Engineers versus Economists

There is a piece today in the Harvard Crimson lauding the Economics course and in effect its instructor. However there is also a comment placed by someone, I really have no idea as to who this person is, but it is on point. The Harvard Economics Professor professes belief that if CO2 is harmful the solution is an economic one, the Pigou Tax. While we believe that such a tax has merit in certain areas we do not believe it functions here. The person commenting is spot on.

As the individual states:

By way of Example: ... is sold on the carbon tax.  "The essential problem of climate change, scientists  tell us, is that humans are emitting too much carbon into the atmosphere, which tends to raise world temperatures. Emitting carbon is what economists call a “negative externality”— an adverse side effect of certain market activities on bystanders." The ability to apply Pigouvian taxes is so addictive that he rather skimmed over the points that the earth hasn't warmed in the last decade, the AGW computer models predict nothing even approaching reality, and nobody really knows how much CO2 in the atmosphere is the best number.

The real issue is that if this is a real problem, and I remain a bit unconvinced having done a bit of work here a few decades ago, then one should seek for a real solution, and that is engineering and not economics. Try to find alternative energy sources, alternative power systems, and let economics play that hand not the hand of taxing which seems to be the standard practice of the left. The terrifying fact is that this Professor is allegedly the economics adviser to one of the dominant Republican Presidential candidates. One should remember that when that candidate was in Massachusetts there was another Professor, this time from MIT, who advised him on health care. Perhaps candidates should be wary of academics, especially economists who have never created a single job, outside of Government work that is.

How Dumb is Google

Now there has been a great flap about Google and its new "privacy" policy. Now privacy can be expected if one just takes oneself from society, the old right to be left alone. Well not anymore with the health care law but that was a tale for another day. No, I am talking about Google gathering info and pushing it on other web sites to continue the sales process. So for example I needed a new sump pump a few months ago. I did a search, and then on almost every web site or blog there were the ads for the same pump. Again and again.

But stupid Google, I bought the stupid thing already, so stop it. I am not buying a dozen sump pumps, there on my weather site, on blogs, etc. I also looked at a jacket, then whamo, it appears on the weather site again, and other sites I see for the first time. Ah, the joy of cookies. But poor Google, I did not like the jacket so I never bought it and in addition I got to hate it more each time they targeted an ad.

Now for searching, they must think I have a lapsing memory. If I ask for something the first ten references are mine! I know what I wrote, I want to see more. So off to Bing.

You see, Google wants to please me, or so they say, and the result is that they are like a nagging mother, eat your peas!

One must be careful, for a one trick pony they must not annoy the audience with the trick by spitting in the face of those paying. Remember if all else fails listen to the customer.

What is in a Word

It is interesting to see economists talk about taxes in the private equity world. Perhaps they will pose theories of astrophysics next.

The problem is that "it all depends". In the simplistic sense if a company pays a dividend and it is taxed at 15% and the company pays 35% tax then indeed the total was taxed at 50%. The problem is no private equity works quite that way. Especially for the general partner types who have really little at risk.

For example, consider a general partner who puts nothing at risk, and a company which has massive tax loss carry forwards which is sold for say $100 million. The funds get distributed to say the PE company. It is a capital gain at 15% depending on what is returned. No 35% was ever paid, just a greater fool found to buy it. That by the way is the PE game. But without the PE player the company may most likely have collapsed.

So how should we view this? Well it is really very complicated and all these economists are apparently clueless finding one scenario after another to justify their conclusion, ad hoc propiter hoc.

How should we look at it? Well each case is separate. It is not simple and it cannot be simply explained by some smart Prof trying to make their point. Details count, welcome to the real world folks!

Words Mean Something, Sometimes

Level Playing Field, Fairness, Quality, Ethics, Integrity etc. What do they mean?

From Through the Looking Glass we have:

Humpty Dumpty took the book, and looked at it carefully. 'That seems to be done right--' he began.

'You're holding it upside down!' Alice interrupted.

'To be sure I was!' Humpty Dumpty said gaily, as she turned it round for him. 'I thought it looked a little queer. As I was saying, that SEEMS to be done right--though I haven't time to look it over

thoroughly just now--and that shows that there are three hundred and sixty-four days when you might get un-birthday presents--'

'Certainly,' said Alice.

'And only ONE for birthday presents, you know. There's glory for you!'

'I don't know what you mean by "glory,"' Alice said.

Humpty Dumpty smiled contemptuously. 'Of course you don't-- till I tell you. I meant "there's a nice knock-down argument for you!"'

'But "glory" doesn't mean "a nice knock-down argument,"' Alice objected.

'When I use a word,' Humpty Dumpty said in rather a scornful tone, 'it means just what I choose it to mean--neither more nor less.'

'The question is,' said Alice, 'whether you CAN make words mean so many different things.'

'The question is,' said Humpty Dumpty, 'which is to be master-- that's all.'

Alice was too much puzzled to say anything, so after a minute Humpty Dumpty began again.

'They've a temper, some of them-- particularly verbs, they're the proudest--adjectives you can

do anything with, but not verbs--however,  I can manage the whole lot of them! Impenetrability!

 That's what I say!'

'Would you tell me, please,' said Alice 'what that means?'

'Now you talk like a reasonable child,' said Humpty Dumpty, looking very much pleased. 'I meant by "impenetrability" that we've had enough of that subject, and it would be just as well if you'd mention what you mean to do next, as I suppose you don't mean to stop here all the rest of your life.'

'That's a great deal to make one word mean,' Alice said in a thoughtful tone.

'When I make a word do a lot of work like that,' said Humpty Dumpty, 'I always pay it extra.'

That is what they mean. Welcome to Washington!

Taxing The Wrong Thing

They are at it again, and they call themselves Republicans. They being in the NY Times, and they state:


Consider the tax on gasoline. Driving your car is associated with various adverse side effects, which economists call externalities. These include traffic congestion, accidents, local pollution and global climate change. If the tax on gasoline were higher, people would alter their behavior to drive less. They would be more likely to take public transportation, use car pools or live closer to work. The incentives they face when deciding how much to drive would more closely match the true social costs and benefits. Economists who have added up all the externalities associated with driving conclude that a tax exceeding $2 a gallon makes sense. That would provide substantial revenue that could be used to reduce other taxes. By taxing bad things more, we could tax good things less. 

Let us again reconsider:

1. The middle and lower classes drive to work, not for pleasure. They often have no alternative. They may live in New Hampshire and drive to Cambridge. They drive say 100 miles a day at 20 mpg for 5 gallons. This Professor then will tax them an additional $10 per day or $3000 per year! That is an additional tax. If we look at China we see the opposite. You see the poor guy in New Hampshire has no other realistic alternative, to get a home he must drive that distance and he must work long hours and he must have a car. In NYC you pay $25 in tolls, $50 for parking and then gas! However you can take public transport for a mere $30 plus a day. Only the self proclaimed elite would deny that person such access. It is a cost of production hidden in a reduction of compensation for the employee. Not everyone can own a mansion on Brattle Street.

2. Live closer to work, like say Newton, or perhaps Lincoln, and at what price? Perhaps South Boston. Somehow the upper reaches have lost touch with those who clean the streets.

3. Now as for bad things, one can truly argue as to these alleged costs. Congestion is due often to timing, accidents were pandemic in Boston because of the insurance system and yes drivers, and local pollution is dominated by other factors such as factories, and as for global warming, well I will not go there.

4. Real bad things are obesity. Just look at the recent JAMA articles. Currently 15% of annual health care costs growing at 15-18% pa, well outgrowing all others. That is a measurable and manageable problem, tax pounds or calories. Not gasoline.

However and whatever one should think through the details. Facts count, even in economics.

Somehow Missing the Point

In the NY Times there is a long piece on Apple and manufacturing in the US. Also why China is getting so much of the work. Now this is hardly new. When I was at Warner in the early 80s we had Pioneer in Japan manufacture our cable converters. Quality, price and performance. That was not even new then. We saw disk drives being made in Asia, then in Mexico, business finds the lowest cost place to do this with possibly a quid pro quo. That gives the American consumer the best price and they then buy more which means ultimately higher profits. It is called business.

Now that is not the way the current administration sees it. The most absurd quote I have ever seen is:

“Companies once felt an obligation to support American workers, even when it wasn’t the best financial choice,” said Betsey Stevenson, the chief economist at the Labor Department until last September. “That’s disappeared. Profits and efficiency have trumped generosity.” 

Nonsense. Total and complete and utter nonsense. One must look to the credentials of the source to see why.

Under our legal system, and under our economic system, at least as understood before the current administration, Companies have a fiduciary duty to make money, and the way they manufacture is a reflection of this. In my opinion the very statement is a demonstration of a gross disconnect with reality, but a reason why we are in the mess we are in. If those in Government believe that a business has a first duty to support American workers over growth and profit then they are just wrong, business does not work that way.

I moved a company from New Jersey to Prague because of lower costs, reliable electrical supply, and good workers. The burdens of the US overhead, poor infrastructure and high taxes, plus regulation on everything, made moving the only alternative. Perhaps Washington should get some people with some real experience.

Career Planning

In 1959 when I was trying to determine what I wanted to do, I dismissed being a pure mathematician, most likely a great idea since I may be good on the applied side the pure stuff can become a bore and I was ultimately not good at it. But what I did was to sit down with the Sunday NY Times and look at the job section and determined that EE and Chem E was where the action was at. It was a rational decision process. There never was a question as to "what would I like to be when I grew up", it was "where are the jobs and how do I get there".

Now I read a report in C&EN, the American Chemical Society news organ and it appears that chemists are falling off a cliff. They state:

The U.S. chemical industry lost 15,000 jobs in 2008, down 1.7% from the end of 2007. That decline, to 847,000 jobs, was almost as bad as the 1.9% decline in jobs for the overall economy, which shed 2.6 million workers. Economists expect the situation to get worse in 2009.

They continue:

Chemical employment peaked at 1.1 million jobs in 1981, and has trended downward since, Swift notes. He attributes the decline to productivity gains, outsourcing, and jobs lost to overseas competitors. The one bright spot had been the pharmaceutical industry, a statistical subset of chemicals, which saw steady job increases over the decade through the end of 2007. However, available data show that pharmaceutical makers cut about 4,700 jobs, down 1.6%, through the end of November 2008.

So from 1981 to now the jobs for chemists has dropped from 1.1 million to 840K, almost 300K jobs while the economy has been growing more than two fold despite the recent downturn. That means this is not a field one wants to enter.

Thus one wonders why anyone would go into chemistry. It is not that chemists are not valuable, they are indeed, but unlike EEs who have a strong entrepreneurial streak the chemists has gone to industry, academia or the government. What is amazing is the growing demand in biotech and especially now in informatics on biotech systems, and the lack of flow in that direction. It is not that the chemist training is out of touch, it may be more mindset rather than any competence deficiency.

The bottom line is now that students are determining what to major in, art history, social work, chemist, why not just look where the future jobs are, for today there is a wealth of information to help you, more than just the Sunday Times. I believe that this idea of doing what you want to do may be at the heart of many of our job problems. There are many in the younger generation who feel they are empowered to get a job they want, not what the economy needs or can provide. Carriage makers were put out by the auto, and auto factory workers by robots and off shore production. Nothing remains constant, one must assess the flow of the economy and then be prepared to change as it does. Creative Destruction is real, it is ongoing, and it is at the heart of a free economy. Trying to prevent it is akin to trying to hold back a broken dam with one's hands.

Pathways, Crosstalk and Melanoma

NEJM has published an interesting article on what can be called cross talk amongst pathways. As is well known now the BRAF mutation found in certain melanomas can be somewhat controlled via the use of vemurafenib. However and possibly surprisingly there is an increase in other cancers.

The authors conclude:

Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions.

Pathways have cross talk, and when one pulls one string another may also be pulled. The authors further note:

The t→a transversion at position 1799 of BRAF (BRAF V600E) is present in approximately 50% of patients with metastatic melanoma.1,2 BRAF V600E induces constitutive signaling through the mitogen-activated protein kinase (MAPK) pathway, stimulating cancer-cell proliferation and survival.2 The clinical development of inhibitors of oncogenic BRAF, termed type I BRAF inhibitors, which block the active conformation of the BRAF kinase, has led to a high rate of objective tumor responses and improvement in overall survival, as compared with standard  chemotherapy.3-5 However, nonmelanoma skin cancers — well-differentiated cutaneous  squamous-cell carcinomas and keratoacanthomas — have developed in approximately 15 to 30% of  patients treated with type I BRAF inhibitors such as vemurafenib and dabrafenib.

This may open a door to several new approaches. First understanding pathways better and deducing the effects on blocking one of the paths, and multi-drug analysis.

A Deal Is Not a Deal Until the Money is in the Bank

I should not be amazed but the commentary by self proclaimed "experts" is amazing. Some writer for the Washington Post under the headline "Bain's Dishonest Deals" and becomes "When Romney ran Bain Capital, his word was not his bond", states:

Here’s how it worked. Private-equity firms are always eager to find companies to buy, allowing them to invest chunks of the billions of dollars entrusted to them and from which they earn hundreds of millions in fees. One ready source of these businesses is Wall Street bankers hired to sell companies through private auctions. The good news is that when a banker puts together a detailed selling memorandum about a company, chances are very high that company will be sold; the bad news is that these private auctions tend to be very competitive, and the winning bidder, by definition, is most often the one willing to pay the most. By paying the highest price, you win the company, but you also may reduce the returns you can generate for your investors.

But for anyone who has ever really done a deal we all know that "A deal is not a deal until the money is in the bank, for a week!"  Deal get renegotiated all the time, the fail to reach completion for hundreds of reasons, agreements are abandoned for frustration of purpose, material adverse changes occur and so forth.

One always finds problems, and often they are fatal. Thus the assumption that a deal is done on a hand shake is naive at best. Negotiations are just that, negotiations. In some places a contract is considered just the start of negotiations, I had found that out the hard way in Asia.

Thus as my daughter tells her fourth grade class, "A deal is not a deal ...", even they know, and these children may be better prepared to deal with reality than some opinion writers. But after all it is just the Post!

Genes, Genes, Too Many Genes

The Scientist has written about a simple same day, $1,000, full genome sequencing system becoming available at about $750,000 per machine. The question is what will you do with all the data.

We know of say a few thousand germ line genes which may relate to their potential for disorders, BRCA and HOX B 13 being two we have discussed recently.

The challenge will be to develop sophisticated testing for prognostic profiles. But this may be a chicken and egg issue. It does however present a threat to the gene testing companies out there, because now the value added is analyzing the complex genetic structure and saying something about it.

The article gives costs as:

The Illumina HiSeq 2500 will allow researchers to generate 120 gigabases of data—40X coverage, or repeated sequencing, of a single 3 gigabase human genome—in 27 hours, the company announced. It is a significant increase in speed over the previous model, the popular HiSeq2000 machine, which sequences up to 5 human genomes (about 600 gigabases of data) simultaneously over 10 days. But the snappy new model comes with a hefty price tag of $740,000, Forbes reported.

The Life Technologies Ion Proton Sequencer, on the other hand, is priced significantly lower at $149,000 and will sequence an entire human genome with 20 to 30X coverage in a day for just $1,000, said company spokesperson Mauricio Minotta. Illumina declined to disclose a cost per genome for the HiSeq 2500.

Thus low costs may turn this into a PC type revolution allowing many people to develop APPS!

What Is Wrong With Academia

There is an article in Forbes by some Professor somewhere wherein he articulates his philosophy. Having taught at MIT, Columbia, George Washington, Polytechnic University and a few other places, and now taking Organic Chemistry, for the second time, at County College of Morris, a community college, I bring a somewhat different perspective. Also as one who has created a few jobs in 20 countries, I have a modicum of knowledge concerning people, some that work and some that don't.

Let me summarize this dictum from on high just a a bit:

First, I do not “take off” points. You earn them. The difference is not merely rhetorical, nor is it trivial. In other words, you start with zero points and earn your way to a grade.

Yes I would agree with that. But there are faculty who do "take off", for spelling for example, on a technical exam. I never did but I experience it now. Thus the issue is what is the content of the course and what is not. Some folks just cannot spell, I am one, perhaps it is the family dyslexia or not. But the function of a good faculty member is to also seek to understand why the student got something wrong. I did that frequently, from an undiscovered illness to severe family problems. Arrogant faculty are the bane of Academia.

 Second, this means that the burden of proof is on you to demonstrate that you have mastered the material. It is not on me to demonstrate that you have not. My assumption at the beginning of each class is that you know somewhere between nothing and very little about basic economics unless you were lucky enough to have an exceptional high school economics course. Otherwise, why are you here? You might say that the course is a prerequisite for other things you want to do, but if that it is the case and you know the material, you’re more than welcome to simply show up for the exams, ace them, and be on your way.

 This is difficult sometimes. Perhaps my exams were too difficult, were wrong, etc. I remember that in December 1970 I gave out a take home exam that required that the students prove A > B. Well oops, I typed the inequality the wrong way, and the exam went out just before Christmas holiday and due Jan 3rd. Funny, all but one student "proved" the inequality the wrong way, one student just said I got the inequality wrong. He got an A the others I gave a pass. I apologized to all. Yet there were a few nooses prepared.

Now as to the assumption that the student comes to class ignorant, well I NEVER assumed that at MIT in EECS. One never knew. In my current Organic class the Instructor assumes we are all ignorant, well there are three MDs and a few other who have come back to refresh. As a Professor I never assumed anything other than we were peers in learning. The game was that the students would always try to find where I made an error, and my counter was to know it so well I never needed a note and I finished my 50 min lecture on the second.

Otherwise, why are you here?

Good question, but perhaps one should not be so presumptive, perhaps you should find out why the student is there. That one phrase is what prompted this response.

Finally, I’m here to be a mentor and instructor. This means that our relationship differs from the relationships that you have with your friends and family. Please don’t infer from this that I don’t care about you, because I do. A lot. I want to see you make good choices. I want to see you understand basic economics because I hope it will rock your world as it continues to rock mine and because the human consequences of lousy economic policy are enormous. That said, you should never take grades personally. 

One of the things I learned early on at MIT once I started as an Instructor in 1969 was the care and attention to understanding each student. We were not necessarily friends, but one of my students became my best man, another an investor, and the list goes on, but that we understood why the student got what they did. We would list every grade for every student and then with the Teaching Assistants go through them one by one during the grading session. Each student grade was personally looked at in light of everything we knew. In a way we were more than a friend or family, we became forgiving of situations, and understanding of what they accomplished. We  "knew" each student as a person, not just a grade.

Did I still have them come and ask why, yes, but when I explained why, which I owed them, then they became true believers also.

Thus I have reason to differ with the good professor, hopefully for good reason.

Happy Friday 13th

It is Friday the 13th, and especially January and Friday. Watch for cracks in the sidewalk!

Homeobox and Prostate Cancer

The Homeobox and its related genes have played an interesting but challenging role in developmental biology and now in cancer pathways. The genes related to this 180 base pair section of DNA are the genes which control the development or organs and the time at which these development occur. Furthermore the structure of this gene collection is preserved across an dramatically large number of species, the human included. Thus it was interesting to see a paper in NEJM discussing the mutation of a specific Homeobox gene, HOX B 13, as relates to prostate cancer.

In the recent NEJM paper by Ewing et al the conclusion of the authors is stated as:

The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer.

Now this appears as a significant new finding and we would like to examine this a bit. The HOX genes are quite unique in their functioning. They are built about a core Homeobox segment, which is preserved across chromosomes and species, and is hen connected with variable regions on differing chromosomes to generate some 4X13 possible genes (HOX (A,B,C,D) (1…13)). These genes are core to the morphological and embryological development of a broad range of species.

Now HOX B 13 is one of many Homeobox based genes. These genes are distributed across 4 chromosomes and have a fixed part called the homeobox part and a variable part. In a sense it is similar to the fixed and variable regions we see in the immune system. The gene is created as below:

Homeobox genes are clustered in the chromosomes and are expressed in the body in the same order in which they occur in the chromosomal DNA. The HOX genes, the concatenation of the respective Homeobox and its variable part are named by chromosome location as A, B, C, D, and then by number 1 through 13 at present. The number reflects what makes the Homeobox genes of interest, namely the genes control the development of the embryos, namely they control what cells do as a part of the development of an entity. The process goes from head to tail, and the numbering goes from the earliest or anterior to the latest or posterior elements in the development process. Thus HOX A 1 relates to an early development and HOX B 13 would refer to a later development of the embryo. The sequencing is shown below.

 Retinoic acid activates the Homeobox genes sequentially in development.

Now the Ewing study examined patients with specific changes:

Given the consistent evidence of prostate-cancer linkage to 17q21-22 markers in our multiplex families with hereditary prostate cancer, we designed a targeted sequencing strategy to analyze 2009 exons of 202 genes contained in the most likely genomic interval defined by our fine-mapping studies. … Probands from four families were observed to have the same nonsynonymous mutation in HOXB13, a change of adenosine for guanine (transition, c.251G→A) in the second position of codon 84 (GGA→GAA), resulting in a nonconservative substitution of glutamic acid for glycine (G84E)

The question is perhaps where does the term Homeobox come from. From Gehring and Hiromi we have the definition:

The term "homeosis" (originally spelled "homoeosis") was proposed by Bateson (8) to describe the transformation of one structure of the body into the homologous structure of another body segment. Homeotic transformation can result, for example, from abnormal regeneration of amputated structures (epigenetically) or from germ-line mutations

Thus the Homeobox genes are key to the development of embryos. They also lead to the discussions

Scott states:

Homeotic genes control cell fates during the development of all animals, as was first revealed by studies of the Drosophila homeotic gene complexes … Many of these genes contain a homeobox, a 180 bp sequence of DNA which encodes an evolutionarily conserved DNA binding domain, the homeodomain … A plethora of mammalian homeobox genes have been reported, among which 38 are located in four clusters. A new nomenclature for the mammalian Hox genes, approved … The new names take advantage of the elegant arrangement of the genes to provide a logical nomenclature system rather than the names given when the genes were discovered. The new system is initially designed only for vertebrate genes, although it is to be hoped that similar systems will be useful, and adopted, for other animals. In order to preserve as much clarity in the literature as possible, it has been agreed by a large number of workers in the field and by the nomenclature committees that homeobox genes not located within the Hox complexes should not be given names containing the word 'Hox'. 

There are four clusters of Hox genes … now to be known as A, B, C, and D. Based on sequence similarity the genes can be sorted into 13 'paralog' groups, each group having, in most cases, a representative in each complex. The order of paralogs along the chromosome is preserved in the four complexes. The genes within a complex are transcribed in the same direction and are numbered according to their paralog group from 1 at the 3' end to 13 at the 5' end. In several cases a representative of a paralog group is absent from a complex, in which case the corresponding gene number is omitted …

HOX genes are key to the development of the embryo, it creates the head to tail and sets up the control of the development of the organs. As Lohmann and McGinnis report:

Hox genes play a major role in the morphological diversification of the anteroposterior body axis of animal embryos by switching the fates of segments between alternative developmental pathways . In their role of controlling segment diversity, Hox proteins are responsible for many different morphological structures and cell types within a given segment. But it is still largely a mystery how a single Hox gene can determine a morphological trait at a specific location within a segment, and why that trait does not appear elsewhere in the same segment or in other segments.

… morphological and transcriptional responses to Hox genes can be highly local, sometimes only in a single cell, allowing one Hox gene to control a cavalcade of different traits within one segment and between different segments, depending on the information present. Another important lesson that we can learn from the papers of Rozowski and Akam and Brodu et al. is that, during development, Hox genes act at all levels in the developmental hierarchy. 

If they act very far down in the hierarchy, as in these two cases, then the output is subtle, with Hox genes acting as cell-type switches rather than as major developmental pathway switches. If they are acting (apparently) far up in the hierarchy, then the fate switch is more dramatic, which is most beautifully demonstrated in the famous four-winged fly. But even at this general level, context is still crucial: loss of Ubx in the haltere does not generate a leg, but a wing.

There are many debates still raging regarding Homeobox and Robert presents an interesting report summarizing some of them. His paper is worth the reading. It builds on the evo-devo issue, evolution and development, the ontogeny recapitulates ontogeny. Namely if the same HOX genes are present across many species, and preserved in structure, then is there really an underlying commonality across species.

We provide the details on the various HOX genes below. They all have the form as we had shown earlier and they are all numbered in a sequence consistent with what we have shown earlier.

 Note all HOX B are from Chromosome 17. In particular HOX B 13 is 17q21-22 region ( see http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&dopt=default&rn=1&list_uids=10481 )

We now show from Kim et al the development of the pathway for the HOX B 13 that we have been discussing. It inhibits CDK and that in turn inhibits the activation via E2F of the cell cycle. It is the inhibition of the cell cycle that is of the most concern.

 As Kim et al demonstrate the HOX B 13 blocks p21 and in turn CDK2 keeping the RB pathway from entering the cell into cell cycle reproduction. They state:

Taken together, the results of this study demonstrated the presence of a novel pathway that helps understand androgen-independent survival of prostate cancer cells. These findings suggest that upregulation of HOXB13 is associated with an additive growth advantage of prostate cancer cells in the absence of or low androgen concentrations, by the regulation of p21-mediated E2F signaling.

Now Ewing at al conclude as follows:

In summary, we have used linkage analysis in combination with targeted massively parallel sequencing to identify a recurrent mutation in HOXB13 that is associated with early-onset and hereditary prostate cancer. From a clinical perspective, testing for germline mutations in BRCA1/2 is recommended in some families, since mutations in these breast-cancer–susceptibility genes are associated with elevations in the risk of prostate cancer, particularly for BRCA2 However, neither of these genes has been shown to contribute to hereditary prostate cancer. HOXB13 G84E is associated with a significantly increased risk of hereditary prostate cancer. 

This work suggests that future DNA sequencing studies using next-generation technology and study populations enriched for genetic influence (as evidenced by an early age at onset and positive family history) may identify additional rare variants that will contribute to familial clustering of prostate cancer. Although HOXB13 mutations will be identified in a minority of men with prostate cancer, rare genetic lesions can identify pathways that are found to be abnormal in more common, sporadic cases.

This leaves one to somewhat guess as to how prevalent this mutation is. The rough numbers given in the Weing paper is about 1.5%. It also begs the question of why as a mutation which is apparently inherited the progression of the cancer is so slow. Ewing at al show that the odds ration can be as high as 32.5:1 when the mutation is present. The age at diagnosis is lower with an odds ratio of 2:1 but with the problem one sees in pathway control one wonders why the cancer does not appear much earlier as seen in BRCA.

Thus this paper raises several questions:

1. The Homeobox mutation is a predisposing genetic risk factor. If tested and found positive for the factor what should be done next. Mastectomy is often what BRCA patients undergo, does this mean prophylactic prostatectomy?

2. The pathway seems to be somewhat understood. The E2F family control the pathway and HOX B 13 controls that pathway. It blocks it to some degree. What can happen to HOX B 13 to cause this change in non-mutated individuals.

3. Can the disease propensity be regulated by genetic pathway control, is this possible as an alternative prophylactic measure.

4. What other pathway elements should be considered. Specifically, if we have a mutation on HOX B 13 then must we have other genes also altered to up surge cell replication. If so which ones. Is HOX B 13 merely a predisposing element. Also is there a HOX B 13 type change in other PCa?

5. Most importantly, why does it take so long for the cancer to develop, are there precursor hits somewhere and this this just eliminates other hits?

Ewing et al have an interesting slide showing normal versus HOX B 13 prostate cells and we replicate it below from the paper.

In the top slide we see well-structured prostate cells with basal and luminal layers not showing and aberrant growth, no PIN. In the slide below from a HOX B 13 patient with a mutation of the form: GGA to GAA Glycine Glutamic acid (See Ewing et al).

References:

1.   Ewing, C., et al, Germline Mutations in HOX B 13 and Prostate Cancer Risk, NEJM, Jan 2012 V 366 N 2 pp 141-149.
2. Jung, C., et al, HOX B 13 Homeodomain Protein Suppresses the Growth of Prostate Cancer, Can Res 2004 V 64 pp 3046-3051.
3. Kim Y, et al, HOX B 13 promotes Androgen Independent Growth, Molecular Cancer, 2010 Vol 9-124.
4.   Lohman, I., W. McGinnis, HOX Genes, Current Biology, 2002, V 12 pp 514-516.
5.   Robert, J., Interpreting the Homeobox; Metaphors of Gene Action and Activation in Development and Evolution, Evo & Dev, 2001 V 3:4 pp 287-295.
6.   Schwartz, J., Homeobox Genes, Fossils, and the Origin of the Species, Anat Rec 1999 V 257 pp 15-31.
7.     Scott, M., A Rational Nomenclature for Vertebrate Homeobox, Nu Acid Res 1993 V 21 No 8 pp 1687-1688.
8.  Gehring, W., Y. Hiromi, Homeotic Genes and the Homeobox, Ann Rev Gen 1986 V 20 pp 147-173.

Health Care Costs

Yesterday the NY Times Editorial praised the low rate of health care costs this year.

They stated:

The data show that total health care spending by public and private sources, including households, rose by 3.8 percent in 2009 and 3.9 percent in 2010. Spending slowed for hospital care, physician services, nursing homes, home care and especially prescription drugs, as consumers increasingly chose cheaper generics. Growth in spending by both Medicare and Medicaid actually slowed in 2010 compared with 2009, even though the federal government ramped up its share of the nation’s total health care spending while private businesses reduced their share. 

 Yet today HHS touts its use of the new act to dampen excessive Health Care costs. It states:

Health insurance premium increases in five states have been deemed “unreasonable” by the U.S. Department of Health and Human Services, ...After independent expert review, HHS determined that Trustmark Life Insurance Company has proposed unreasonable health insurance premium increases in five states—Alabama, Arizona, Pennsylvania, Virginia, and Wyoming.  The excessive rate hikes would affect nearly 10,000 residents across these five states. In these five states, Trustmark has raised rates by 13 percent.  For small businesses in Alabama and  Arizona, when combined with other rate hikes made over the last 12 months, rates have increased by 27.2 percent and 18.1 percent, respectively. In addition to the review of rate increases, many states have the authority to reject unreasonable premium increases.  Since the passage of the health care reform law, the number of states with this authority increased from 30 to 37, with several states extending existing “prior authority” to new markets. Examples of how states have used this authority include:

• In New Mexico, the state insurance division denied a request from Presbyterian Healthcare for a 9.7 percent rate hike, lowering it to 4.7 percent;
• In Connecticut, the state stopped Anthem Blue Cross Blue Shield, the state’s largest insurer, from hiking rates by a proposed 12.9 percent, instead limiting it to a 3.9 percent increase;
• In Oregon, the state denied a proposed 22.1 percent rate hike by Regence, limiting it to 12.8 percent.
• In New York, the state denied rate increases from Emblem, Oxford, and Aetna that averaged 12.7 percent, instead holding them to an 8.2 percent increase.
• In Rhode Island, the state denied rate hikes from United Healthcare of New England ranging from 18 to 20.1 percent, instead seeing them cut to 9.6 to 10.6 percent.
• In Pennsylvania, the state held Highmark to rate hikes ranging from 4.9 to 8.3 percent, down from 9.9 percent.

So which of the two comments is true. And a better question is why the difference.

Free Will, Predestination, Augustine and Obesity

Augustine of Hippo in his attack on Pelagius, the British monk who alleged that man has free will and thus can do good acts and achieve salvation, restructured the concept of free will and introduced the concept of grace and perforce led the way to predestination. Simply man cannot achieve salvation unless God grants him individually grace and then his salvation is preordained since he cannot do anything which would then mitigate that end result.

What is the will and what do we mean by free will? Both have significant philosophical and theological facets and understandings.

Augustine fought Pelagius and to do so he had need of clarifying two elements; free will and grace. Now the will was well discussed in philosophical literature with Aristotle expanding upon it in Nicomachean Ethics. The concept of grace as a facilitator was a residual from Paul and his writings. The interaction of the two became a major factor in Augustine’s thought.

Let me first begin with the concept of free will, or the will. In broad terms the will is the human element which allows the individual to make a choice, and in an sense as used by Augustine a moral choice. In contrast the ideas of Schopenhauer allows the will to be expansive and become an integral part of every human action. We will not look at the conjoined will of Schopenhauer but the more dualist will of Augustine. In our particular example the will to say no to a piece of cake or a serving of French fries.

Stump makes the following assessments regarding free will and Augustine (Stump, p 124, Augustine, Cambridge) which I shall paraphrase somewhat. She argues that there are at least two schools of thought regarding free will and they can be characterized as follows:

Compatibilism: The world can be causally determined yet a person can commit free acts with full moral responsibility.

Libertarianism: Consists of two claims:

(i) a person acts with free will only if the act is not causally determined by some exogenous agent, or:

(ii) a person acts with free will only if the person could have acted otherwise.

Stump adds a third form of a “Modified Libertarianism”, it is defined as:

(iii) A person acts with free will only if their intellect and will are the sole determinants of the act.

In all of these cases the will is in many ways a dualistic forced, within the person, whereby the act they take is one amongst many yet this force allows the person to make a choice. The choice presented for selection one could argue have relatively equal compelling arguments, a possibly poor term but reasonable under the selection of having the intellect involved, for their selection.

Thus one may ask does a person who is “addicted” to say heroin have the free will to say no and eliminate that dependence? This would be problematic under many of the above definitions. However we know by experience that people can and do choose to stop drug use, tobacco use, even caffeine use. People stop consuming certain types of food, by choice. Thus is this not a clear example of free will. Yet we know that physiologically the drug addict finds the cessation a painful experience, the cessation of eating can also be physically painful and socially difficult.

Thus free will is part of the equation for Augustine. The other element is Grace, the “gift of God” to assist the will and the intellect in making the correct moral choice. Grace is needed according to Augustine because without it man is all too often prone to make the bad choice, read it evil or sinful. One must wonder whether this would apply to all things that the Augustinian will would be involved in, say eating a date versus a fig. But it is the need for this Grace that allows the will to act in a correct and moral manner. If God gives you grace then you can act accordingly, if God withholds grace then you cannot do the right thing, and for Augustine that would mean ever do the right thing.

Thus in the Augustine context one has a duality of body and will, a will which is fee, and a need for Grace to facilitate right choices. For Pelagius man could perforce of his fee will make those choices, and in a natural extension it would be via that free will per say that many passes or fails the acid test of living a moral life. To Augustine man needed Grace and thus God, by himself, with free will, he was still lost. Thus the Augustinian view of Grace is that being God given you need it to do truly good works, devoid of such good works one is lost, and God grants grace on his own choices and thus one has the Augustinian basis for predestination, and the resultant Calvinistic views.

Now to obesity and genes. Instead of Grace we have genes, and instead of the free will to do right and wrong in a simply moral manner we have the will, assumed to be free, to eat or not eat. The current world view by many is in a sense an Augustinian extension of predestination, if you have the right genes you are fine and if not it is not your fault, the genes made you do it. Namely the strength of will alone is useless.

We need a Pelagius, we need the anti-Augustine to state that indeed man has free will, and that it is the will, in what may be a dualist manner, which can save us, genes notwithstanding. Pelagius may have had a point, albeit pushed to an extreme at the time. Pelagius recognized the power of the will for good and evil, the power of the will to select between what is good for one, albeit uncomfortable, and what is bad. Choosing is what makes humans somewhat unique. Understanding that was Pelagius’ contribution. We should dismiss the Augustinian crutch of some exogenous factor which lets our free will take a back seat.

Frustration of Purpose and the EPA

The NY Times has posted an article indicating that the EPA is fining oil companies for failure to include a bio fuel in gasoline when the bio fuel does not exist.

The article states:

When the companies that supply motor fuel close the books on 2011, they will pay about $6.8 million in penalties to the Treasury because they failed to mix a special type of biofuel into their gasoline and diesel as required by law. But there was none to be had. Outside a handful of laboratories and workshops, the ingredient, cellulosic biofuel, does not exist. 

 One wonders why the citizens have no faith or trust in their Government. Under standard contract law a contract is deemed null and void if there is a frustration of purpose, namely if for reasons beyond the control of the parties the agreement under the contract cannot be met. Classic English Law holds this principle to be a key element. One could see it evolving even from the Magna Carta and even Salic Law! But not in Washington.

Just wait until these characters get a hold of health care! Perhaps one should just die early and avoid the mess.

Proton Therapy

A recent posting commented on the Emanuel piece which somewhat denounced the efficacy of the proton means of therapy for prostate cancer. Although proton therapy is less damaging than classic X ray therapy it has been problematic in prostate cancer, for a variety of reasons.

A recent study by Hoppe et al concludes:

Although the benefits to patients of reduced radiation-dose exposure with PT are quite obvious, concerns still exist regarding whether these dosimetric benefits are cost-effective. In a study by Konski et al,... the cost-effectiveness of PT was compared to that of IMRT with the assumption that PT could deliver a 10-Gy higher dose than IMRT, resulting in a 10% improvement in 5-year BFFS compared  with IMRT. However, despite the improvement in BFFS, the resulting cost of PT for a 60-year-old man  was $65,000, compared with $40,000 for IMRT, which would result in a cost-effectiveness of $56,000  per quality-adjusted life year (QALY). When compared to the commonly accepted standard of $50,000  per QALY, the value for PT indicated that it was not cost-effective. Although this study reaches some intriguing conclusions, the results are based on models and do not take into consideration a number of critical factors. First, Peeters et al... have predicted that PT may allow for hypofractionation, which would reduce the treatment costs of this therapy. Studies currently investigating hypofractionation with PT are ongoing at both Loma Linda University and the University of Florida Proton Therapy Institute. Second, a reduction in significant rectal and urinary toxicity afforded by PT will have a positive impact on overall costs of care in prostate cancer patients. Finally, the dose escalation and dose intensification via hypofractionation permitted by PT may result in increased cure rates, particularly in intermediate and high-risk prostate cancer patients,... which may also translate into reduced costs of care.

Namely it is a costly procedure. This has always been a concern. Proton machines are tens of millions, approaching in excess of 100 million, and thus are often prohibitive. They work well for certain childhood malignancies and in uveal melanomas of the eye. However there are still major clinical concerns.

The clinical conclusions of the paper state:

With a minimum follow-up of 2 years, the grade > 3 GU toxicity rate was 1.9% and the grade > 3 GI toxicity rate was <0.5%. Two studies out of Japan have also published early outcomes for PT for prostate cancer. Mayahara et al  reported on 287 patients treated to 74 CGE with 190- to 230-MeV protons using opposed lateral fields; the rate of grade > 3 GU toxicity in this study was 1%, and the rate of grade > 3 GI toxicity was 0%. Nihei et al[30] reported on a multi-institutional phase II study from Japan in which 74 CGE was delivered in 37 fractions in 151 patients. With a median follow-up of 43 months, only 1% of patients developed grade > 3 GU toxicity, and 0% developed late grade > 3 GI toxicity. These studies, which are reported in the Table, confirm the safety of PT for prostate cancer over the first 4 years following treatment; however, longer follow-up is needed to confirm the low rate of late toxicity and long-term efficacy of the treatment (and the high rate of BFFS). Interestingly, Massachusetts General Hospital and Loma Linda University have reported a smaller series of patients treated with PT alone to 82 CGE, with a slightly higher rate of toxicity than observed in the University of Florida Proton Therapy Institute series with the same dose and dose per fraction.

It appears as if there is still an open issue here. More clinical trials are needed. Yet the clinical progress seems to be moving forward.

College, For Whom?

There has been a great deal of discussion regarding the usefulness of college. Now from a personal perspective let me comment:

In June 1971 I got awarded a few doctoral degrees, in real stuff. However in the spring of 1971, for example, there were no job interviews at MIT and Harvard Med were sending grads still into the military. It was Vietnam. Furthermore there was no money for anything near research and Nixon just took us off the gold standard. So today is wonderful compared to June 1971.

But alas I had a plan B. I was thanks to my father an electrician. I could work with my hands, install circuits, switches, motors, etc. I had a skill and moreover my father now had a company that did electrical work on explosive sites, BU Gas and Exxon. Thus I had a job! Not in EE, medical research, just working with my hands, and yes head, and with a salary.

But upon telling the MIT faculty of my career movement I found myself back on campus teaching, I believe at $8,000 pa! I was making at the time, I believe, $50 per hour on my non-union electrician job. But back I went, remembering that if all else failed I could go back again, thanks to dad. The two rules he instilled in me were: (i) always have your own company and (ii) always have a skill which can be monetized, namely people are willing to pay you because you can do something of value. Plumbing, carpentry, electrician.

Thus this need for college for everyone is a total waste. There are more than 10 times the number of PhDs at MIT now than when I was there. Are there 10Xs the number of competent people, doubtful but there are clearly NOT 10X the number of jobs. And not one electrician in the bunch!

Business and Economics

Krugman has written a piece asking why anyone would think a person who is successful in business has any skills as an economist.

He pontificates as usual:

For the fact is that running a business is nothing at all like making macro policy. The key point about macroeconomics is the pervasiveness of feedback loops due to the fact that workers are also consumers. No business sells a large fraction of its output to its own workers; even very small countries sell around two-thirds of their output to themselves, because that much is non-tradable services.

For years I had a sign:

"If all else fails listen to the customer!"

Talk of feedback! No matter how good you are customers must buy the stuff you make. As a business man you see the effects of your policy real time and you understand feedback better than any economist!

Ever hear of a Board dumping an economist! Just look at the overload at universities and the government. Just look at Romer, she stated that the Stimulus would do X and it did A. Fired, not really, writes on economic policy at the times.

I am a Darwinian and Spenserian at heart, survival of the fittest. Business does that, it tests the market and ones ability to respond to it. Now I do not include bankers here, in fact after the past few years I exclude them. The only thing that can get a banker fired it appears is saying the wrong thing about the administration, or really being away from the switch.

Krugman does not seem to understand business. It is not some Asmovian world, it is a market, a place where one can succeed or fail, depending on both your performance and the response to the market in toto.

Would I want some MIT Aero Prof who may understand the theory at the stick of a supersonic fighter in a dog fight, not likely, unless they flew for the Israeli Air Force perhaps, and I have met a few, but at least the Aero Prof knows how to design a plane. It appears that there is no such ability or consensus amongst economists. Thus the Krugman argument is without any merit. As usual it appears.

The Cost of the Academy

TNR has an article suggesting ways to reduce the burden of college costs.

In the midst of the article the author states:

This is essentially the story of public higher education over the last thirty years. Diplomas are, of course, not apples. But they are more like apples than colleges like to pretend. In particular, highly-profitable lower division courses in common subjects like Economics, Calculus, and Psychology have similar curricula at most colleges and rely on many of the same nationally-marketed textbooks. They are often taught by people with no formal training in teaching. These courses are, in the education context, commodities.

 The last statement is typical of the union backing left wing of the Democrat Party. Namely that only by being trained to "teach", aka being in a union, can you teach. Nonsense! Universities often use their best faculty to teach the under graduates, at least the top universities. Yes they have TAs and Instructors who are PhD candidates but hospitals also have residents.

A hospital resident is a licensed physician, albeit one still in training, who is legally allowed by the state to practice, not by a union. A TA may very well be a PhD candidate, one who has a Master's Degree and has passed doctoral Board exams demonstrating exceptional competence.

Now a union high school teacher has allegedly learned teaching methods but may very well be clueless as to the subject matter. And worse is in a union. Imagine Harvard becoming GM! It may also go bankrupt. In more ways than one.

The Rejection of the Will and the Creation of the Victim

The victim, the creation of our current society, is the person who through their own overt actions has found themselves in a bad situation and demands the rest of us bail them out. Drugs, bad school choices, homes they cannot afford, and of course obesity.

The NY Times epitomizes this today with an article on childhood surgery for obesity. They state:

There was no question, at 5-foot-1 and more than 250 pounds, she was overweight. But she resisted, saying she could diet. “I’ll lose weight,” (the patient) assured her doctor. (The doctor) said, prophetically, “It’s not your fault, but you’re not going to be able to do it.”Along with the obesity epidemic in America has come an explosion in weight-loss surgery, with about 220,000 operations a year — a sevenfold leap in a decade, according to industry figures — costing more than $6 billion a year. 

The article continues:


The operation took about 25 minutes. Child Health Plus, a state insurance plan for low-income families, covered the $21,369 cost. Medicaid in almost every state and many private health plans now cover bariatric surgery, often more readily than diet or exercise plans. On many days, (the surgeon) performs three or four operations in a row. 

 The cost is not Medicaid, it is the taxpayer, that 50% of the working force who pays for the rest of the workers and those not working.

The above two statements; (i) it is not your fault, (ii) Medicaid pays ... $21,369, reflect the problem as it is posed. No responsibility and not understanding who really pays.

The irony is that in Mankiw's blog today he refers to his Pigou tax as as a way of saving lives with regard to drinking and driving. Yet a year ago he rejected the same out of hand regarding a carb type tax. Mankiw highlights:

A conservative estimate is that the federal tax reduced injury deaths by 4.7%, or almost 7,000, in 1991.

When the above highlights $6 B  in costs due to an ever increasing tax burden. One could argue about the analysis referred by Mankiw as possibly flawed, it regresses on the amount of alcohol consumed but there clearly are multiple other factors as well, but with obesity the number are clear. 

Obesity is the driving factor in health care costs. Stories as the above clearly demonstrate that we would rather pay exorbitant costs to solve it afterwards than prevent it. Here is a clear and direct case of a Pigou tax, one of the few I can believe in. Ironically the proponents of such taxes place them more freely on gasoline and alcohol,  ones where it in my opinion are much more specious.

Finally the success of this surgery is highly erratic. Oftentimes the patient regresses back to the original state, after all they were told it was not their fault and there is no disincentive to reduce caloric consumption.

Happy Birthday NEJM

The New England Journal of Medicine celebrates its 200th anniversary this year. It is in many ways a main stay of American Medicine, and also from time to time a sounding board for health care policy, for better or worse.

The above is a copy of the first article in that first issue from NEJM. It is interesting to think that heart problems were the first to be discussed.  Nabel and Braunwald have an interesting article detailing cardiology over this period. What is compelling about the article is Figure 1 which depicts an almost 80% reduction in heart death over this period. Yet the cost of achieving this has been substantial. In light of the current debates on health care costs one should look at this and consider progress versus costs.

As the authors state:

Until 1961, patients with acute myocardial infarction — if fortunate enough to survive until they reached a hospital — were placed in beds located throughout the hospital and far enough away from nurses’ stations that their rest would not be disturbed. Patients were commonly found dead in their  beds, presumably from a fatal tachyarrhythmia. Indeed, the risk of death occurring in the hospital was  approximately 30%. The development of the coronary care unit, which provided continuous monitoring  of the electrocardiogram, closed-chest cardiac resuscitation, and external defibrillation, reduced  in-hospital mortality by half among patients admitted with acute myocardial infarction.

Was it better in 1961, for the costs were lower, or are we better off today. I would argue the latter, but there are some who believe the costs are excessive, until perhaps they become that 30%.