Sunday, October 16, 2016

Global Whatever

In a recent Nature article there is a presentation of the cycling of global temperatures as shown above.

They note:

Here I present a spatially weighted proxy reconstruction of global temperature over the past 2 million years estimated from a multi-proxy database of over 20,000 sea surface temperature point reconstructions. Global temperature gradually cooled until roughly 1.2 million years ago and cooling then stalled until the present. The cooling trend probably stalled before the beginning of the mid-Pleistocene transition, and pre-dated the increase in the maximum size of ice sheets around 0.9 million years ago. Thus, global cooling may have been a pre-condition for, but probably is not the sole causal mechanism of, the shift to quasi-100,000-year glacial cycles at the mid-Pleistocene transition. Over the past 800,000 years, polar amplification (the amplification of temperature change at the poles relative to global temperature change) has been stable over time, and global temperature and atmospheric greenhouse gas concentrations have been closely coupled across glacial cycles. A comparison of the new temperature reconstruction with radiative forcing from greenhouse gases estimates an Earth system sensitivity of 9 degrees Celsius...

Not really clear what this data/simulation leads us to conclude. Other than cycles and noise.

How Good is CRISPR?

We have been following CRISPR technology for the past three years. Logically it makes sense. The CRISPR guide RNA targets a sequence and the Cas 9 or equivalent cuts it. There are few issues however. One is it creates a double stranded break which often creates a worse situation than before. Second, the RNA target may not find the sport we sought but some other identical but wrong sequence.

As noted in STAT:

As always, what worked in mice might not in patients. A constant concern with CRISPR is that it edits genes it isn’t supposed to, because the guide RNA mistakes a healthy region of DNA for the mutation. Testing the most likely of these “off-target” sites, the scientists found that the one that was mistakenly CRISPR’d the most often wasn’t a gene at all, or even near any genes. Other off-target sites were CRISPR’d in fewer than 0.10 percent of cells. But even that low level of error might be dangerous, perhaps triggering a cancer-causing gene, so Corn and his team are running more animal studies of whether their CRISPR approach will be safe.

 In a recent Science Translational Medicine they note in applying this to blood disorders:

Genetic diseases of blood cells are prime candidates for treatment through ex vivo gene editing of CD34+ hematopoietic stem/progenitor cells (HSPCs), and a variety of technologies have been proposed to treat these disorders. Sickle cell disease (SCD) is a recessive genetic disorder caused by a single-nucleotide polymorphism in the β-globin gene (HBB). Sickle hemoglobin damages erythrocytes, causing vasoocclusion, severe pain, progressive organ damage, and premature death. We optimize design and delivery parameters of a ribonucleoprotein (RNP) complex comprising Cas9 protein and unmodified single guide RNA, together with a single-stranded DNA oligonucleotide donor (ssODN), to enable efficient replacement of the SCD mutation in human HSPCs. Corrected HSPCs from SCD patients produced less sickle hemoglobin RNA and protein and correspondingly increased wild-type hemoglobin when differentiated into erythroblasts. When engrafted into immunocompromised mice, ex vivo treated human HSPCs maintain SCD gene edits throughout 16 weeks at a level likely to have clinical benefit. These results demonstrate that an accessible approach combining Cas9 RNP with an ssODN can mediate efficient HSPC genome editing, enables investigator-led exploration of gene editing reagents in primary hematopoietic stem cells, and suggests a path toward the development of new gene editing treatments for SCD and other hematopoietic diseases.

 Thus there is potential but also a concomitant risk.

Thursday, October 13, 2016

Bob Dylan, Congratulations

Being of a certain age I can appreciate Dylan differently than others. In the summer of 1962, I was a Lifeguard in New York City and somehow, I really don't recall how, I got this blind date with a girl from Brooklyn, at Nostrand and Newkirk. So off I go, from Staten Island, across the Ferry, then into the bowels of Brooklyn. I am then told by the young lad, I don't recall her name of looks, but I remember Nostrand and Newkirk, that she wanted to go into the Village and see some guy in some coffee house. So back on the subway and off the Village to some place you walked down stairs to the basement and drank dark coffee in small cups amongst a few dozen people all of whom smoked except for me. Subway fare at $0.15 each way for each person was equal to half a pack and I wanted to spend my money on transport.

So up come this guy with a guitar, frizzy hair, and a harmonica hanging off his neck. He started to sing, the sound was like a cat dragged by the tail, but the words, well the words had meaning. He was not the Kingston Trio or Buddy Holley; he definitely was not Elvis. He was Bob Dylan. The memory festered in my head after I dropped the young lady back in Nostrand and Newkirk, and then back to the Ferry and then straight to work, for you see New York was not an easy place to get around. I would find it easier to get to Moscow by plane than Brooklyn by train, and yes Ferry.

About a year later my roommate Bob Glasser had become a Dylan fan. He had a guitar and that stupid harmonica, and song after song he imitated the dead cat howling, but the words, they were the same, and that was the power. He would sing Dylan and then listen to Jean Shepherd, or Shep, on the radio. It was a time when words meant something. Dylan stirred the soul, and Shep the imagination. You did not need an iPad, an iPhone, or an iWhatever. You heard words and used your mind.

Then in the summer of 1966 I went to a Dylan concert in New York, after the Dylan transmogrification into a rock personality. It meant less, but then I had changed as well.

So where does this lead? To a Nobel prize, and one I feel as a minor observer, well deserved. Dylan made many of us think, not wiggle with Elvis, sing along with the Beatles, or blend in with Peter Paul and Mary.

To my surprise some you person who appears to have a view of their own greatness feels the opposite. It appears in the NY Times, where else? After all it is the NYT, that rag of record, which has dragged its front page down the level of current day politics. One does wonder what else is going on in the world. But alas, one gets more from China Daily or RT, or even The Guardian and Le Monde. But from this lost lass we are told:

The committee probably did not mean to slight fiction or poetry with its choice. By honoring a musical icon, the committee members may have wanted to bring new cultural currency to the prize and make it feel relevant to a younger generation. But there are many ways they could have accomplished this while still honoring a writer. They could have chosen a writer who has made significant innovations in the form, like Jennifer Egan, Teju Cole or Anne Carson. They could have selected a writer from the developing world, which remains woefully underrepresented among Nobel laureates. They could have picked a writer who has built an audience primarily online, like Warsan Shire, who became the first Young Poet Laureate of London in 2014. Instead, the committee gave the prize to a man who is internationally famous in another field, one with plenty of honors of its own. Bob Dylan does not need a Nobel Prize in Literature, but literature needs a Nobel Prize. This year, it won’t get one.

My first response was; just who are you? My second was; oh well it is just the NY Times. Communicating ideas, complex thoughts, emotions, are literature, and doing so as did Dylan, especially at that time, was world changing. He started a process that lasted but a short while but which had great and lasting consequences. My question would be; what let's this young lass make such baseless a set of comments. The answer, the New York Times. Pity.

Wednesday, October 12, 2016

What's Old is New Again

The debate on the use of PSA in Pca continues. In a response to a recent NEJM article, a renowned researcher concludes:

For today, we can conclude on the basis of level 1 evidence2 that PSA monitoring, as compared with treatment of early prostate cancer, leads to increased metastasis. Therefore, if a man wishes to avoid metastatic prostate cancer and the side effects of its treatment,3 monitoring should be considered only if he has life-shortening coexisting disease such that his life expectancy is less than the 10-year median follow-up of the current study.2 In addition, given no significant difference in death due to prostate cancer with surgery versus radiation and short-course androgen-deprivation therapy, men with low-risk or intermediate-risk1 prostate cancer should feel free to select a treatment approach using the data on health-related quality of life3 and without fear of possibly selecting a less effective cancer therapy.

Yes, if one has a diagnosed PCa, or a PSA that is indicative of such, with subsequent positive biopsy, chances of not going with mets is not "watchful waiting" but acting.

Monday, October 10, 2016

Employment October 2016

We have been tracking the employment situation after the eight years since the collapse. It frankly is not as good as one suspects. Let's examine some numbers.
The above is a comparison by sector between 2005 and last month. As we have been noting the higher paying jobs are down and the service and lower paying jobs are up.
The growth in Government supported jobs continues. Government employment is starting a rebound and Health and Education is advancing ever more quickly. Since both sectors are effectively tax payer supported they become a true weight on growth.
The above is a metric for participation rate which still is decaying. Thus the putative employment numbers are highly skewed.
The Core versus Government sectors are rebounding so that as we noted earlier more people are being supported by fewer.
Sector changes are shown above with Mining taking a massive hit.
The same is shown above.

Overall things really are not getting better despite the verbiage.

Tuesday, October 4, 2016

What Business is Google in? Redux

Over the last eight years we have seen Google wander into businesses with great fanfare that frankly they had no core competence in. Google is in the software business, search and OS. Now they tried Nexus, and I was a buyer, early. The unit died promptly and when calling the customer service line you got Valley Speak, Silicon Valley speak. They "shared" my concern but alas when I sent the unit to the Executive I had worked with on a Presidential Panel, well, never got a reply. Google, you see, does not like people, in my opinion. It likes computers and getting them to do stuff and then getting commercial entities to ride on that stuff and pay them money.

There is a fantastic summary of "Google's Follies" in ArsTechnica which states:

Google is definitely pushing itself as a hardware company like it never has before, but this is hardly the company's first effort to get into the smartphone hardware business. The first was the Nexus One, which drew iPhone comparisons when it was launched. But low sales almost killed the brand—Eric Schmidt said in 2010 that the Nexus One “was so successful [in helping Android along], we didn’t have to do a second one”—before it was resurrected and pointed at the developer-and-enthusiast niche. The second and more serious effort began in 2011, when Google bought Motorola for $12.5 billion. After clearing out the old Motorola’s product pipeline, in 2013 and 2014 the company introduced a series of high-end and midrange Moto phones that were critical darlings for their price tags, their focus on fundamentals, and their fast Android updates. These were three non-broken things that Lenovo promptly “fixed” after it bought Motorola from Google for just $2.9 billion three years later. Google made no mention of its Motorola experiment onstage today, even though the same guy who ran Motorola is now running Google’s hardware efforts. But the sense that all of this has happened before is just one of the contradictions of Google’s new mobile strategy. More importantly, the company’s actions and stated goals contradict one another, to the extent that I wonder just how committed Google is to its hardware plans and, on a related note, just how good its chances of success are.

The author however has forgotten Google Fiber, the ongoing stumble  that could clearly have been avoided by a simple conversation with folks who had done this before. Instead they follow a pure tech and then a pure sales led strategy. Unfortunately even if you can build it, and can sell it, for nothing it is a political and operational problem, expertise which seems anathema at Google.