Thursday, April 30, 2015

Middle Class Entrepreneurs

I am always amazed by the economists who take something that works, albeit in a very select manner, and then argue to its generalization. A recent article by two such types in the left wing blog, Project Syndicate, argues that what makes Silicon Valley work can be copied to create more middle class jobs.

They state:

The University of Virginia’s Miller Center recently created a commission ... to identify strategies to support the creation of middle-class jobs through entrepreneurship. The ideas proposed in the commission’s report include providing training and mentors for prospective entrepreneurs and startups, creating “ecosystems” of supporting infrastructure, and reducing regulatory barriers.The report also highlights the importance of unlocking capital for “Main Street” entrepreneurs, who struggle to find the funding they need to launch, sustain, or scale up their operations, particularly as the recent recession drove out many of the community banks on which they had traditionally relied for credit. Silicon Valley startups, by contrast, enjoy the generous support of VC funds, having received 30-35% of all venture investment deployed in the US since the 1980s. 

VC funding, and its like, which I have been doing for some 30 plus years, is a ruthless business, it is Creative Destruction real time. It requires motivated, intelligent, competent people. It is not a world for the reconstruction of the "middle class". We do not invest in a new candy store, at least I would not. We focus generally on game changing ideas that can be implemented with a dedicate team.

As I was once told, "A Good Idea Does Not a Business Make".  It takes a team whose sole focus, not even their day job, is dedicated to. To this team, failure is no option, and there is no life other than the new business. One cannot go home for dinner at night. 

Whose capital is being unlocked for Main Street? I suspect it is the taxpayers. That model just does not work. It never has. The Government is the worst entity to choose winners and losers. There is too much politics. Political favorites get taxpayer money and they most likely are good at getting political favors and not starting a business.

One must be wary of the advice rendered by these types of economists.

Interesting Melanoma Therapeutic

Melanoma is an aggressive malignancy and has been approached by pathway blockers, BRAF V600, and via immune therapy, including targeting PD-1. As we had discussed two years ago, T-VEC, a viral based therapeutic, had significant potential. The FDA has approved its use yesterday for melanoma. This means that we now have three axes to deal with melanoma; pathways, immunologic, and viral. All three are malignant cell specific and one suspects that a combination therapy may be best, one yet to be determined.

In OncLive states: 

Although the current review is for single-agent use, multiple clinical trials are currently assessing T-VEC in combination with immune checkpoint inhibitors. A phase II randomized study is ongoing that will evaluate the safety and efficacy of T-VEC in combination with ipilimumab versus ipilimumab alone. Additionally, other ongoing clinical trials will investigate T-VEC in combination with immune checkpoint inhibiting antibodies, such as those targeting PD-1.

This tripartite approach is worth following.

Sunday, April 19, 2015

Antitrust and the Brit

And now the Brit at the Guardian takes after Google. He states:

For all their promise of openness and equality, the technologies of the internet also promote the creation of giant companies. The question facing us as a society is what trade-offs we make: does the bigger danger lie in allowing the creation of unalloyed corporate power, or instead in curbing technology’s potential to prevent it? The question could become moot: in practical terms, if Google trounces the EU on all counts after several years, few other competition authorities will want to take on the company, and they may even be deterred from pursuing other internet behemoths. A decade or so without a challenge may make a new normal near irreversible.

This is not a logical argument, it is a crie de coeur, French is always a good way to bemoan the Brits,  especially those who appear to be totally ignorant of monopolies. Just because a company has a large market share does not make it a monopoly. Perhaps it is just better! And oh by the way it is free!

One could not do what one creats today without Google. Yahoo is a cacaphony of ads, nonsense, and useless blather. Bing is Microsoft, incomprehensible and insulting. Google, well it just works. So the Brits now want it dead! Yes, those same characters who, after the Danes, came and occupied the last vestige of intellectual acumen in the 11th century with the near imbecile of a King, John!

Perhaps we should return to a court with Henry VIII and the beheading of spouses, or perhaps they can take that out of the History books, except perhaps Wolf Hall, or whatever that is.

Saturday, April 18, 2015

Antitrust and the Danes

The Irish can still recall the Danes invading in the 800s, driving up the Shannon, destroying and plundering, the monasteries and massive libraries of documents, driving the then both religious and educated into ever present terror. Then when Henry II arrived and he gave Ireland to his somewhat less than competent son John, it began a thousand year occupation which seems to continue to the present. Yet to a reasonable degree it was the Danes and their ships that destroyed what could have been a few hundred year leap on civilization.

Now to antitrust. This has always been a rather messy quagmire. I have written extensively on the topic and it may be worth an examination. One need look at just two cases; IBM and AT&T. At the time the dropping of IBM was totally correct. There was competition, just look at IBM today, going through another metamorphosis. On the other hand AT&T was also correct. It was a Government sanctioned monopoly that actually stifled any competition. I examined this in detail in 1990. Had DOJ not broken up AT&T we most likely would still have black rotary dial phones and would be leasing them for $1,000 per month!

Now to the Dane and Google. In a sense Google is akin to the Irish monks, providing knowledge universally, along with some of their services, but it is the knowledge that counts. Then comes the Dane, not on a long boat this time but with the power of the EU, that mighty fortress that seem just two shakes from collapse.

As the NY Times notes:

Last year, as Ms. Vestager was leaving her job as Denmark’s minister of the economy, she gave her successor a hand-knit toy elephant — she often works on them during staff meetings — noting that the animals “bear no grudge, but they remember well.”

Sounds like the Danes and their long boats! Off to the monasteries and their libraries, burn them down!

The Times continues:

In Brussels last Wednesday, she filed formal antitrust charges against the company, saying that the search engine giant had abused its market dominance by systematically favoring its own comparison shopping service over those of its rivals. If Google fails to refute the charges, the company could face a fine of more than 6 billion euros.

 Google has competition. It is not an AT&T, perhaps it may become an IBM, but never an AT&T. Technology changes daily, regulators look backward, and project forward their worst visions. The Times continues:

That direction was filing formal charges, called a statement of objection, accusing Google of favoring its own comparison shopping service, called Google Shopping. In practical terms, the commission found that when a consumer used Google to search for shopping-related information, the site systematically displayed the company’s own comparison product at the top of the search results — “irrespective of whether it is the most relevant response to the query,” Ms. Vestager said in a commission-issued statement about the charges.

 The Dane does not seem to understand that the mechanism used is how Google pays for the service. It is a service, it costs money, and frankly anyone else can build their own such service. There is no monopoly, there is no barrier to entry, it is not AT&T preventing any competition. The Dane seems to be clueless about the world of business, but then most likely did her ancestors as they pillaged up the Shannon, past my ancestors. This may just be 21st Century pillage, again the Danes!

Friday, April 17, 2015

The EHR and Its Performance

The NY Times bemoans the status of the EHR. As it states:

The ability to transfer electronic medical records from one doctor or hospital to another is essential to the smooth functioning of the health care system and to providing the best possible care to patients. Yet all too often these transfers are being blocked by developers of health information technology or greedy medical centers that refuse to send records to rival providers. This will not be an easy problem to fix, but some possible approaches were detailed in a report to Congress last week from the Office of the National Coordinator for Health Information Technology, a unit of the Department of Health and Human Services.

The problem, as we have noted over the past several years is several fold:

1. First, the Government directed the process. The same group who did the portal for ACA. In addition in my opinion the management team were politically selected not professionally selected.

2. The system should have been patient centered and not practice centered. Namely the system should have take advantage of a secure cloud based approach minimizing physician costs and overhead and allowing single points of collection and correlation. Unfortunately we have a plethora of systems which will be outdated and underused.

3. The system should be multimedia enabled. Now it is merely a text file system with some adjunct access for radiologists and perhaps pathologists. Other multimedia elements are piecemeal and unconnected.

4. The system should provide a customizable dashboard. If the patient is a Type 2 Diabetic one should see their BMI changes as well as HbA1c and others. If the patient has COPD the same.

The problem is NOT the vendors. The problem was in my opinion the very people who created this mess. We noted as such six years ago, but alas, it is this Administration.....And tens of billions of tax money has been spent and added costs to practices...not to mention physicians typing while not examining the patient!

Ad Hoc Propiter Hoc

It is always amazing to see what amounts to research. In a recent MIT News release there is a study that alleges to show that people raised in well off families are smarter than those in poor families because of the difference in income. At least that appears to be the gist, an academic study to justify income transfer and the elimination of income disparity. (This is funded by the Gate Foundation, somewhat ironic.)

The article states:

A new study led by researchers at MIT and Harvard University offers another dimension to this so-called “achievement gap”: After imaging the brains of high- and low-income students, they found that the higher-income students had thicker brain cortex in areas associated with visual perception and knowledge accumulation. Furthermore, these differences also correlated with one measure of academic achievement — performance on standardized tests. “Just as you would expect, there’s a real cost to not living in a supportive environment. We can see it not only in test scores, in educational attainment, but within the brains of these children,” says MIT’s .... Professor in Health Sciences and Technology, professor of brain and cognitive sciences, and one of the study’s authors. “To me, it’s a call to action. You want to boost the opportunities for those for whom it doesn’t come easily in their environment.”

Now I think of Faraday,  orphaned and apprenticed as a bookbinder. His work was prolific and established the basis for our electromagnetic world today. One can go across MIT alumni and see all too many who came from what they would call less advantaged homes. In fact MIT was where one achieved from humble beginnings as compared to Harvard where one achieved from family pedigrees. I would hazard to say many MIT alums did more intellectually for society than Harvard. After all we had fewer politicians and that alone is an achievement.

But I suspect the facts belie the conclusions above. I think of the many MITES students I worked with and befriended. Talk of hard times. Yet look at them now! Could they have done better? Frankly I believe that they did what they did because they had been challenged, not despite it. Probably the one of whom I am most proud went from a Mississippi rural area to heading a major investment fund in Africa!

Also one must remember all the well off kids that go nowhere. The "real cost" is in my opinion a political statement and lacks any factual reality.

The Selfie

There is an article in The Guardian discussing the Millennials and how they bemoan their situation in life. The rather self absorbed author writes:

Life is often referred to as a “highway”, to borrow from Tom Cochrane, and for my generation that hasn’t changed. “Adulthood today lacks a well-defined roadmap”, writes Steven Mintz, in his forthcoming book The Prime of Life. “Today, individuals must define or negotiate their roles and relationships without clear rules or precedents to follow”. This is especially true for us millennials, who are the product of a terrible economy that has required us to hit the emergency button in our lives. But it’s becoming evident that we have been given a roadmap to a road that we are not even on and then are blamed for going in the wrong direction.

But this self absorbed statement is bettered by the photo atop the article, which is a collection of these individuals engaged in the Selfie. This in many ways defines them. They look inward, at themselves, and they see what they may not like. Albeit adoring themselves and their small worlds captured in this image or video, they are not looking outward.

Now they bemoan a "terrible economy". Are you nuts! My parents in the 30s had no economy to speak of, and survived on jobs at $14 per week. You could not even pay you cell phone bill with that. How about Viet Nam and the 60s, for a male you had almost a 50:50 chance of going there as cannon fodder for Johnson. Equally you had the military say at Kent State killing innocent students and there was no justice for that event.

A second article bemoans the "following of your dream". It is some student whose life on food stamps as they go about following their dram is decried as not enough:

a twentysomething graduate student, knows something about trying to live on food stamps. One of the so-called millennials, ... took an unpaid internship fresh out of college in 2012 and had to rely on food stamps to help supplement her income. Currently enrolled in graduate school at Oregon State University, ... is making do with $800 a month. “I was following my dreams, which I realized really quickly I could not afford to do. I was working as an intern at the Boston Review [during the week] and was unpaid. I was eating through my savings and applied [for food stamps] because I realized that I was not going to be able to continue pay rent and be able to buy food at the same time,” she said. It was actually Boston Review that had suggested she apply. “I guess other interns they had in the past had done it.”

 If you want to "follow your dream" then you have a price to pay. I should not have to pay your price, I did that when I ate rutabagas and drank powered milk. If you are willing to take an unpaid job then that economic choice has consequences.

Dreams do not an economically stable society make. It appears that the Selfie is a true metaphor for this group, inward focused and self absorbed. Talk of a "lost generation". Yet I look at many of those who have managed to squeak across our borders as at sunrise they line up looking for a days work and then applying themselves for fifteen or more hours and then doing it again and again. Never saw them take a Selfie.

Wednesday, April 15, 2015

Cancer and Outliers

Decades ago I spent a considerable amount of time trying to logically develop a basis for rejecting outliers. When collecting data oftentimes most of the results look like the random variations one would expect, except for those few outliers.

At the time I noted:

When data are taken in many experiments there often are points which bear no resemblance to the actual experiment being performed but arise from other, possibly undefined, sources. These data points are called outliers and the data analyst seeks ways to identify them and accurately reject them from the data base. Statisticians have developed many techniques for recognizing and rejecting outliers, but their approaches have usually been centered upon techniques where time variations in the measurements were absent.

Namely I was concerned about rejection where we had some underlying but possibly uncertain dynamic process governing the system. Outliers can be viewed in many ways:

1. Just a bad data point.

2. A data point which is one of a kind.

3. A data point which represents a significant system underlying it.

Now consider the many new therapies for treating cancers; immunotherapy and pathway control therapy. We often see say 20% of the patients are "cured". The other 80% regress to normal status and do not survive. Are the 20% outliers, and should be rejected or are they representative of a different dynamic system and we should really try to identify that system. Forty years ago I felt the latter. Namely we observe data and if it divides into two distinct terminal states then we have two distinct underlying systems, pathways or immune responses, driving them there.

In Nature this week there is an interesting paper examining this issue. The authors note:

By definition, exceptional responses are rare, which makes them hard to study. Their anecdotal nature seems to contradict the teachings on statistically sound results in biomedical research. In a clinical trial, even if there are several exceptional responders, a drug will fail to achieve approval because it does not improve the health of the majority of patients. This means there has been little incentive for researchers or drug companies to investigate thoroughly why a few people respond so well.

This has typically been the result that these outliers are just bad data. In reality they are good data, great data, but for another reason. Find that reason, namely identify the system that allows the patient to respond. If something works for even one patient, then it is not a failure but a success. Yet the statistical approach to clinical trials means we declare the trial a failure. That was NOT my approach 40+ years ago, and it should not be the case now. Somehow we seem to reject success, small as it may be, rather than ask why.

The Nature article continues:

Vincent Miller, a former MSKCC oncologist, agrees that views about outliers are changing and thinks that many more such individuals might be found. Any oncologist has a handful of patients in whom cancer just melts away with no obvious explanation, says Miller, who is chief medical officer of Foundation Medicine in Cambridge, Massachusetts, a company that performs genomic analysis of samples from people with cancer. In January, the pharmaceutical company Roche, based in Basel, Switzerland, bought a majority stake in Foundation Medicine, which is also involved in the ERI.

 Yes, physicians must learn to think differently. They must go beyond answering what and how, diagnosis and treatment, and start asking why. We now have means and methods to assist in attaining the answer, they are tools from systems identification and analysis.

Finally the article states:

For research on outliers to be of greatest help, the outlier cases must be rigorously selected. Only then can the analysis deliver sound results despite the fact that it remains a profile of only one person, says Friend. Taylor agrees, pointing out that molecular analysis of tumours from patients is increasingly possible and that there is growing acceptance of studying outlier patients. “Nevertheless,” he says, “it requires that we stay focused on exploring the most significant outlier responses to ensure the greatest return for patients.”

 Yes selection helps but we must also use verifiable models of the disease or the putative curative process. If we have some immune response technique, then perhaps it is not a PD-1 problem, but some receptor we do not know yet. Find it, work into the shadows, and assume that it is there and then go looking.

Tuesday, April 14, 2015

Free Range Kids

Tom Sawyer and Huck Finn were a prototype free range child. Whether down the Mississippi or convincing others to do their work, it was a process of learning and development. In the present day one gathers that even walking home from school becomes the business of the state. As Cato notes:

On Sunday afternoon Montgomery County, Maryland police and Child Protective Services seized the free-range ...v children, 10 year old ... and 6 year old ..., after their parents, .. and her husband .., had again let them play by themselves at a park in Silver Spring, just outside D.C

Now back some sixty plus years walking to school or anywhere in New York was de rigeur. In fact when I was I believe 9, I set out on my bike, across State Island, then across the Goethals Bridget, up Route 1 and 9 to Newark Airport. Doing that a few time got me to know the pilots. Then on board an Eastern shuttle, a Constellation, and well, today we would have dozens of folks under some legal mess.

Adventures are part of childhood. Understanding risks, and understanding the world come hand in hand. Government nanny states destroy the fundamentals of individualism and imprint stateism. Free Range children are individuals in search of adventure. We need more of them.

Foreign Policy and the Church

Foreign Policy and treaty negotiations is really complex. In my experience back in the 1970s working on the Comprehensive Test Ban Treaty with the then Soviets I learned that nothing is necessarily as it appears to be. Later while having one of my companies in Russia I was able to add some dimensions to that complexity. Now add to that the Iranian situation, I also had some folks there as well before the revolution, I could see that nothing is really what it may appear to be.

The main interests should be the security of US interests and furthermore a stable world situation is good for all. But we now have many wild cards. Iran is one and unfortunately so is Russia. China has its own games to play and it is not clear that having an unstable Middle East is good or bad for them.

Now add to the mix the US Bishops who for reasons known only to them have written Congress asking approval of a phantom deal. Nothing is in writing, and in fact what was oral was denied by the other side. But the Bishops write:

Despite the challenges, it is vital to continue to foster an environment in which all parties can build mutual confidence and trust in order to work towards a final accord that enhances peace. For this reason, our Committee continues to oppose Congressional efforts that seek to undermine the negotiation process or make a responsible multi-party agreement more difficult to achieve and implement. The alternative to an agreement leads toward armed conflict, an outcome of profound concern to the Church. We welcome the most recent step the United States and its international partners have taken with Iran and encourage our nation to continue down this path. Now is the time for dialogue and building bridges which foster peace and greater understanding. We urge Congress to support these efforts.

Nice but  I recall the days of Soviet nuclear threats and plans such as RISOP 9B, a total devastation of humanity by some insane nuclear power. As I had said in the late 1970s regarding the USSR and its positioning, one must be vary careful who to trust, even more so, trust but verify is perhaps not enough.

The old MAD, mutual assured destruction, plan of Kahn and the others in the 1960s made sense only if the other side wanted to survive. If on the other hand the other side is seeking total destruction as some religious salvation, then one may face a true dilemma. From Xerxes onwards we have been in a push and shove with Persia. Now add a religious element and it makes it ever so more threatening. This is not the distribution of loaves to the poor. This is a matter of the survival of civilization.

The End of Social Security and Medicare

One of the potential Presidential contenders has proposed both an increase in the age of both Social Security and Medicare and an elimination of any Social Security is perchance you were somewhat successful in life, no where near the top 1%, well below that.

NJBIZ states:

On Social Security, the potential 2016 Republican presidential candidate proposed gradually raising the national retirement age to 69, hiking the early retirement age to 64 and imposing income caps on payments. Under ...s plan, future retirees making $80,000 annually in income exclusive of Social Security will see benefits gradually phased out and those making in excess of $200,000 annually will see them eliminated entirely. “I’m suggesting that Americans pay into this system throughout the course of their life knowing that it will be there if they need it to support them. So that seniors will not grow old in back-breaking poverty,” ... said in prepared remarks distributed by his Leadership Matters for America PAC. “But if you are fortunate enough not to need it, you will have paid into a system that will continue to help Americans who need it most. That is what we have always done for each other through private charity and good government. This is fair and it is what we must continue to do by changing Social Security.”

That's right, you pay into this plan and if you were successful you get nothing, zip, da nada, zero, zilch, whatever. Thus if one follows the rule the year you sell your home, the profit becomes income and as a result of the ACA you are taxed 3% for Medicare and this new plan then makes certain your SSI is terminated! Wow.

I would vote for Elizabeth Warren who seems to be well to the right of this erstwhile candidate!

What's Up Watson?

I am always amazed when massive companies make monumental announcements about some new thing. I recall back when IBM tried to get into the satellite data business with SBS. Tons of money spent with a management who really did not understand the technology. Then they tries on line services with Trintex with almost the same cast of carriers, and the list goes on. Gerstner seemed to have a focus by bringing them to the world of professional services, giving their customers what they wanted. All too often telling customers what they should have has not been an IBM forte.

Now comes Watson and Medicine. I would like them to consider a recent NEJM case D is for Delay. I like this one because it exemplifies the current practice of medicine. Simply a patient who has taken poor care of himself enters a hospital after many prior admissions with a list of complaints. Then off they go looking for the zebras only to find that he has a niacin deficiency. Not that the professionals did anything wrong, it was just a messy case. There were many shadows. How would a Watson handle this?

Becker's states:

1. IBM introduced a new healthcare unit, IBM Watson Health, which will use cognitive computing to advance innovation using the volume of personal data that is created everyday. The health unit will be headquartered in the Boston area.
2. The company is also establishing the Watson Health Cloud, a secure and open platform for physicians, researchers, insurers and other healthcare companies to access individualized insights and a holistic image of what can affect people's health.
3. To help support IBM Watson's foray into health IT, the company is collaborating with Apple, Johnson & Johnson and Medtronic to create new offerings that leverage information collected from health, medical and fitness devices.
4. With Apple, IBM will provide the new Watson Health Clod as a secure platform and analytics offering for Apple's HealthKit and ResearchKit. IBM will de-identify and store health data in the cloud to foster an "open ecosystem environment" that also offers researchers and developers to utilize IBM's data mining and predictive analytics capabilities.
5. Johnson & Johnson and IBM will collaborate to create intelligent coaching systems regarding preoperative and postoperative patient care for procedures including joint replacement and spinal surgery. The new solutions will utilize Waton's cognitive capabilities and access Watson Health Cloud's data. Additionally, J&J plans to launch health apps focused on chronic conditions.
6. Leveraging insights from Watson Health Cloud, Medtronic and IBM plan to develop personalized care management solutions for people with diabetes. The solutions will gather and analyze patient information from Medtronic devices, such as glucose monitors and insulin pumps, and provide personalized management strategies to patients and their providers.

Now that is a great deal of investment and involvement in a market rant with regulation.  I am reminded of many a physicians difficulties dealing with the "shadows", namely symptoms that may lead anywhere but with no clear path. A recent example was that of an individual with intermittent head pain, somewhat localized, and not controlled. The age was an issue and thus one looked after vasculitis, lesions, strokes, trigeminal neuralgia, and the list goes on. And yes even dental issues, with three different dentists. Lots of suggestions, down the trail of differential diagnosis but to no avail.

Then the patient just gave up, went to an oral surgeon and said to take out the damn wisdom tooth. Well, guess what, the root had wrapped around the trigenimanl branch and could not be seen, and after surgery, problem solved. Try that one Watson, it was the patient who found the solution!

Sunday, April 12, 2015

“You didn’t build that”

Boudreaux at George Mason has a bit of a sparkling post on the left wing's current stupidity on “you didn’t build that” stuff. It is akin to the "privilege" non-sense that they spout. What Boudreaux seems to miss is my personal example of building a company in 20 countries, outside of the US. Do I thank Vladimir Putin for my Russian operations? Frankly yes, in a strange way. Now in Czech Republic, who do I thank there, well frankly my Czech partners who believed in me and trusted what we did and worked their hearts out!

Did Senator Warren and the US help at all? Frankly the success was despite the US, because locals had seen the arrogance of the AT&T's and the US public companies, what I gave them was self ownership, not vassalage.

Thanks for nothing may be my mantra here. It was the FCC and many other US entities that stood in the way. It was Russian, Czech, Austrian, Polish, Slovak, Bulgarian, Hungarian, Thai, Korean, etc creativity that made it work. Thus Boudreaux should consider those of us who set out with a credit card and some local contacts and created something extra the US. Frankly there is only one country more complicated and Government controlled to work in, Greece.

No, I didn't build that, we built it! Yes it included the Russians, one of the best of partners.

Friday, April 10, 2015

There Once Was a Time When People Did Something

I read an MIT press release article which stated:

As director of the MIT Mediated Matters group,  .... explores “material ecology” — the practice of integrating design principles inspired by nature into digital fabrication. In her TED presentation, ... debuted a wearable digestive system that could be worn by future inhabitants of Jupiter’s moons. Powered by photosynthesis, the system is designed to digest matter, absorb nutrients, and expel waste. “Think of it not as evolution by natural selection but evolution by natural design,” suggested .....

Just think of what your alumni donations are going for, "poop" on Jupiter! I spent my day trying to clarify melanoma pathways and means to attack them to see if there was a way to reduce the suffering to those inflicted. I guess being on Jupiter the UV rays will be lower and the risk likewise, so perhaps I was wasting my time.

One really cannot make this stuff up. It is generational, give them one of those mikes that looks like a skin lesion and put them on a stage, and they act...not create...who will be left to build real things I wonder.

Thursday, April 9, 2015

Coming Up Short?

Frankly I could not resist this one. In NEJM of all places there is an article purportedly showing that short people have greater risk of heart attacks.

The conclusion is:

There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.)

Now several observations:

 1. The number of authors almost exceed the number of patient samples. Just kidding but there appears to be several dozen authors. This is an ever evolving trend, at some point the list of authors may eventually exceed the length of the paper.

2. The result may be interesting but it is not prognostic or diagnostic. Also there is not much we can do about being short. Then again look at Napoleon.

3. This is a British funded project, wonder of NIH would do the same here.

4. Obesity is a much more significant risk factor for which we can really do something. Why even do this study and why in NEJM?

Every once in a while it is worth looking at the other side of the weighty research.

Wednesday, April 8, 2015

Post Docs: A Career Choice?

In the current issue of Nature there is a superb discussion of the post-doc phenomenon. Simply stated, there has been an explosion in post-docs, even in such applied fields as engineering. Frankly give the Silicon Valley world etc one wonders why there is even a post doc in an engineering school, they should be out earning a living doing engineering. Engineers with PhDs are trained to do engineering, that ultimately means doing something to make something, not research for the sake of research.

How did this come about? Simple, the Government and its funding mandates. Now we see the big name labs. Got to any campus and you will not see say the "Antibody Lab" or the "Electromagnetic Lab". You now see the "Joe Smith Lab" in the "Sally Jones Center" of the "Fred Brown School" of the XYZ University. Everything has a name of some person; researcher of funder. Strange, imaging the MIT Rad Lab being the "Harry Hopkins Lab" for example.

The Government now funds well funded labs which are few but they get bigger by getting more low cost researchers. The researchers in question are post-docs, paid less than most of the cleaning help, and working three times as hard. They somehow "believe" that they are doing productive research and as a result will eventually get their own chance. My comment is; read whose name is on the Lab Door, the Building Entry etc.

Secondly the Government now also wants both multidisciplinary and multi-institutional funded research. Thus we have papers with fifty authors. That means that tenure opportunities get muddled, one may ask what "you" really did.

As Nature states:

These highly skilled scientists are a major engine driving scientific research, yet they are often poorly rewarded and have no way to progress in academia. The number of postdocs in science has ballooned: in the United States alone, it jumped by 150% between 2000 and 2012. But the number of tenured and other full-time faculty positions has plateaued and, in some places, it is even shrinking . Many postdocs move on to fulfilling careers elsewhere, but those who want to continue in research can find themselves thwarted. They end up trapped as ‘permadocs’: doing multiple postdoc terms, staying in these positions for many years and, in a small but significant proportion, never leaving them. Of the more than 40,000 US postdocs in 2013, almost 4,000 had been so for more than 6 years

 Is there a solution to such a problem? I believe there is. One saw it after WW 2 with such Labs as Lincoln, Hopkins, JPL, and the like. They were non-departmental laboratories doing research and were off campus. One was an employee of the Lab and one could advance. One had the dignity of being employed, compensated on industry par and yet "affiliated" with a first class institution.

Perhaps getting the post-docs, who are professionals, into a professional environment is a reasonable alternative. The current system is unsustainable.

Sunday, April 5, 2015

Employment Numbers April 2015

The employment numbers are always akin to reading tea leaves. We examine them again here are are always reminded of the Romer guesses of January 2009. Those prognostications seemed never to even come close to reality, but after all it was from an economist.
The above is the data we have from March 2015. A slow growth but still not return to full employment from what we had in 2005.

The above shows employment and population growth which somehow we never see discussed in the presentation of the numbers. Much of the population growth remain unemployed which is still a major concern.
This is the most worrisome. Namely the workforce participation rates. It has sunken and seems never even to try to return. Of all the numbers this is the long term concern. First because we do not get taxes from these people and second because they have a social cost.
Finally this is the articulation of that measure. The red line depicts the difference between jobs created and new people in the workforce. I has drop dramatically in this quarter. That does not bode well for the year.

Prostate Cancer Metastasis

Cancer metastasis has generally considered that cancer is clonal, namely it starts with a single cell and that cell starts a process that laves its local environment and through a process of continual change manages to metastasize throughout the body. We examine a recent paper by Gundem et al which examines the metastatic behavior of prostate cancer and as a result of GWAS they show that it can be poly clonal and continually changing.

We the return to a paper we prepared well over a year ago regarding Cancer Dynamics and show that in that paper we had not only anticipated this but more. Although that paper does not yet treat epigenetic factors, nor does Gundem et al, it can be readily modified to do so.

The results have some significant consequences. Mostly is the treatment of such cancers. Namely if we have polyclonal metastatic propagation then pathway methods may have to be multifaceted, namely dealing with the multiplicity of differing pathway anomalies.

Recent Research

In a recent paper by Gundem et al the authors describe an analysis they have performed on metastatic prostate cancer cells in a group of patients. Their general conclusions seem to be two fold; (i) that there are certain metastases that are polyclonal, namely there are multiple cells initiating the process, (ii) that the progression of the metastases is complex with ever increasing changes in genetic expression.

Gundem et al state:

By plotting the cancer cell fractions of mutations from pairs of samples, we determined the clonal relationship between the constituent subclones and found evidence for polyclonal seeding of metastases,

This is a powerful observation. Their approach was in simple terms to do genome wide analysis and doing so over a set of metastatic locations. Then using a clustering method they could determine with reasonable accuracy the clonal and polyclonal results as well as the progression. Specifically:

Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer ... We identified a set of high-confidence substitutions, insertions/deletions, genomic rearrangements and copy number changes present in each tumour sample….

They conclude as follows:

Our analyses allow us to view with unprecedented clarity the genomic evolution of metastatic prostate cancer, from initial tumorigenesis through the acquisition of metastatic potential to the development of castration resistance. A picture emerges of a diaspora of tumour cells, sharing a common heritage, spreading from one site to another, while retaining the genetic imprint of their ancestors. After a long period of development before the most recent complete selective sweep, metastasis usually occurs in the form of spread between distant sites, rather than as separate waves of invasion directly from the primary tumour. This observation supports the ‘seed and soil’ hypothesis in which rare subclones develop metastatic potential within the primary tumour, rather than the theory that metastatic potential is a property of the primary tumour as a whole. Transit of cells from one host site to another is relatively common, either as monoclonal metastasis-to-metastasis seeding or as polyclonal seeding. Clonal diversification occurs within the constraining necessity to bypass ADT, driving distinct subclones towards a convergent path of therapeutic resistance. However, the resulting resistant subclones are not constrained to a single host site. Rather, a picture emerges of multiple related tumour clones competing for dominance across the entirety of the host.

The challenge in the above analysis is to note as we had in Cancer Dynamics that as the genetic profile of the cancer cells change, there is a survival of the fittest occurring, namely a certain cell tries to dominate, and there is also the issue of stem cells and stem cell control and proliferation. The issue is one of understanding just what constitutes metastatic growth. Clearly the cells are in a steady state of genetic change, altering in a survival based manner to dominate.

Figures 3 and 4 of the paper are the most significant. In Figure 3 we see depicted the evolving changes in gene structure in clonal and polyclonal mets. In Figure 4 we see the same in a Nuclear Medicine scan showing the mets. We show that Figure from Gundem et al below since it is of such significance.

The above shows the mutations or gene expression alterations and as they progress. This is a complex but quite important description of the process. (NOTE: The above is Figure 3 as modified from Gundem et al, Nature, 2015).

As Shen states in a Nature commentary on the Gundem et al paper:

Next-generation DNA sequencing technologies have made it apparent that primary tumours are not clonal (consisting of a single population of genetically identical cells). Instead, they are composed of subclones, subpopulations of genetically identical cells that can be distinguished from other subclones by the mutations they harbour. Such subclones compete for dominance during cancer progression, and drug treatment can lead to formerly minor tumour subclones becoming dominant if they are resistant to treatment. Thus, clonal evolution shapes the properties of tumours and can explain their plasticity in response to therapy. Until now, however, clonal evolution has not been explored in detail in the context of metastasis…..Taken together, the current studies might explain why, given the prevalence of circulating tumour cells in patients with solid tumours, successful metastasis is relatively rare — metastasis may be facilitated by seeding by cell clusters containing cooperating clones with distinct properties. If so, it is attractive to speculate that disseminated single cells could remain dormant until reawakened by interaction with a cooperative metastatic cell arriving at the same secondary site. Such a model has the potential to revise our conception of the properties of tumour-initiating cells, as well the metastatic niche, and may have implications for therapeutic strategies. For example, understanding the signalling pathways that mediate such clonal cooperativity may lead to effective therapies using drugs that target these pathways.  

The signally pathway issue is a complex one especially since we know that suppressing one pathway may excite another. The problem will be targeting all of the cells.

Previous Work

We have considered this before when we wrote a detailed paper in 2013 on Cancer Dynamics. In our analysis we examined a set of continually changing cancer cells, and we further assumed that any cell may have changed to a cancer cell. We then further assumed a diffusion/flow model for the propagation of those cells and at the same time assumed a continual process of genetic change. We also assumed that we could find an organ specific environment which may be most favorable to growth via ligand/receptor combinations. Finally we also assumed that cell to cell communications could facilitate the process. We did not consider at that time any epigenetic factors.

Namely when considering cancer propagation we must consider the genes, the pathways and the whole body. It is a complex process which we had developed in the referred to paper.

  The equations for the propagation over space and time for a specific type of cell containing a specific genetic makeup has been shown below. Here n(x,t) is the concentration or density of a specific cell type, let us assume a malignant prostate cancer cell, and with a specific genetic profile. If we examine the Gundem paper we see that this is what they are looking at from the perspective of a GWAS study of metastatic PCa. However we have already developed a model and further we had developed an identification process to provide the drivers in the model itself. Note below that the general equation is a diffusion plus flow model, diffusion due to evolving concentrations and flow due to movement within the body itself such a blood flow dissemination.

 The L value are operators and the others are constants determined in the paper. Our model then allows for polyclonal development and moreover a complex cell to cell growth stimulus as well


Now Cancer UK comments on this work as follows[1]:

The team has already revealed a huge amount of genetic diversity between cancer cells taken from different sites within each man’s prostate…this new study shows that, despite the diversity, prostate cancer cells that break free from the tumour and spread share common genetic faults unique to the individual patient.

Study author … said: “We gained a much broader view of prostate cancer by studying both the original cancer and the cells that had spread to other parts of the body in these men. And we found that all of the cells that had broken free shared a common ancestor cell in the prostate. The common faults we found in each man could potentially offer new targets for treatment. But we found that, once cancer cells have spread, they continue to evolve genetically, so choosing the most effective treatments will remain a key challenge.”

“The diversity we’ve found suggests multiple biopsies might be needed to identify the ‘trunk’ of the cancer’s tree of mutations – we need treatments that target these core weaknesses to destroy all cancer cells in a clean sweep, rather than trimming the branches. We must also study more patients to learn how to apply these findings to develop more personalised treatments for people with the disease.”

“In the phylogenetic trees that our data have produced, we see that most of the oncogenic mutations are shared clonally by all the tumour sites in each patient. This common genetic heritage is a potential achilles heel of the metastases, however, many of these shared mutations are in tumour suppressor genes and our approach to therapeutically targeting these needs to be prioritised.

“It takes a while before a tumour develops the ability to metastasise but once it does the patient’s prognosis changes significantly. We have to zoom in on this crucial junction and gather more data on the impact different therapies have on prostate cancer’s evolution and spread.”

Moreover there are many more concerns. For example:

1. Epigenetic Factors: The analysis does not appear to deal with the epigenetic factor such as methylation, miRNAs, lncRNAs and the like. We clearly know that they also have significant impact.

2. Stem Cell Issues: There is also the issue of the stem cell. Is there such a factor included in or includable in this analysis?

3. Pathway Modifying Therapeutics: As discussed by one of the commentators the therapeutic implications are evident but in our opinion not at all clear.

4. Prognosis Analysis: Here we have a significant concern. Many prognostic tests have been developed. However if we examine for one gene profile are we missing many others due to poor sampling. Namely one type of polyclonal cells may be in the profile match but another may not. How, then does this observation impact the many PCa prognostic profiles out today?


1.                  Gundem et al, The evolutionary history of lethal metastatic prostate cancer, Nature 2015. doi:10.1038/nature14347
2.                  McGarty, T., Cancer Cell Dynamics, Telmarc, TWP January 2014,
3.                  Shen, M., The complex seeds of metastasis, Nature, 2015, doi:10.1038/nature14377

Thursday, April 2, 2015

New CRISPR Vehicles

In Nature we have an article demonstrating a variant on the now standard CRISPR cas9 vehicle. As they first note:

Type II CRISPR-Cas systems require only two main components for eukaryotic genome editing: a Cas9 enzyme, and a chimaeric sgRNAderived from the CRISPR RNA (crRNA) and the noncoding trans-activating crRNA (tracrRNA). Analysis of over 600 Cas9 orthologues shows that these enzymes are clustered into two length groups with characteristic protein sizes of approximately 1,350 and 1,000 amino acid residues, respectively

Thus the classic source is  Streptococcus pyogenes and as noted:

The RNA-guided endonuclease Cas9 has emerged as a versatile genome-editing platform. However, the size of the commonly used Cas9 from Streptococcus pyogenes (SpCas9) limits its utility for basic research and therapeutic applications that use the highly versatile adeno-associated virus (AAV) delivery vehicle. 

But the same vehicle with a Cas9 is in many other bacteria and they note:

 Here, we characterize six smaller Cas9 orthologues and show that Cas9 from Staphylococcus aureus (SaCas9) can edit the genome with efficiencies similar to those of SpCas9, while being more than 1 kilobase shorter. We packaged SaCas9 and its single guide RNA expression cassette into a single AAV vector and targeted the cholesterol regulatory gene Pcsk9 in the mouse liver.

Thus we have a variant but the same functionality. They conclude regarding in vivo changes:

Here, we develop a small and efficient Cas9 from S. aureus for in vivo genome editing. The results of these experiments highlight the power of using comparative genomic analysis in expanding the CRISPR-Cas9 toolbox. Identification of new Cas9 orthologues, in addition to structure-guided engineering, could yield a repertoire of Cas9 variants with expanded capabilities and minimized molecular weight, for nucleic acid manipulation to further advance genome and epigenome engineering. ...We examined these sites in liver tissue transduced by AAV-SaCas9 and did not observe any indel formation within the detection limits of in vitro BLESS and targeted deep sequencing. Importantly, the off-target sites identified in vitro might differ from those in vivo, which need to be further evaluated by the applications of BLESS or other unbiased techniques such as those published during the revision of this work. Finally, we did not observe any overt signs of acute toxicity in mice at one to four weeks after virus administration. ....these findings suggest that in vivo genome editing using SaCas9 has the potential to be highly efficient and specific.

 This an an interesting next step. 

California and Water

In a recent post Mankiw has proposed using pricing as a control mechanism for water in California. Generally that is a sensible and correct way to manage the problem. However, from many trips to out of the way places in California I believe that there are many unintended consequences that drive the problem. Let me explain two:

1. Most of California is desert. San Diego has but a few inches or rain a year and people there want lawns etc. The climate supports at best a few cacti and scorpions. Not much more. Then add humans and you get a mess.

2. Almonds. Now a few years back I spent time with almond growers. Almonds are those nuts that airlines used to serve in Business Class before dinner. I do not know anyone who really eats almonds. But USDA subsidizes almond growing in the I5 valley, thousands of acres and billions of gallons of water. These almonds must be stored somewhare, I do not know where. Yet USDA policies mandate what is grown and who gets paid. Thus in some perverse manner the USDA policy and payments mandate excess agriculture and thus massive amounts of water usage.

3. Lawns: People moved from the East to California and wanted it to look the same. New York gets 45" of rain a year and it has winters and dormant plants. LA gets less than half that and no winter. Thus trees and lawns are fed by water to do what they would not do normally. The result is the sucking of water from where it was naturally for eons.

Thus charging more may help but perhaps examining the underlying Government rules and realigning them would help. Try peanuts and get rid of almonds!

Wednesday, April 1, 2015

CRISPR Cas9 Toolbox

We have published a DRAFT paper in CRISPR Cas9 as a tool for genomic engineering. This is an attempt to outline the essential elements in its operations. This enzyme/RNA complex is quite powerful yet has concerns regarding its less than beneficial applications.

MOOC Assessments

The assessments of MOOCs has been a spotty effort yet MIT has published some detail in 2014 and it has been announced by MIT that they will be publishing an up to date assessment. We highlight and comment on what is made available:

First, while many MOOC creators and providers have increased access to learning opportunities, those who are accessing MOOCs are disproportionately those who already have college and graduate degrees. 

 That is interesting in a way. First I have observed many via Discussion groups who have little or no experience. Further those who may have limited in the fields in which they are trying to gain knowledge. Perhaps a better sampling at more detailed levels is necessary. For example how many PhDs in what fields, and when it was obtained. I suspect that many spend some time getting some knowledge but often drop out because of time spent and also because of poor teaching techniques.

Second, if improving online and on-campus learning is a priority, then “the flow of pedagogical innovations needs to be formalized,” Chuang says. For example, many of the MOOCs in the study used innovations from their campus counterparts, like physics assessments from MIT and close-reading practices from Harvard’s classics courses....The real potential is in the fostering of feedback loops between the two realms,” Chuang says. “In particular, the high number of teacher participants signals great potential for impact beyond Harvard and MIT, especially if deliberate steps could be taken to share best practices...

 Indeed feedback would be useful. For example, a classic presentation is Lander's. Others could learn from video style. Others could also learn from presentation style. An interesting analysis would be a critique of the instructors and then cross tabbing the instructor with the demographics of the ones doing the critique. There is a great deal of improvement and learning in style of presentation. The instructor who just "presents" as the always do and then assumes that a video of it is sufficient is truly making a mistake. The Lander presentation is wonderful because on the one hand he acknowledges and works with the students in class and also acknowledges the person online, albeit displaced in space and time. In many ways the MOOCs must learn the way early television did, there must be producers and directors, and style is as important as content.

Also the feedback is critical. Now, frankly, there is none. Discussion groups may be there but the TA or equivalent is monitoring at best. Focus Groups would be essential, online focus groups with the instructors would be a substantial benefit. This is especially true when one has such a diverse group of participants.

Third, advancing research through MOOCs may require a more nuanced definition of audience. Much of the research to date has done little to differentiate among the diverse participants in these free, self-paced learning environments.

 Marketing was always a part of television. They needed advertisers and the advertisers really wanted to know what the audience watched and wanted. Perhaps that element is necessary. Market segmentation has always been a part of the research and that segmentation should be part of what the MOOCs do. If all else fails listen to the customer!