Thursday, April 28, 2016

Department of Energy

Most people do not know that the largest portion of DoE's business is nuclear weapons. Somehow over the decades from Carter thru the current administration we have had Secretaries who at times were clueless as to their domain. Perhaps that has been planned, after all you can get a lot more done if your boss has no idea that you may even exist. But generally we do not appoint Secretary of Defense individuals who cannot distinguish a tank from an aircraft carrier. But well all too often have Sec DoE who would not know a MIRVed warhead from an electric car!

I just noted, perhaps with some humor, but also with possible abject terror, the Hill stating a potential DoE head. As The Hill states:

Trump said early in his campaign that he’d welcome the GOP’s 2008 vice presidential nominee into his administration — “I’d love that,” he said in July — and Palin wasted little time specifying the post she’d want. The former Alaska governor said she’d like to head the Energy Department — for the opportunity to dismantle it. “I think a lot about the Department of Energy, because energy is my baby — oil and gas and minerals, those things that God has dumped on this part of the Earth for mankind’s use instead of us relying on unfriendly foreign nations,” Palin told CNN last fall. “I’d get rid of [the DOE], and I’d let the states start having more control.”

This is concerning. You could get rid of the electric car project at DoE but what of those nukes! It is not as if the understanding of DoE is unknown by all, the Russians and the Chinese are very familiar with DoE weapons programs. Perhaps for once we could get a DoE head who knows something about its core business, the potential destruction of all life on the planet!

Sunday, April 24, 2016

Ginkgo Nuts, Biodiversity and Climate Change

Some twenty five or so years ago I got some ginkgo nuts from the New York Botanical Garden. I planted them and last year one of the trees, a female, was filled with nuts. Fantastic. The squirrels did not seem to have any interest, smelly seed coats, but well that was not the end. Come Spring, the coat had gone and the squirrels managed to consume every one! The ginkgo has managed to survive some 100 million plus years but it had not faced the squirrel.

Now as we go further north we see the grey squirrel also going there as the warming occurs and thus many flora that were dependent on small consumption by red squirrels will be under siege by grey ones. The issue of changing and complex biodiversity means that there will be challenges to flora and fauna.

I make this comment because I have read a paper by Dr. Victoria Karchenko at The Botanical Garden Institute in Vladivostok where she states:

Now the climate changes become more pronounced. This affects to biodiversity and distribution of plants. Therefore, we need to study of the biodiversity and trends distribution of plants in specific environments. In this connection is necessary to clarify real composition of species in the of regional floras potential of their variability of and disseminating. A pressing problem remains the creation of a unified database of the flora of Russia, which takes into account the data of regional studies.  Research program allows executing posed problems if it would coordinate with other botanical gardens. This program will allow revealing structural and functional adaptation of species to various environmental conditions. This will help create a basis for design ways to regulation the development of plants and biotops.

As I had indicated, the paper by Dr. Kharchenko presents a very compelling argument for the development of a detailed flora for Russia especially the Eastern parts. We have been using certain sentinel plants such as Hemerocallis which are native to this part of Russia to measure long term climate changes. It is essential to have a detailed data base not only of the flora per se but more importantly an understanding of their propagation status based upon the balance with pollinators as well as fauna which may consume the plants before they can complete their re population cycle. We have seen not only a shift in bloom time and divergence with pollinators but more importantly animal predators on plants growing in numbers. This is a critical study especially in this highly bio-diverse area.

Eastern Russia is an relatively unexplored treasure trove of biological species. Many of my Hemerocallis are from there and there are still new species of that genus being discovered. However there may have been a balance in biodiversity for millennium but as we see warming we would expect drastic changes. To understand the changes we need a baseline and the proposal to establish such a well defined baseline is essential. There clearly should be substantial support for this effort, since one would expect the time scale for change to be quite short.

Trusting the Kindness of Strangers

Silicon Valley gets stranger by the day. I recall my first start-up in the Fall of 1969. It was funded by EG&G whose main business at the time was photographing nuclear explosions. The company had a great idea, as many start ups do. In 1969 stores had credit cards but no computers and the printed every week a phone book size document containing all the bad cards in numerical order. When you wanted to charge something the cashier would first take your card and read through the book to see if it was a bad card. If not then you could charge.

Well these folks came up with the following idea. The could take the bad card numbers and put them on a 45 RPM record, and then when you came to the cashier they would type in the credit card number and if it was not bad the green light came on and if it were bad the red light lit. Now the 45 RPM was coded so that N grooves in were numbers n(N) which were in some range. This the unit knew if you entered a number it would be N grooves in so it dragged the record needle some N-M grooves and started reading the data until it went past your number. It was one of the first disk drives, but with a 45RPM record and dragging across grooves. Now the grooves would wear out but the solution was to coat the disk with some coating which allowed it to work for a couple of weeks. Great idea before any internet.

Well it worked for about a week. Then someone forgot to coat the records and Voila they all scratched out and so did the company. Details count. Lesson one.

Now in Scientific American there is a great piece on Theranos. The author notes:

Just a few weeks before regulators proposed banning Holmes and Theranos President Sunny Balwani from the blood-testing industry, the company tried to remedy this by bulking up its medical advisor board with well-qualified experts in chemistry, pathology and clinical chemistry. It’s hard to imagine these experts would have signed on amid all the bad publicity and allegations without demanding proof that the technology works, but who knows? It still remains possible that Theranos has discovered a breakthrough technology that can do hundreds of lab tests on a drop of fluid from a patient’s finger. But even if this increasingly unlikely prospect is a reality, Holmes' erstwhile acolytes need to remember the lessons learned from the pantheon of past pied pipers and summed up by statistician W. Edwards Deming:  In God we trust; all others must bring data.
 Now the lesson is that due diligence is essential, it means that you did enough work to determine if there are any fatal flaws. I have been through the process dozens of times. Often we find things. People have done it on my companies and I have done it on others. The first thing you must do is understand the validity of the offering. You must understand it. Second you must examine the team. In Silicon Valley having no experience is valued. I would not climb Mt Everest with a Guide who had never been outside of Florida! I want experience and I would due due diligence. Somehow major investors and major corporations just blew it. That may not be good for some careers but it is also not good for the industry.  However it may be great for the lawyers!

Wednesday, April 20, 2016

CRISPR Mushrooms!

As I watch my Hemerocallis slowly emerge from the ground and wonder what I could do if I let CRISPR techniques go wild I read today in Nature about the CRISPR mushroom.

They note:

The US Department of Agriculture (USDA) will not regulate a mushroom genetically modified with the gene-editing tool CRISPR–Cas9. The long-awaited decision means that the mushroom can be cultivated and sold without passing through the agency's regulatory process — making it the first CRISPR-edited organism to receive a green light from the US government. “The research community will be very happy with the news,” says Caixia Gao, a plant biologist at the Chinese Academy of Sciences’s Institute of Genetics and Developmental Biology in Beijing, who was not involved in developing the mushroom. “I am confident we'll see more gene-edited crops falling outside of regulatory authority.” Yinong Yang, a plant pathologist at Pennsylvania State University (Penn State) in University Park, engineered the common white button (Agaricus bisporus) mushroom to resist browning. The effect is achieved by targeting the family of genes that encodes polyphenol oxidase (PPO) — an enzyme that causes browning. By deleting just a handful of base pairs in the mushroom’s genome, Yang knocked out one of six PPO genes — reducing the enzyme’s activity by 30%.

 I wonder what I could do with flower colors!

Sunday, April 17, 2016

Cancer Stem Cells

I have been spending some time on examining the issue of the cancer stem cell concept again. The literature is expanding yet there seems to be no convergence or consensus. This brief set of quotes is from more than a dozen major sources and at best one may become further confused. Just thought this would be an interesting exercise.  

1   The Challenge 

 Definitions are important. In mathematics and law, the definition will determine the outcome. In engineering we define certain parameters and we design accordingly. If there is a concern, we spend a great deal of time on the definition. In cancer studies the term "cancer stem cell" has been introduced.

Definitions should be clear and they should be actionable. Namely the definition should present a way to ascertain through objective measures readily understood by someone trained in the science or art to determine if what is presented satisfies the definition. Namely we should with a good definition know if what we have is a cancer stem cell.

The results below are a sample of what seems to be definitions from the literature. Reading these one can readily see what the complexity is in understanding this topic.The descriptions are each from the source noted. 

2    Definitions 

Ailles, and Weissman: Cancer stem cells (CSCs) are cells that drive tumorigenesis, as well as giving rise to a large population of differentiated progeny that make up the bulk of the tumor, but that lack tumorigenic potential. CSCs have been identified in a variety of human tumors, as assayed by their ability to initiate tumor growth in immuno-compromised mice… In addition, specific signaling pathways play a functional role in CSC self-renewal and/or differentiation, and early studies indicate that CSCs are associated with a micro environmental niche… several important biological properties of CSCs: first, what is the cell of origin for a given tumor? Second, what are the signaling pathways that drive self-renewal and/or differentiation of CSCs? Third, are there molecules uniquely expressed on CSCs, regardless of whether they are functional, that will allow targeted therapies to be developed? Fourth, what are the mechanisms by which CSCs escape conventional therapies and can we defeat these mechanisms?

Burgess: Should stem mitotic activity become unregulated or uncontrolled, a tumorigenic and perhaps malignant phenotype may result hence the term cancer stem cell…tumor initiating sells that have malignant properties have been referred to as CSCs…

Dalerba et al: Stem cells are defined by three main properties:

1. differentiation—the ability to give rise to a heterogeneous progeny of cells, which progressively diversify and specialize according to a hierarchical process, constantly replenishing the tissue of short-lived, mature elements;

2. self-renewal—the ability to form new stem cells with identical, intact potential for proliferation, expansion, and differentiation, thus maintaining the stem cell pool;

3. homeostatic control—the ability to modulate and balance differentiation and self-renewal according to environmental stimuli and genetic constraints   

Like their normal tissue counterparts, tumors are composed of heterogeneous populations of cells that differ in their apparent state of differentiation. Indeed, the differentiation features of a tumor, morphological and architectural, are the key parameter used in routine clinical practice by surgical pathologists to define a tumor’s primary anatomical origin.

This simple observation suggests that tumors are not mere monoclonal expansions of cells but might actually be akin to “abnormal organs,” sustained by a diseased “cancer stem cell” (CSC) population, which is endowed with the ability to self-renew and undergo aberrant differentiation. This hypothesis is further reinforced by the fact that cancer is known to result from the accumulation of multiple genetic mutations in a single target cell, sometimes over a period of many years (3). Because stem cells are the only long-lived cells in many tissues, they are the natural candidates in which early transforming mutations may accumulate.

Dubrovska, A., et al: One possible explanation for the initial positive response to therapy followed by androgen-refractory disease is that although current therapies eliminate the bulk of the tumor, they fail to eliminate cancer stem cells (CSCs) or tumor-initiating cells (TICs). In fact, it has been argued that many cancers are maintained in a hierarchical organization of rare CSCs, rapidly dividing cells, and differentiated tumor cells; the CSCs are not only a renewable source of tumor cells but are also a source of tumor resistance leading to tumor recurrence, metastasis, and tumor progression. Support for this hypothesis came with the identification of TICs in leukemia in 1994 and, subsequently, in a variety of cancers, including solid tumors. In addition, cancer cell lines have been shown to harbor cancer stem-like cells and are a promising model for CSC research because these progenitors can be readily expanded under anchorage independent (sphere formation) serum-free conditions

Fang et al: Recent studies suggest that cancer can arise from a cancer stem cell (CSC), a tumor-initiating cell that has properties similar to those of stem cells. CSCs have been identified in several malignancies, including those of blood, brain, and breast.

Hurt et al: The cancer stem cell hypothesis suggests the existence of a small subpopulation of cells within the tumour that give rise to differentiated tumour cells. It is thought that the cancer stem cells survive conventional treatment to later re-emerge more resistant to therapy. To date, putative cancer stem cells have been identified in blood, brain, breast, lung, skin, pancreas, colon, and prostate….

Jordan et al: Stem cells have three distinctive properties: self renewal (i.e., at cell division, one or both daughter cells retain the same biologic properties as the parent cell), the capability to develop into multiple lineages, and the potential to proliferate extensively. The combination of these three properties makes stem cells unique. The attribute of self-renewal is especially notable, because its subversion is highly relevant to oncogenesis and malignancy. Aberrantly increased self-renewal, in combination with the intrinsic growth potential of stem cells, may account for much of what is considered a malignant phenotype.   Biologically distinct and relatively rare populations of “tumor-initiating” cells have been identified in cancers of the hematopoietic system, brain, and breast. Cells of this type have the capacity for self-renewal, the potential to develop into any cell in the overall tumor population, and the proliferative ability to drive continued expansion of the population of malignant cells. Accordingly, the properties of tumor-initiating cells closely parallel the three features that define normal stem cells. Malignant cells with these functional properties have been termed “cancer stem cells”

Lawson and Witte: Two theories were proposed to explain this paradox. The stochastic theory suggested that all cancer cells are equally malignant but only clones that randomly possess favorable biological properties will grow upon transplantation. An alternative theory predicted that tumors are hierarchical like normal tissues and only the rare subpopulation of cells at the pinnacle of that hierarchy have the unique biological properties necessary for tumor initiation. Studies by John Dick and colleagues provided evidence for the hierarchy model. This group demonstrated that only the small subpopulation (0.1%–1.0%) of Lin–CD34+CD38– cells within human acute myelogenous leukemia samples were capable of initiating disease when transplanted into immune-deficient mice (10). These cells possessed the same antigenic profile as normal human HSCs, which are at the pinnacle of the normal hematopoietic hierarchy. This population also had the unique capacity to selfrenew to propagate the disease as well as differentiate to produce the many leukemic cell types represented in the original leukemia. Since these cancer cells possess properties unique to normal tissue stem cells, they have been termed “cancer stem cells” (CSCs).

Lobo et al: Stem cell: a primitive cell defined by its capacity to self-renew and differentiate into at least one mature cell type Cancer stem cell: a self-renewing cell within a tumor that has the capacity to regenerate the phenotypic diversity of the original tumor

NCI: The theory of the cancer stem cell (CSC) has generated as much excitement and optimism as perhaps any area of cancer research over the last decade. Biologically, the theory goes, these cells are distinct from the other cells that form the bulk of a tumor in that they can self-perpetuate and produce progenitor cells, the way that traditional stem cells do. The progenitors’ job is then to repopulate tumor cells eradicated by treatments such as chemotherapy or radiation.  But for all the attention and fanfare CSC research has received, the findings reported to date are far from clear-cut, investigators acknowledge. For example, most of the studies that have identified human CSCs have used mouse xenograft assays and cells from only a small number of human tumor samples, making it difficult to draw firm conclusions. In addition, other researchers haven’t always been able to replicate initially reported findings. And while these tumor-initiating cells, as they are also called, have been described as being a rare class, several studies have found that the number of cells that can form tumors in these mouse experiments is actually quite large, suggesting that perhaps CSCs aren’t such a privileged breed.

Pavlovic and Balint: As the stem cells that created the tumor to begin with are so few in number, scans following treatment usually fail to identify populations of CSCs in this limited population….[1]

Perego et al: Although there is no definitive consensus on the phenotype and frequency of CSCs in the majority of human tumors, much experimental evidence supports the contentions that many tumors of both epithelial and nonepithelial origin have operationally defined CSCs (cells able to propagate tumors in immunodeficient mice) and that the presence of these CSCs affects tumor biology. 

Rajasekhar: The "cancer stem cell model" CSC …envisions tumors as "pathological organs" sustained in their aberrant growth by a mutated population of stem cells, in which normal homeostatic controls on tissue expansion have been lost.

Roesch et al: The CSC concept postulates a unidirectional hierarchy of tumor cells…According to the traditional CSC concept, tumor initiation is regarded as an exclusive characteristic of CSCs

Rosen and Jordan: Thus, the CSC paradigm refers to the ability of a subpopulation of cancer cells to initiate tumorigenesis by undergoing self-renewal and -differentiation, like normal stem cells, whereas the remaining majority of the cells are more “differentiated” and lack these properties.

Soltysova, et al: Normal stem cells in the adult organism are responsible for tissue renewal and repair of aged or damaged tissue. A substantial characteristic of stem cells is their ability for self-renewal without loss of proliferation capacity with each cell division. The stem cells are immortal, and rather resistant to action of drugs. They are able to differentiate and form specific types of tissue due to the influence of microenvironmental and some other factors. Stem cells divide asymmetrically producing two daughter cells – one is a new stem cell and the second is progenitor cell, which has the ability for differentiation and proliferation, but not the capability for self-renewal. Cancer stem cells are in many aspects similar to the stem cells. It has been proven that tumor cells are heterogeneous comprising rare tumor initiating cells and abundant non-tumor initiating cells. Tumor initiating cells – cancer stem cells have the ability of self-renewal and proliferation, are resistant to drugs, and express typical markers of stem cells. It is not clear whether cancer stem cells originate from normal stem cells in consequence of genetic and epigenetic changes and/or by redifferentiation from somatic tumor cells to the stem-like cells. Probably both mechanisms are involved in the origin of cancer stem cells. Dysregulation of stem cell self-renewal is a likely requirement for the development of cancer. Isolation and identification of cancer stem cells in human tumors and in tumor cell lines has been successful.

Visvader: It is important to note that the cell of origin, the normal cell that acquires the first cancer-promoting mutation(s), is not necessarily related to the cancer stem cell (CSC), the cellular subset within the tumour that uniquely sustains malignant growth. That is, the cell-of-origin and CSC concepts refer to cancer-initiating cells and cancer-propagating cells, respectively. Although the tumourinitiating cell and the CSC have been used interchangeably, the tumour-initiating cell more aptly denotes the cell of origin. There is considerable evidence that several diverse cancers, both leukaemias and solid tumours, are hierarchically organized and sustained by a subpopulation of self-renewing cells that can generate the full repertoire of tumour cells (both tumorigenic and non-tumorigenic cells). The cell of origin, the nature of the mutations acquired, and/ or the differentiation potential of the cancer cells are likely to determine whether a cancer follows a CSC model. In most instances, the phenotype of the cell of origin may differ substantially from that of the CSC. Normal cellular hierarchy comprising stem cells that progressively generate common and more restricted progenitor cells, yielding all the mature cell types that constitute a particular tissue. Although the cell of origin for a particular tumour could be an early precursor cell such as a common progenitor, the accumulation of further epigenetic mutations by a cell within the aberrant population (in this case expanded) during neoplastic progression may result in the emergence of a CSC. In this model, only the CSCs (and not other tumour cells) are capable of sustaining tumorigenesis. Thus, the cell of origin, in which tumorigenesis is initiated, may be distinct from the CSC, which propagates the tumour. 

3    References

1.     Ailles, L and I. Weissman, Cancer stem cells in solid tumors, Current Opinion in Biotechnology 2007, 18:460–466
2.     Burgess, R., Stem Cells, Wiley (New York) 2016.
3.     Dalerba et al, Cancer Stem Cells: Models and Concepts, Annu. Rev. Med. 2007. 58:267–84
4.     Dubrovska, A et al, The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations, PNAS, Jan 2009 V 106 N 1
5.     Fang et al, A Tumorigenic Subpopulation with Stem Cell Properties in Melanomas, Cancer Res 2005; 65: (20). October 15, 2005
6.     Hurt et al, CD44þCD24prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis, British Journal of Cancer (2008) 98(4), 756 – 765
7.   Jordan et al, Cancer Stem Cells, NEJM, 355;12 September 21, 2006
8.     Lawson, Witte, Stem cells in prostate cancer initiation and progression, The Journal of Clinical Investigation Volume 117 Number 8 August 2007
9.     Lobo et al, The Biology of Cancer Stem Cells, Annu. Rev. Cell Dev. Biol. 2007. 23:675–99
10.  Pavlovic, M., B. Balint, Bioengineering and Cancer Stem Cell Concept, Springer (New York) 2015
11.            Perego et al, Heterogeneous Phenotype of Human Melanoma Cells with In Vitro and In Vivo Features of Tumor-Initiating Cells, Journal of Investigative Dermatology (2010), Volume 130
12.            Rajasekhar, V., Cancer Stem Cells, Wiley (New York) 2014.
13.  Roesch et al, A Temporarily Distinct Subpopulation of Slow-Cycling Melanoma Cells Is Required for Continuous Tumor Growth, Cell 141, 583–594, May 14, 2010
14.  Rosen, J., C. Jordan, The Increasing Complexity of the Cancer Stem Cell Paradigm, Science, 26 JUNE 2009 VOL 324.
15.  Soltysova, A., et al, Cancer stem cells, NEOPLASMA, 52, 6, 2005
16.  Visvader, J., Cells of Origen in Cancer, Nature, V 469 20 Jan 2011.

[1] This book is near incomprehensible in my opinion. It appears impossible to find a definition, only secondary referral characteristics at best!

Thursday, April 14, 2016


Back in the 60s when I first started in Academia we did not focus on Patents. The laws had not yet made it a potential profit center for Universities and Start Ups had been few and far between. We published everything, usually with one or at most two authors. Now Academics patent everything and papers have thousands of authors.

The CRISPR wars are just heating up. As Nature notes:

Last month, in an extraordinary dispute before the US Patent and Trademark Office (USPTO), university lawyers laid out their clients' legal strategies for claiming patents that cover the celebrated gene-editing technology CRISPR–Cas9. Over the next year, the USPTO will receive volumes of evidence centred on who first invented the technology. Battles over scientific priority are as old as science itself. But the CRISPR–Cas9 patent dispute is unusual because it pits two leading research institutions against one another for the control and industrial development of a foundational technology: the University of California, Berkeley (UC Berkeley), and the Broad Institute of MIT and Harvard in Cambridge, Massachusetts. As scientific institutions increase their involvement in the commercialization of research, it is worth considering the potential consequences for science if more institutions follow the path of UC Berkeley and the Broad Institute.

The battle is costly. Litigation can cost millions and result in outcomes that are counter productive. We remarked when the CRISPR patent was issued that it was a first for the PTO. Less than six months from filing to issuance.

Perhaps when stones are overturned in the litigation one may find things that would have best been hidden. Also it puts one of the game changing technologies in Limbo for a while.

Of Mice and Men

Obesity is a growing threat to overall health. It is not just the development of Type 2 Diabetes and its sequellae but the other sequellae that arise directly. Strangely many studies focus on mice and genetic aberrations that lead to obesity. In NEJM they discuss such a case.

They note:

A recent study by Dalgaard and colleagues forces us to rethink aspects of the heritable component of obesity. Dalgaard et al. characterized mice carrying a mutation in the gene encoding tripartite motif–containing 28 (Trim28). Trim28 is a zinc-finger transcription factor that enhances transcriptional repression — in other words, a mutation in one copy of Trim28 causes an unexpected heritable bimodal (on–off) obesity distribution that seems to depend on certain environmental factors to “flip the switch.” The average weight gain (approximately 7 g) in the obese (“on”) mouse with the Trim28 mutation was largely due to an increased mass of adipose tissue distributed uniformly across all adipose depots and a very slight increase in length (1 to 2%), whereas the weight in the “off” phenotype did not differ from that in wild-type animals. The approximate doubling of the adipose-tissue mass in the “on” phenotype was accompanied by a doubling in the number of adipocytes in the tissue.

Well first off, they are mice. Give a mouse food and they will eat it. Some more than others. I look at our bird feeder and there is one squirrel that is just stuffing herself all day. Perhaps she has a gene but also perhaps she is just a deliberate over eater. Perhaps a lot of things. Humans however have scales, they should have will power, they should see the damage caused. We humans do not exercise as much as squirrels. Thus the comparison has many faults.

Regarding humans they note:

Are these findings relevant to obesity in humans? The bimodal obesity phenotype was obvious in the inbred Trim28 mice, and the authors obtained suggestive data that polyphenism is also manifested in human populations. They observed that TRIM28 expression levels in human adipose tissue sorts samples into one of two subsets. Persons with low levels of TRIM28 expression have IGN1 dysregulation and are more likely to be obese than are persons with high levels of TRIM28 expression, a finding that is in line with the observations in mice. In addition, they report that the distributions of body-mass index within a homogeneous pediatric cohort (4000 children of European ancestry) as well as within a heterogeneous cohort (persons of black American, Mexican-American, and Han Chinese ancestries) fit two distinct gaussian distributions rather than a single gaussian distribution. However, we note that there could be other explanations (e.g., skewed social and environmental stratification) for a bimodal distribution. The regulation of TRIM28 expression in humans remains unknown.

 What does all of this mean? Good question. Humans with their will power can refrain from heavy caloric intake. There is a movement to portray obesity as a disease akin to say breast cancer. It is not, it can be controlled at no cost. Thus the search is in my opinion just another way to offset blame to some third party entity.

Monday, April 11, 2016

The MOOC Fallacy

The MOOC fallacy is that "students" can grade other students; honestly, fairly, and competently. I bemoaned a course I took a year ago where some 10-20% of one's grade was via "peer review" grading.

Namely the concept is to take students, often not having English as a first language, or even second, and let them grade other students. Now besides the language barrier this means people who have no knowledge grade those with some knowledge. Furthermore what I also observed was gaming of the system by ganging up on those grades of what was clearly say Americans by those from other countries to suppress the American grades.

This year the course has raised the percent of the grade subject to this less than ethical practice to a level of some 36%. That means collections of students can target others and suppress grades for their benefit.

Anyone who has ever taught knows gaming. This system however verges in my opinion on the immoral. One subjects themselves to the rigor of the material only to have it grades by some one having no understanding of the material along with an interest in them succeeding and you failing. This is a wonderful example of a rigged game. It also in my opinion is an example why no one really trusts these systems.

Facts Still Count, As Well As Details

In an MIT study they claim that the lower income groups have almost a 15 years shorter life span than the high income groups. They state:

Poverty in the U.S. is often associated with deprivation, in areas including housing, employment, and education. Now a study co-authored by two MIT researchers has shown, in unprecedented geographic detail, another stark reality: Poor people live shorter lives, too. More precisely, the study shows that in the U.S., the richest 1 percent of men lives 14.6 years longer on average than the poorest 1 percent of men, while among women in those wealth percentiles, the difference is 10.1 years on average. This eye-opening gap is also growing rapidly: Over roughly the last 15 years, life expectancy increased by 2.34 years for men and 2.91 years for women who are among the top 5 percent of income earners in America, but by just 0.32 and 0.04 years for men and women in the bottom 5 percent of the income tables.

Now what of this fact. We have examined this in detail back in 2009 when looking at the proposed Health Care Plans. The real problem is that the lower income have the worst health habits. Obesity is rampant in lower incomes. Their diet is atrocious. They are smokers and are drinkers. They also do get poorer medical care but for reasons often less related to availability and economics than to mindset and attitude.

The upper income are more readily inclined to visit a physician and to address lifestyle issues. The lower income individuals often live neglectful lives regarding their health due to fear of doctors.

Thus the fact in the study may be correct the reasons are far to complex than just the income differences. It is a shame in my opinion that such research get so biased a coverage. Details count, not just the facts.

Friday, April 8, 2016

Indentured Servitude?

The problem of the high price of the university education is due to the unnecessary explosive investments in "pyramids" built on campuses which result in voracious appetites for maintenance. Build a $200M new research center from wealth alumni and be strapped with a 10% pa maintenance bill growing at inflation plus. No sensible business person would take on that liability unless of course you have an ever ending ability to tax the "consumer".

So as the NY Times notes the next way to get money is to monetize the economic lives of your graduates. One can envision multiple hedge fund type strategies to make profit off of this process. As the Times notes:

At Purdue University, some undergraduates will have a new option to help finance their degrees: pledging to pay a percentage of their future incomes in return for funds today. Starting this fall, juniors and seniors will have access to the school’s Back a Boiler program, an alternative financing arrangement known as an income-share agreement. Such programs are not loans. Instead, students get funds to cover current education expenses, and, in return, they agree to pay a percentage of their future income over an agreed-upon period of time. When that repayment term ends, so does the student’s obligation, even if their total payments are less than the amount they received. Though an emerging corner of the educational finance industry, such programs help ease the often crushing debt many American college students face after graduation, proponents say. A small number of lenders have tested the model in recent years, but Purdue is the first American university to officially embrace the concept.

This is in my opinion an indentured servitude, and servitude to whomever holds the note. Hopefully students can be more astute but in today's world the helicopter generation has no competence in determining the impact. They will walk freely like lambs to the slaughter. 

Good Job Space-X

Space-X just launched a package to the space station and then landed the first stage back on a seaborne platform. Ars Technica has a great video. It is amazing what private industry can do. The Government spent tens of billions and decades, since 1966 is when I first recall, on electric cars and space vehicles.

Great job folks!

Monday, April 4, 2016

Another Diagnostic Tool

The ongoing debate about PSA and PCa in men continues and the search for an improved diagnostic tool has also progressed. Three years ago we wrote a piece on Oncosomes. Recently in a JAMA Oncology Editorial the authors speak of this technique as if it has now been accepted. The Editorial concludes:

Currently, we do not have a single population-based screening test to supplant PSA-based  stewardship in screening for prostate cancer. However, McKiernan and colleagues have introduced a novel urinary gene expression signature that may be the least invasive of available options by not  requiring a digital rectal examination or phlebotomy as a reflex test in men for whom PSA testing  raises the suspicion of prostate cancer.7 In the near future, a panel of markers associated with the risk of high-grade prostate cancer may decrease the rate of overdiagnosis and overtreatment of  prostate cancer that prompted the US Preventive Services Task Force to issue a grade D recommendation for prostate cancer screening.

The paper by McKiernan et al presents a several year definitive study of this oncosome approach. They conclude:

This urine exosome gene expression assay is a noninvasive, urinary 3-gene expression assay that discriminates high-grade (≥ GS7) from low-grade (GS6) cancer and benign disease. In this study, the urine exosome gene expression assay was associated with improved identification of patients with higher-grade prostate cancer among men with elevated PSA levels and could reduce the total number of unnecessary biopsies.

 The question is; how effective will this be in saving lives at the cost of saving on unnecessary prostate biopsies. We have commented on this conundrum lately. It is a complex issue. In light of the "Moonshot" approach of the Vice President, this is still somewhat in the pre Galileo period of celestial dynamics.

Another War on Cancer

Preparing charts, developing strategies, allocating expenditures, all flow from any new initiative. Cancer is a highly complex disease. As we have been noting for a decade in just a few cancers, a "simple" and significant cancer such as that of the prostate has hundreds if not thousands of genetic complex profiles. Thus diagnosis and prognosis not to mention treatment must and will be tailored personally. It is not one size fits all.

In an article in NEJM the NIH authors announce the key elements of their program:

Cancer vaccines: Produce Epstein–Barr virus (EBV) vaccine for human safety testing; explore development of other vaccines for high-risk persons.

Early cancer detection : Develop tools and techniques to improve sensitivity, specificity, and utility of molecular-detection assays.

Single-cell genomic analysis: Conduct single-cell analyses to uncover the -omic spectrum of malignant and nonmalignant cells in the tumor microenvironment.

Cancer immunotherapy: Support basic research to further elucidate cancer immunology and extend the reach of immunotherapy to all kinds of cancer.

Pediatric cancer: Prepare and screen new libraries of compounds chosen for their potential to interfere with these transcription factors; intensify the collection and analysis of very rare childhood cancers.

Data sharing: Expand capacity of the National Cancer Institute Genomic Data Commons to handle and analyze genomic and clinical data from patients and health care providers.

Exceptional Opportunities in Cancer Research Fund : Pursue previously unanticipated and novel scientific opportunities to improve basic and applied cancer research.

It is worth examining the above. 

Vaccines have some value on well known virus that can be directly linked to cancers. There are few at this stage and of course we always want to identify others and prevent them. However this may be far from number 1. Early detection is a complex issue due to several factors, First we really do not know what to look for. Second it is expensive. Third most people just will not seek the opportunity until too late. The smoker, the alcoholic, the obese person all present risks far in excess of viruses. Single cell analysis is another door that is just opening. As we have indicated elsewhere in PCa the expression is massively different in almost ever presentation and in every part of the body. Furthermore we do not understand the dynamics of the stem cell. Immunotherapy with MABs is moving along. But the more we learn the more we can fine tune the approach. Pediatric cancers are devastating and always worth a try. Data sharing can and is being done already so what is new here? Doing something new; of course.
NIH also announces the Blue Ribbon Panel to work this Program. They state:

“This Blue Ribbon Panel will ensure that, as NIH allocates new resources through the Moonshot, decisions will be grounded in the best science,” said the Vice President. “I look forward to working with this panel and many others involved with the Moonshot to make unprecedented improvements in prevention, diagnosis, and treatment of cancer.”

The Moonshot metaphor has always been misplaced. Having spent a few years in the 60s on Apollo Program I know something about it. We had Kepler and Newton, we had Kalman and Battin, we had computers and Gyros. We even had improved German rockets. It was a matter of scale and not new knowledge. Cancer still has many unknowns. We want accuracy and NOT precision. It is akin to saying that we will land on the planet at exactly noon, and it will be Mars or Jupiter. Very precise but not very accurate.

They conclude:

Fueled by an additional $680 million in the proposed fiscal year 2017 budget for the National Institutes of Health (NIH), plus additional resources for the Food and Drug Administration, the initiative will aim to accelerate progress toward the next generation of interventions that we hope will substantially reduce cancer incidence and dramatically improve patient outcomes. The NIH’s most compelling opportunities for progress will be set forth by late summer 2016 in a research plan informed by the deliberations of a blue-ribbon panel of experts, which will provide scientific input to the National Cancer Advisory Board.

 Regrettably Boards are managed by Government Staff and we don't have the Feynmans to participate and add reality. Hopefully they accomplish something other than just assuage the grieving.

The Top Ten

I am always amazed about the top ten choices of anything. Back in 1999 the NY Times opined on their view of the top 10 of the 20th Century in Non Fiction.They stated:

3. ''UP FROM SLAVERY,'' Booker T. Washington
4. ''A ROOM OF ONE'S OWN,'' Virginia Woolf
5. ''SILENT SPRING,'' Rachel Carson
6. ''SELECTED ESSAYS, 1917-1932,'' T. S. Eliot
7. ''THE DOUBLE HELIX,'' James D. Watson
8. ''SPEAK, MEMORY,'' Vladimir Nabokov

Now The Guardian has somehow gotten into the act. The state:
1. The Sixth Extinction
2. The Year of Magical Thinking
3. No Logo
4. Birthday Letters
5.  Dreams from my Father
6. Brief History of Time
7. The Right Stuff
8. Orientalism
9. Dispatches
10. The Selfish Gene

This is an interesting comparison. Two on the first list are women, three on this list are. One on the Times is about science and two on the Guardian.  Personal recollections there are many. One could make up lists that have had impact. In the Guardian list one could ask; who has read more than three at best. 

The key question is; did any of the books have a lasting impact and which ones. Clearly Keynes did. Silent Sprint eliminated DDT yet tens of million of humans died of malaria while the same number of birds survived. Good trade off? Watson records a tale of human intellectual competition. Brilliant and highly readable. Mencken ages too quickly in a caustic culture. Adams is too New England. Sixth Extinction is a trendy catastrophe book, and suppose it will fall in the genre of all the others so one wonders why it was Number 1. Dawkins does stimulate and writes well. I guess the President's alleged recollections is compulsory for The Guardian. The Time book was a great seller but I doubt many truly grasped it or even more so if any of it makes a difference in daily existence.

Marx and his writings made a difference as did Locke, Mill, Montesquieu and others. People read them and it changed their lives. I doubt than any of the Guardian list did any of that.