like him are welcome to write on any topic they please, and are even free to take sides in line with their prejudices. Indeed, all he has done is to paint a very recent paper in a not particularly highly-ranked journal as the final word in the debate, while coolly ignoring well-regarded studies which arrive at differing conclusions in significantly higher-ranked journals.

All one asks is, when writing on a much-debated topic like this one, they should at least show the intellectual sincerity to mention divergent points of view, and not try to create a false impression for the lay reader that they have been conclusively addressed. That is neither very honest nor commendable.

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Genetics Might Be Settling The Aryan Migration Debate, But Not How Left-Liberals Believe - Swarajya

Nazneen Rahman: ‘Science and music are mediums in which I create’ – The Guardian

Nazneen Rahman at the day job: head of genetics, Institute of Cancer Research and the Royal Marsden Hospital. Photograph: Wellcome

Ive had an exciting and unusual few weeks. My group published a scientific paper revealing a new genetic cause of a childhood kidney cancer called Wilms tumour. This discovery has been of immediate benefit to families, providing an explanation for why their child got cancer, and information about cancer risks for other family members. During the same period, I also released my second album of original songs, called Answers No Questions. On one day, I found myself singing live on Radio London in the morning and talking genetics to the World Service in the evening.

Over the past few weeks, I have found it increasingly difficult to know quite how to answer the ubiquitous question what do you do?

For most of my adult life, I have replied: Im a scientist and a doctor. It is an accurate description. I am professor of human genetics at the Institute of Cancer Research, London, and head of cancer genetics at the Royal Marsden Hospital. For 20 years, my work has focused on identifying gene mutations that predispose us to getting cancer and then using that information to help patients and their families.

But I am also a singer-songwriter. This is a smaller activity than my science, but far more than hobby. I release music that people pay good money to experience.

As my music has become better known, more and more people have asked me about my unusual career combination. Dubiously, admiringly, wistfully, jealously, but most often simply because they are intrigued by the motivations and the practicalities.

This has forced me to consider how, if at all, these parts of my life are related. At first, I was adamant they were distinct facets of my character. I railed against modern societys pervasive need to simplify and pigeon-hole the human spirit. Most people have multiple passions and drivers. I am fascinated by these subterranean pursuits. One of the joys of sharing my previously secret musical existence (its not been all joy but thats another column) is that many scientists now share their secret passions with me pot throwing, flugel playing, novelty cakemaking, fire eating scientists are as wondrously idiosyncratic in their appetites as the rest of society.

I also rail against the cliche that people are drawn to science and music because they both have a mathematical basis. It may be true for some, but it has no relevance to my passion for music. I was singing complex harmonies to pop songs long before I learned the theory of music. I am an intuitive, emotional, spontaneous songwriter with little idea of the key, notes or time I am composing in until I have to write it down. There is little science in my music, but I have come to believe there may be music in my science. There is a kinship in how I do science and how I make music that flouts the division of science and the arts that our education system promotes.

My branch of science is genetics. Genetics is underpinned by a simple four-letter DNA code (designated by A, C, G, T). This code dictates how our bodies work. And how they can fail. This beautiful code is framed, shaped, constrained and enhanced by a multitudinous orchestra of associates that determine when, how, where, how long and how strong different parts of the code are played in each of our 30tn cells. DNA is also extraordinary in being able to copy itself with unbelievable accuracy while retaining the ability to mutate and evolve. The sophisticated controls and balances are breathtaking in their elegance. Our recent childhood cancer gene discovery revealed some insights into these control mechanisms and how cancer can occur if they go wrong. Studying genetics provides an endless variety of patterns to unravel, problems to solve, questions to answer. Gratifyingly, it also provides endless opportunities to bring benefits to humanity. In a hundred lifetimes I would not run out of genetic questions that excite me.

Music is underpinned by a simple 12-letter note code (designated by C, C#, D, D#, E, F, F#, G, G#, A, A#, B). These notes can be layered in almost infinite ways to produce music. In a hundred lifetimes I would not run out of music to write. My challenge has never been about finding the time to write songs, it has always been about finding the time to not lose songs. Snippets of music and lyrics are my constant companions. Most disappear into the clouds like lost balloons. But every now and again, I reach up, grab a string and tie one down, just before it is lost for ever.

Science and music make me feel like Im swimming in infinity pools of possibility, but within structures that keep me from drowning. The potential and expectation to keep delivering new things can be daunting to scientists and artists. The DNA code in genetics and the note code in music are my lifelines. They let me be audacious and unfettered. They give me confidence to dive in, even when I cant see the shore on the other side.

And the practicalities of delivering science and music are quite similar for me. Science is typically funded as three- to five-year projects. For example, I am currently leading a 4m collaborative programme, called the Transforming Genetic Medicine Initiative, which is building the knowledge base, tools and processes needed to deliver genetic medicine. To get science funding, you need to present, in great detail, a persuasive, innovative concept that seems worthwhile and feasible. But once you receive the funding there is considerable creative licence to alter the project, within the overall concept, because science is fast moving. You cannot predict everything you will do at the cutting-edge of knowledge, five years in advance.

My albums have also had three-year lifespans, though I didnt plan it that way. I dont plan them at all. My songs tend to be stories about the complexities of everyday life, inspired by words, subjects or images that briefly, randomly, ensnare me. I dont know what the songs will be about before I write them. There is no overall concept for the albums, at least not consciously. And yet I see now that each album had a central theme that wasnt apparent to me when I was writing them. Cant Clip My Wings, which I released in 2014, includes songs about how we adapt to loss. Lost loves, lost lives, lost dreams. My new album, Answers No Questions, includes songs about choice the complexities, burdens, excitement, pain and joys of making choices.

As I am writing this, I wonder if I am forcing these connections, if they are a post-hoc construct that allows me to give a more pleasing answer to why I am both scientist and songwriter. But I have truly come to believe that, in me, science and music are different manifestations of the same need. A central deep desire to create new things elegant, beautiful, new things. It doesnt much matter if its a scientific discovery, a clinic protocol that makes things easier for patients or a song that tells a human story from a fresh perspective. When it works it feels amazing. Even when it doesnt work, the journey is always paved with nuggets of enlightenment that feed into future creations.

So what do I do?

I think, at my core, I am a creative, though it would be perplexing to many if I started to describe myself this way. Science and music are the mediums in which I happen to create, undoubtedly an unusual combination. But maybe only because we are relentlessly conditioned, from an early age, to believe we must choose whether we are in the science or the arts camp. People from the arts camp routinely tell me they were hopeless at science, sometimes apologetically, sometimes as a badge of honour, a mark of their creativity. Likewise, scientists worry that any proficiency in creativity might be interpreted as a deficiency in objectivity, the bedrock of science. It seems our society has lapsed into considering activity in the sciences and the arts a zero-sum game. It is not.

What would happen if we stopped constraining ourselves and our children in this way? If we embraced and fostered fluid boundaries between the sciences and the arts? If many more people were able to cross freely in and out of both worlds, successfully and unapologetically?

I believe science, art, individuals and society would reap countless benefits.

Answers No Questions is out now; nazneenrahman.com

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Making New Friends: The Genetics of Animal Domestication – lareviewofbooks

JUNE 18, 2017

THERES A SCENE in Antoine de Saint-Exuprys The Little Prince where the alien prince, fallen to Earth, comes across a fox. Come and play with me, he proposes to the fox, who replies, I cant play with you. Im not tamed. The prince, whos never heard the word tamed before, asks what it means. Its something thats too often neglected, the fox tells him. It means, to create ties. [] If you tame me, well need each other. Youll be the only boy in the world for me. Ill be the only fox in the world for you. [] [I]f you tame me, it will be as if the sun came to shine on my life. I shall know the sound of a step that will be different from all the others.

In 1952, nine years after Saint-Exuprys book was published, the Russian geneticist Dmitri Belyaev set out, like the Little Prince, to tame a fox or rather, foxes. His goal was to better understand how domesticated dogs evolved from the wolf, and he proposed to do this by domesticating the silver fox, the wolfs genetic cousin. By mimicking the wolfs transformation with a close relative, Belyaev thought, we could better understand one of the great mysteries of prehistory: the dogs route to domestication.

We know more about this process now than we did when Belyaev embarked on his research project decades ago. To his scientific peers, Belyaevs belief that he could replicate 10,000 years of evolution and breeding in a few decades with a species that had never been domesticated before, seemed entirely fanciful. But he turned out to be right: within a few years of starting his experiment, the foxes were already showing signs of domestication; within decades, they were on their way to becoming their own species. How to Tame a Fox (And Build a Dog) traces the history of Belyaevs experiment against the background of first the Soviet Union and then postCold War Russia. Its co-authored by the geneticist Lyudmila Trut, who joined Belyaevs team early on and has been the lead researcher of the fox domestication project since 1959, and the evolutionary biologist Lee Alan Dugatkin.

Domesticated animals exist in a peculiar gray area between the world of humanity and the rest of nature. From the Book of Genesis to the modern environmental movement, we tend to understand nature as something that we stand apart from and exert power over, whether to dominate or to protect. But cats, dogs, horses, and other domesticated creatures exist in a liminal space between these two worlds. As W. G. Sebald says of the dog, His left (domesticated) eye is attentively fixed on us; the right (wild) one has a little less light, strikes us as averted and alien.

Domestication is not simply the engineering of a change in animal behavior; it is a matter, as Dugatkin and Trut write in their opening pages, of constructing a brand new biological creature. Dogs, after all, are a separate species from wolves, and housecats are so different from their feline cousins that its not entirely clear from which species they were domesticated (though most biologists agree that it was probably the Middle Eastern wildcat). Domestication is not just a question of selectively breeding some traits at the expense of others; its about fundamentally changing the animal.

Across species, domesticated animals seem to share a number of traits that differentiate them from their wild counterparts. Most have shorter faces and curly and floppy tails, traits associated with delayed physiological development and remaining in a stage of perpetual adolescence; biologists refer to this as neoteny. Domestic animals also tend to develop different coloration patterns, and unlike their wild cousins, who mate only once a year, theyre fertile year round. Other traits are significant but harder to measure: a dog may not have the same apparent aptitude for solving puzzles as a wolf, but will display more social intelligence in its ability to manipulate human emotions.

The riddle of domestication has always been how to unravel this ball of traits, and learn how they came to be associated with one another. Were early domestic animals selected for their usefulness to humans (cats for pest control, dogs for security and hunting), and then socialized from there? Were their neotenic traits necessary for their domestication, as animals that remained juveniles were perhaps easier to train? Was the wolfs nature as a pack animal, and responsiveness to socialization and group identity, crucial to its taming? And what of the superficial aesthetic differences do they have any bearing on domestication? Farmers raising cows, after all, had nothing to gain from their cows having black-and-white spotted hides, Dugatkin and Trut note. Why would pig farmers have cared whether their pigs had curly tails?

Belyaevs hypothesis was that the single most important defining trait was comfort around human beings. Zebra and deer, for example, share many traits in common with horses but have long resisted any attempts at domestication. Zebra, under constant threat from predators, have developed a fierce defensiveness, whereas deer remain skittish and are universally nervous around humans. What separates both of these animals from their close genetic cousin the horse is the latters tolerance of humans. Early attempts to domesticate horses, DNA evidence suggests, were based on selecting for agreeableness and manipulating the horses innate fear response.

Among the numerous traits that identify domestic animals, then, Belyaev used as his sole criterion tolerance for human beings. Foxes tend to be either aggressive or skittish around humans; Belyaev and his team focused on those that seemed least defensive. These were bred together, and successive generations were likewise measured for their tolerance for humans, with the researchers hoping that eventually this quality could be bred in offspring.

Within three breeding seasons, the researchers were seeing results: Some of the pups of the foxes theyd selected were a little calmer than their parents, grandparents, and great-grandparents, Trut and Dugatkin write. They would still sneer and react aggressively sometimes when their keepers approached them, but at other times they seemed almost indifferent. Even more surprising, though, was how quickly these behavioral changes were accompanied by other differences. In a matter of years, hormones associated with stress decreased, while levels of serotonin (which decreases anxiety and elevates ones mood) increased. The foxes went from being merely indifferent around the researchers to actively soliciting their affection. Eventually, their tails would even wag at the sight of humans something no other animal besides a dog has been known to do.

Selecting for tameness also led to a series of physical changes: Belyaevs foxes had bushier tails, shorter faces, lighter fur. Which is to say: Traits that were not in any way selected for nonetheless began to assert themselves. At one point, the foxes began making a sound that at first confounded Trut and her team, until she realized that they appeared to be mimicking human laughter. As they ultimately concluded, the tame foxes were making this noise in order to attract human attention and prolong interaction with people. They were displaying the same kind of social intelligence that dogs do when they perform tricks for their masters.

The fox experiment bore out Belyaevs initial hypothesis about tolerance for humans as the key to domestication. These results suggest that many of the various other traits associated with domestication are in fact already latent in animals genetic codes; its just that, in the wild, these traits are inactive, rarely expressing themselves. Selective breeding can allow them to come to the fore relatively quickly. Shake up the fox genome by placing foxes in a new world where calm behavior toward humans is the ultimate currency, Dugatkin and Trut conclude, and youll get lots of other changes mottled fur, curly, wagging tails, and better social cognition as well.

The story of Belyaev and Truts decades-long experiment is fascinating, though in How to Tame a Foxs telling some important details get left out. In crafting a heartwarming story of how easy it was to create docile, loving pets, Dugatkin and Trut dont dwell on the fact that they were also trying to create exceptionally aggressive foxes to further test the hypothesis. Nor were they just breeding foxes: other species, including rats and beavers, were also bred for both aggressiveness and tameness. According to one anecdotal report of the project that isnt mentioned in the book, Soviet officials had planned to use the most aggressive beavers as a line of defense against a possible US invasion. One wonders what other strange tidbits might have come to light had the authors not chosen to selectively shape their narrative. As a result, the book itself feels much like its subjects: bred for tameness.

It might have been better had How to Tame a Fox not been co-written by one of the principal researchers, so as to introduce a modicum of objectivity and critical distance into the writing. At times the book reads like a third-person memoir: Pushinka [one of the foxes] lay by Lyudmilas feet while she worked at her desk, and she loved for Lyudmila to play with her and take her for walks around the area. A favorite game was when Lyudmila would hide a treat in her pocket and Pushinka would try to snatch it out. Such passages are often lovely and do help to convey the remarkable level of domestication the foxes had achieved in such a small span of years (and only the coldest hearted wont melt at the photos of the foxes themselves). But in a book that largely skimps on the scientific and philosophical implications of its narrative, they can feel a bit too sentimental. It is also odd to read passages that describe Trut as a woman of great warmth and an unassuming demeanor, whose formidable energy and determination made her a force to be reckoned with when she is also listed as a co-author of the book.

One thing How to Tame a Fox does reveal is the precariousness inherent in government-funded research, with lessons that go far beyond Soviet Russia. In the early 50s, when Belyaev began his project, the entire field of genetics was under assault in the USSR. A well-placed friend of Stalin, Trofim Lysenko, had promised that he could increase crop yields by freezing seeds before planting. Lysenkos claim was not only false, it ran counter to the prevailing understanding of crop genetics. Since Lysenko knew geneticists could unmask him as a fraud, he began a campaign to discredit the entire discipline, labeling them as saboteurs. Thus, when Belyaev first described his research program to Trut, he told her it could not appear to have anything to do with genetics; instead, it had to be described as an inquiry into fox physiology.

After Stalins death, Lysenkos stranglehold on the discipline loosened, and geneticists could once again work without fear of reprisal. But with the fall of the Soviet Union and the economic crash of the 1990s, research budgets were slashed, and the project nearly ended for lack of funds. Trut took to begging passersby for food to feed her starving animals; eventually she was forced to sell some of the domestic foxes for pets, and some in the control groups for fur. Only an internationally published paper on her results saved the project, triggering a fundraising campaign that kept the animals alive.

Belyaev died in 1986, but he had hoped to one day write a book himself, which he planned to call Man Is Making a New Friend. How to Tame a Fox (and Build a Dog) is not far off from what Belyaev envisioned: written for a general audience, it chronicles the story of a scientific gambit that was more successful that even its creators had dreamed. Its an inspiring reminder of how much we still dont know about the world, and how much can be learned by taking bold chances. Its also a cautionary tale about the risks of state-funded science that has nearly as much relevance to Trumps United States, where federal research budgets are in danger of being slashed right and left, as it does to Stalins Russia.

But Belyaevs experiment didnt just produce new knowledge; it also created a new species of animal, one thats become entirely dependent on humans, and its worth asking what the ethical and philosophical consequences of this might be. Some scientists believe that wolves actively participated in their own domestication; thousands of years ago, certain wolves may have made the calculation that, by sucking up to humans, they could live an easier life. These wolves gave up autonomy and freedom in exchange for food, shelter, and protection. The gamble ultimately paid off: there are now only about three hundred thousand wolves in the wild, and over half a billion dogs.

But a dogs life is not an easy one, especially without a human being to care for it. Many contemporary breeds lack the skills to fend for themselves, having depended on their masters for generations. Perhaps in the future wild foxes will go extinct, and the only foxes that remain will be the domesticated ones, the ones that have endeared themselves to humans to such a degree that even in times of strife and scarcity we will look out for them. But the precarious state of Belyaevs project may well signal another outcome, one in which these foxes, whove thrown their all in with their human protectors, may find a darker fate awaiting them. If the money to keep the program going dries up, and theres no market for them as pets, what then? In The Little Prince, Saint-Exuprys protagonist does indeed tame his new friend, but before he does the fox offers this warning: People have forgotten this truth. But you mustnt forget it. You become responsible for what youve tamed.

Colin Dickey is the author, most recently, of Ghostland: An American History in Haunted Places.

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Making New Friends: The Genetics of Animal Domestication - lareviewofbooks

Malky Mackay: we are fighting genetics and a Scottish diet – The Times (subscription)

Malky Mackay leaves no stone unturned in his efforts to improve the Scottish game. Graham Spiers reports

When Malky Mackay was making his way in football he studied for and received a Certificate of Applied Management from the Warwick Business School. It helped Mackay that he is, by nature, a voracious reader of books and a man who thirsts after knowledge.

Mackay once spent a day with the SAS because he wanted to understand the mechanics of key decision-making in pressured situations. I wanted to understand their team-work and leadership: who can handle a stressful situation under real pressure? he said. These guys are so good at what they do. And it is about life and death: if they dont get it right, if they dont have the right team-work, then thats it.

Last year Mackay travelled to America to spend time

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Malky Mackay: we are fighting genetics and a Scottish diet - The Times (subscription)

Scientists Find Genetic Mutation That Could Increase the Male Lifespan – Gizmodo

Jiroemon Kimura, the oldest man ever (Image: YouTube/Screenshot)

Professor S. Jay Olshansky once told Gizmodo, In the world of aging sciences, if you want to live a long life, choose long-lived parents. So genetic markers linked to longevity are interesting as hell. But if youve got the wrong genes, then the wrong moves might do you in.

A team of researchers from universities in the United States wanted to figure out the role of genetics in human lifespan, specifically relating to growth hormone. The researchers work shows two main things: first, that a mutation in mens DNA relating to growth hormone might lead to a longer lifespan. And secondly, that treating older people with growth hormone might be dangerous if they dont have the variation.

Gil Atzmon, the studys principal investigator from Albert Einstein College of Medicine and the University of Haifa in Israel, was most excited by how a slight change in DNA could have such a big impact. Delete a few base pairs, and you still have a functional protein that now makes people live longer, he said. I think this is phenomenal.

This is complex, so Im going to take it slow and possibly oversimplify things. Basically, theres one system in question, the IGF-1/GH axis. Each of these are genes that code for different molecules in your body.

Researchers have already had a hunch that IGF-1 can regulate height at the expense of longevity, like the case in dogs. More IGF-1 means taller but shorter lifespan and less IGF-1 means shorter but longer lifespan. This should make senseits akin to the way big dogs live shorter lives than small dogs.

The researchers studied 800 men and women from across four populations and found something surprising. Indeed, the IGF-1 levels were lower in the centenarians, but many of the men were also taller. The data showed the researchers that theres more than just IGF-1 at play.

Centenarian males were often missing a specific snippet of DNA in their GHR gene. These people seem to be more sensitive to growth hormone and grow taller. So, even though their IGF-1 levels were lower (they lived longer), they still grew taller from their special GH gene. The people with this mutation seemed to live ten years longer, on average.

And the study really was huge. The replication across the four different populations makes our result more accurate and globally translated.

Atzmon himself admitted that all this is pretty complex. But its definitely new, important evidence pointing to the role that this IGF-1/GH axis plays in simultaneously determining your height and your lifespan, explained Andrzej Bartke, Professor of Physiology and Internal Medicine at Southern Illinois University School of Medicine, in a conversation with Gizmodo.

But were not at some level of life-hacking clarity. Clearly more research is needed to understand exactly why this type of GH receptor favors extreme longevity, why the effect was seen only in men and why the results in people studied by these investigators differ from some of the previous findings in different groups of human subjects with the same type of receptors, said Bartke.

Theres a catch to all this. Their results seemed to show that folks who dont have the GH variation might actually be sensitive to growth hormone therapy. This is a stark reminder that administering growth hormone as an intervention to slow agingwhich is still being done in the anti-aging medicine industry is not warranted by the scientific literature, Olshansky told Gizmodo. In fact, could actually be harmful.

So, youre still going to die one day. But as to when, that answer probably doesnt reside in what you eat (or in young blood) nearly as much as it does in what your DNA looks like.

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Scientists Find Genetic Mutation That Could Increase the Male Lifespan - Gizmodo