Thursday, December 29, 2016

CRISPR Blocking

Day by day new tools are being found to manage CRISPRs. In Cell today they announce:

Bacterial CRISPR-Cas systems utilize sequence-specific RNA-guided nucleases to defend against bacteriophage infection. As a countermeasure, numerous phages are known that produce proteins to block the function of class 1 CRISPR-Cas systems. However, currently no proteins are known to inhibit the widely used class 2 CRISPR-Cas9 system. To find these inhibitors, we searched cas9-containing bacterial genomes for the co-existence of a CRISPR spacer and its target, a potential indicator for CRISPR inhibition. This analysis led to the discovery of four unique type II-A CRISPR-Cas9 inhibitor proteins encoded by Listeria monocytogenes prophages. More than half of L. monocytogenes strains with cas9 contain at least one prophage-encoded inhibitor, suggesting widespread CRISPR-Cas9 inactivation. Two of these inhibitors also blocked the widely used Streptococcus pyogenes Cas9 when assayed in Escherichia coli and human cells. These natural Cas9-specific “anti-CRISPRs” present tools that can be used to regulate the genome engineering activities of CRISPR-Cas9.

Likewise in The Scientist they note:

The researchers found these Cas9 blockers by searching bacterial genomes for both a CRISPR sequence and its target, under the assumption that the genome likely contained an inhibitor to prevent CRISPR from cutting that target in the bacterium’s own genome. Indeed, Rauch and colleagues uncovered several anti-CRISPRs in Listeria whose sequences had been left behind in the bacterial genome by prior phage infection. “Just as CRISPR technology was developed from the natural anti-viral defense systems in bacteria, we can also take advantage of the anti-CRISPR proteins that viruses have sculpted to get around those bacterial defenses,” Rauch said in the statement. Two of the inhibitors blocked Cas9 from Streptococcus pyogenes, the form of the DNA-cutting enzyme frequently used in genome editing. In a study published earlier this month in Cell, a different team of researchers reported the discovery of several anti-CRISPRs that block Cas9, but none of them acted against the activity of the Cas9 from S. pyogenes.

It seems we are building up a powerful tool box for cell manipulation. Hopefully the patent war can be settled in 2017.

Wednesday, December 28, 2016

Preparedness of Government

Consider the US Interstate System. It is a mass of disparate roads paid by the taxpayer and under the jurisdiction of the State and Local police. Now consider contingency plans. For example ice, snow, or well let us just consider a car wreck.

Specifically let us look at the state of Pennsylvania and its Interstates. They are for the most part half a century or more in age and almost without exception two lanes. They have no tolls and thus invite the trucks, tons of them, and truck drivers who are in a rush and often less capable of doing what they are.

Now look at today on I81 in Carlisle. An eighteen wheeler going northbound collides apparently with a pickup which cross the divider and both are destroyed and fatalities.

So what does the State have for a contingency plan? Nothing. Zip! Da Nada! One would assume that the State should have a contingency, but do not make that assumption. They are the Government after-all. Traffic is back up for hours, no exits, more than 40 miles sitting and burning fuel.
One would assume there would be a plan, directions, traffic control. The objective should be the care and safety of all, not just a gathering on a closed Interstate. One must ask; who is in charge? I have seen this again and again especially with many different State Police. Some are good, such as here in New Jersey, but if one were to cross state lines then all bets are off. There should be plans for this type of incident. One cannot just close the highway and leave tens of thousands to sit and wait, No Exit Sartre and all!

Then again one should ask; where is the Governor? The people stranded, some with health problems, others effecting commerce, ultimately all assume some modicum of care and attention. But not likely in Pennsylvania!

So how does one drive from New Jersey to Ohio? East through Moscow! Then to Vladivostok. Keep going East! Avoid Pennsylvania at all costs.

Some Have Long Memories

China Daily reports:

Japanese Prime Minister Shinzo Abe's visit to Pearl Harbor, criticized by China as lacking in sincerity, was quickly followed by one of his Cabinet ministers visiting a Tokyo war shrine on Wednesday. According to analysts, Abe's visit to Pearl Harbor, the target of the 1941 Japanese surprise attack on Hawaii, had hawkish intentions at heart, not pursuing peace and reconciliation. The purpose, they said, was to broaden Japan's military capabilities and curb the rise of China by strengthening the alliance with the United States. On Tuesday, Abe and US President Barack Obama laid wreaths at the USS Arizona Memorial. Afterward, in a speech, Abe said that Japan would never again wage war. On Dec 7, 1941, the Japanese attack on Pearl Harbor killed more than 2,400 US citizens and drew the US into World War II. Not long after Abe spoke, Masahiro Imamura, the minister in charge of reconstruction of northern Japan after the 2011 tsunami, offered prayers at the Yasukuni Shrine, which honors Japan's war dead, including 14 Class-A war criminals from World War II. Class-A convicts were found guilty of plotting and carrying out the war. Chinese Foreign Ministry spokeswoman Hua Chunying said Japan should reflect upon its war crimes in a sincere manner rather than "make political shows repeatedly". She spoke at a regular news conference on Wednesday.

 For almost fifteen years Japan raped and plundered China so it is reasonable to have some lingering recollection. Also from 1941 through 1945 Japan slaughtered Americans and Allied forces as well as their own people.

Perhaps China has a point. For everyone.

Monday, December 26, 2016

Could Not Agree More

What is Economics? That question is what was the start of this Blog. Now I am not an economist, nor do I pretend to affect any tenancy thereto. I have studied Economics, I have critiqued Economics, I have even disdained Economics. You see, unlike the real world, and one would think Economics is more real than anything, Economics is in today's world opinion and not science. It is a collection of idea, emboldened by mathematics, that state the way the world should work from the eyes of the presenter.

Now in a recent piece Skildelsky states:

What unites the great economists, and many other good ones, is a broad education and outlook. This gives them access to many different ways of understanding the economy. The giants of earlier generations knew a lot of things besides economics. Keynes graduated in mathematics, but was steeped in the classics (and studied economics for less than a year before starting to teach it). Schumpeter got his PhD in law; Hayek’s were in law and political science, and he also studied philosophy, psychology, and brain anatomy. Today’s professional economists, by contrast, have studied almost nothing but economics. They don’t even read the classics of their own discipline. Economic history comes, if at all, from data sets. Philosophy, which could teach them about the limits of the economic method, is a closed book. Mathematics, demanding and seductive, has monopolized their mental horizons. The economists are the idiots savants of our time. 

Indeed,  if Economists were first engineers, physicians, plumbers, carpenters, or some professions based in reality then perhaps so too would be there prognostications. Remember the employment rate curves sent out eight years ago by the Administrations incoming Economists. Never worked so what did they do? Changed the rules. Eliminated tens of millions from those looking for jobs. If your theory does not work, change the data.

Try that one on a bridge. Gravity is not as kind!

Sunday, December 25, 2016

Gene Drive Issues

Gene Drives are an interesting interplay with a set of "tools" available to gene manipulators. The current capabilities of gene manipulation, also we can probably call it gene engineering, is that we have an ever growing collection of "tools". These tools allow bench folks to add this or subtract that from a cell. We can do this with a somatic cell, an existing cell in an existing organ and a germ line cell, a cell from which the organism will eventually be derived. We can add or delete genes and we can in so doing insert a mechanism which will carry on this editing process no matter what the cell becomes as the organism develops. Furthermore if we get this process working in the germ line cell then we can be assured that as the next generation proceeds this inserted tool for manipulating genes within the organism, if not now within the total species, proceeds in a dramatic manner. We lose Mendelian genetics and the tool insertion now produces a single unaltered lineage.

If this gene is of a certain type, say one which produces only a male, then by blocking in all subsequent lines of any females we can effectively wipe out this species when we have just surviving but non-producing males.

This assembly of tools by the genetic engineer has been called "gene drives". In a sense it "drives" certain genes into all members of a species. At least that is the hope. As the Broad Institute states in its licensing statements[1]:

Gene drive. This is a way to rapidly spread a new gene throughout an entire species in nature. This approach might be used to block the transmission of malaria by mosquitoes, but has the potential to disrupt ecosystems… After consulting with external experts and careful internal consideration, the Broad Institute has decided to make available non-exclusive research and commercial licenses for the use of CRISPR technology in agriculture -- but with important restrictions. These include: Gene drive: We prohibit the use of the licensed technology for gene drive.

Now to repeat a simplified version of the Gene Drive we present the steps simplified below. The basic principle is to insert a gene into a species, yes species, which will alter the entire species, such as making them all males and thus no longer able to reproduce.



Start with the above, two sets of chromosomes from a wild type in a species. Classic Mendelian genetics would apply. Now we want to introduce some gene to alter then entire species. Usually was can do that say in an embryo but it would remain on one or even both chromosomes but would filter out. Yet if we could somehow also say introduce a CRISPR/Cas9 combo to rewrite this gene over and over then it would spread across all embryos and thus the species.

Thus the next step is:



Namely figure out the gene, use say a Cas9 or other similar endonuclease, and a target CRISPR to  guide the new gene.
We use some insertion mechanism such as a lentivirus in the embryo with some reverse transcriptase to insert these genes.
Then in the embryo it duplicates and the entire embryo reflects the gene and duplication mechanism.
Then the mating is between this modified and enabled vector with any wild type.




And we introduce the little factory in all off-spring.



Which perform the same tasks and reproduce the gene throughout the targets. Thus we could get all male insects and drive the species to extinction!

As The Scientist notes:

The United Nations (UN) biodiversity meeting, held in Mexico this month, could have ended poorly for scientists working on gene drives, genetic elements that can perpetuate specific mutations and may help cull dangerous mosquito populations. But in spite of environmental activists pushing the UN to ban gene drives, citing the risk of accidental release, the UN’s final agreement—penned December 16—merely urged caution in testing gene drives, Nature reported. Overall, the organization broadly supported further research in synthetic biology. “I’m very relieved,” Andrea Crisanti, a molecular parasitologist at Imperial College London who works with gene drives, told Nature. “It would have been a disaster for developing the technology.”By engineering mutations that render organisms infertile or less infectious, then perpetuating these mutations with gene drives, scientists may be able to reduce the occurrence of certain mosquito-born illnesses and cull invasive species. Gene drives have already been tested in yeast, fruit flies, and mosquitoes, and may soon be enlisted in the fight against malaria. One team hopes to conduct field trials in Africa as soon as 2024.


 In a similar fashion Nature states:

When the CBD last met in South Korea in 2014, gene drives were a largely theoretical idea. They are genetic elements that can quickly spread through sexually reproducing populations. In general, an organism's two copies of a gene — known as alleles — each have a 50% chance of being passed on to its offspring. This limits the pace at which a genetic modification can spread through a population. But gene-drive technology tilts the odds, so that a specific change to one allele is inherited by a higher proportion of progeny. In theory, an entire population could quickly carry the same modification. In the past two years, researchers have lab-tested gene drives in yeast, fruit flies and mosquitoes that are based on a gene-editing technology called CRISPR–Cas9. Crisanti’s team, for instance, is working on gene drives in the malaria-carrying mosquito Anopheles gambiae that perpetuate mutations causing females to become infertile. Spread of this mutation could mean that mosquito populations plummet to levels that do not support the transmission of malaria. The researchers' project, called Target Malaria, has attracted tens of millions of dollars in funding, and the scientists hope to conduct field trials in Africa as early as 2024. Other groups are developing gene drives to quell island rodents and other pests.

This development takes the next step and it presents a rather double edged sword. It is essential to be watched as we move forward.

As I have noted again and again. Silicon Valley apps pale to what bio tech is doing. In bio tech, there is a potentially deadly field at play and any country and enter the game. The cost is low, expertise is required, and somehow we seem to be providing it in our Institutions.

Look Who Is Talking

Having watched technology change over some almost seventy years, one thing you can say if that it is unpredictable.

Silicon Valley back in the early 60s was a Defense haven, filled with technical people focusing on developing new ways to combat the perceived Soviet threat. Salaries were reasonable and living conditions likewise.

My first exposure to a start up was in the late 60s where the result was a great learning experience. Failure results in decapitation and details count. Thus the world of venture investment could be ruthless, it was not a DoD contract of cost plus.

Then the 70s and the Nixon years of Creative Destruction. DoD work disappeared, Congress mandated more and more, and out of the Carter mess came entrepreneurs. My first exposure was a meeting in San Francisco to see if I wanted to join a VC fund, my answer was no, better to create than to try and pick winners and losers.

Then the 90s, and the Clinton I explosion. No more enemies, global markets, and the technology we had used in the military and space efforts was consumerized. Chips got smaller, cheaper, more powerful and "services" became a mantra. The "dot com" boom and bust. Such things as Pets.com came and went to be supplanted by Amazon.

Now dis intermediating classic distribution channels, which is what most of Silicon Valley does, is a business model for a while it does not afford a long term stable plan. Long term is fifty to a hundred years. After every millennial is walking around heads down on a iPhone what else is there.

Now one of the losing Presidential advisers notes that she has a set of recommendations for the winner. These "suggestions" is of course from a lawyer, not anyone who has apparently in my opinion done anything. She recommends:

First, the next Administration must have an aggressive strategy to develop the human capital necessary to power the digital economy in this country. That means educating our people in computer science and STEM education from an early age. ... If talented students from abroad come to American universities and obtain advanced degrees in STEM fields, we should be bringing them into our economy, not pushing them out.

First if all, STEM is really Science and Engineering. Math is a science and technology is a support function. Second, I firmly believe that only a small percent of the population has both intellect and personal drive to prosper in that space. It is not something we just spend billions on educating everyone. It is achieved by supporting winners and, sorry to say, neglecting losers. Sixty years ago Gov. Rockefeller has NY State Regents Scholarships and then Science and Engineering Scholarships. If you demonstrated competence you got free tuition in New York schools. You rewarded the achiever. Second, I agree that keeping people who we educate with our tax dollars is essential. I have seen mass numbers of MIT graduate students get funded on US Tax dollars for PhDs and then go back and compete against us. That frankly is insane. Again the proponent seems to miss this fact. It is a remnant from Clinton I.

Second, the next administration needs a plan for promoting widespread entrepreneurship and inclusion in the digital economy. Tech shouldn’t just be a Silicon Valley story; we should see similar innovation clusters emerging across our country, creating millions of jobs as well as products and apps that consumers demand. One policy... proposed in that vein was to support incubators and accelerators for 50,000 new entrepreneurs in underserved areas. Another was to increase access to capital for small and mediums-sized businesses and startups, especially for minority and female entrepreneurs.

New companies survive and prosper only in a ruthless Darwinian environment. I have spent the last five years wandering around these Millennials warm spots where everything is supplied, and they have whatever they need until reality strikes. Success from these is zero percent! It would be nice if the proposer of this idea had the slightest understanding from a hands on perspective. Lawyers just do not.

Third, there must be a commitment to connectivity. We should settle for nothing less than universal, high-speed broadband for every household. To ensure people can get online through free wifi, we should replicate and extend programs like e-rate, which was successful at hooking up public schools and libraries to the internet, ...

Again she proposes more Government spending. Take a look around. There is lots of WiFi. It is at all libraries, schools, and even public housing. That is NOT a problem.

Finally, helping tech succeed means keeping the internet open, as well as private and secure for users. That begins with embracing the FCC’s net neutrality rules, the staple of a free and open internet, rather than seeking to undo them. It means ensuring that users—all of us—continue to trust our internet-based communications platforms. 

Internet Neutrality is more than just an Open Internet. It is an issue of  privacy, autonomy, individuality, and the right to be informed, a corollary of the First Amendment. We clearly do not want any carrier to throttle our information. Frankly here many Republicans are father to the Left than Joe Stalin and it is shameful.

I conclusion perhaps one should examine these policy and strategy proposals. They reflect an echo chamber and isolated view of reality.

Where is real technology going. Simple. Biotech. Whether it is immune therapy, CRISPR, Gene Drives, and the like, it will be a period of Darwinian development of new ways to manage the world in a way we never anticipated. The Apps folks in my opinion will be left behind. Programming may for the most part become the 1950s Secretary Pool of the future. Understanding the plethora of bio tools in the tool kits and expanding them into what we see today in software will be the basis of a new change.

This environment will not be Theranos like but it will be the explosion about Kendall Square in Cambridge. It will be as a massive a change as we can imagine. Some will be in Silicon Valley, bit much may move East.

The proposals made reflect what the Press sees as technology. Wake up and smell the Cas9.

Merry Christmas 2016

1 And it came to pass in those days that a decree went out from Caesar Augustus that all the world should be registered.
2 This census first took place while Quirinius was governing Syria.
3 So all went to be registered, everyone to his own city.
4 Joseph also went up from Galilee, out of the city of Nazareth, into Judea, to the city of David, which is called Bethlehem, because he was of the house and lineage of David,
5 to be registered with Mary, his betrothed wife, who was with child.
6 So it was, that while they were there, the days were completed for her to be delivered.
7 And she brought forth her firstborn Son, and wrapped Him in swaddling cloths, and laid Him in a manger, because there was no room for them in the inn.
8 Now there were in the same country shepherds living out in the fields, keeping watch over their flock by night.
9 And behold, an angel of the Lord stood before them, and the glory of the Lord shone around them, and they were greatly afraid.
10 Then the angel said to them, “Do not be afraid, for behold, I bring you good tidings of great joy which will be to all people.
11 For there is born to you this day in the city of David a Savior, who is Christ the Lord.
12 And this will be the sign to you: You will find a Babe wrapped in swaddling cloths, lying in a manger.”
13 And suddenly there was with the angel a multitude of the heavenly host praising God and saying:
14 “ Glory to God in the highest, And on earth peace, goodwill toward men!
15 So it was, when the angels had gone away from them into heaven, that the shepherds said to one another, “Let us now go to Bethlehem and see this thing that has come to pass, which the Lord has made known to us.”
16 And they came with haste and found Mary and Joseph, and the Babe lying in a manger.
17 Now when they had seen Him, they made widely known the saying which was told them concerning this Child.
18 And all those who heard it marveled at those things which were told them by the shepherds.
19 But Mary kept all these things and pondered them in her heart.
20 Then the shepherds returned, glorifying and praising God for all the things that they had heard and seen, as it was told them.

Saturday, December 24, 2016

Replace the Rockettes

Perhaps the Rockettes and their Union may like to feel what American manufacturing labor has felt over the last decade. Simple, get Vladimir to send over the Bolshoi. We move from Crass to Class, but there would be some tariff involved I think.

As the NY Times states in its even fully complete coverage of the details of the new President:

The day of statements followed reports that a Rockette was “embarrassed and disappointed” that the decision to perform had been made for her. The dancer’s private Instagram post was published .... and quoted widely by news outlets. That dancer... did not respond to multiple requests for comment on Friday, nor did several of her fellow performers. Not long after those reports, a statement relayed ...a spokeswoman for the Madison Square Garden Company, said that dancers’ appearances are voluntary.

 I suspect that "voluntary" could be transliterated into Russian with a slight change in emphasis. 

Frankly this would be a great step forward in multiculturalism.

Friday, December 23, 2016

CRISPR and other enzymes

The Scientists reports the identification of new enzymes to effect CRISPR targeting. Recall that CRISPR is a targeting RNA sequence and the enzyme, such as Cas9 is used to cut and then allow splicing of segments. CRISPR targets the gene position and the enzyme does the cutting. Cas9 does DSB or double stranded breaks. Other enzymes allow for sticky ends.

As The Scientist states:

Banfield’s team searched the genomes for sequences that were both near cas1, which encodes a conserved CRISPR protein, and close to characteristic sequence repeats. The researchers found sequences for Cas9 in two archaeal genomes extracted from the Richmond Mine in Iron Mountain, California. Previously, archaea were known to use class 1 CRISPR systems, but class 2 had only been identified in bacteria. “We don’t really know how it performs, because that has not been achieved in the laboratory yet,” said Banfield. “Archaea have different biology. The fact that [my collaborators] haven’t yet managed to show its function probably means there are components of the system that we don’t yet know about.” The group also uncovered new types of Cas proteins from groundwater and soil bacteria, dubbed CasX and CasY. “They’re really small, especially CasX,” said Banfield. “That means it’s potentially more useful.” CasX is made up of only 980 amino acids, whereas other Cas enzymes are larger. For instance, the commonly used Cas9 from Staphylococcus pyogenes contains 1,368 amino acids, while a smaller one from S. aureus is made up of 1,053 amino acids (CasY is around 1,200 amino acids). “This is important biotechnologically, because if you look at if from the angle of genome editing, the delivery of small genes into cells is much easier than the delivery of large genes,” ... In partnership with UC Berkeley’s Jennifer Doudna, Banfield’s team demonstrated that CasX and CasY are functional. The researchers introduced CRISPR-CasX and CRISPR-CasY into E. coli, finding that they could block genetic material introduced into the cell.

The article appears in Nature.  The article states:

CRISPR-Cas systems provide microbes with adaptive immunity by employing short sequences, termed spacers, that guide Cas proteins to cleave foreign DNA. Class 2 CRISPR-Cas systems are streamlined versions in which a single Cas protein bound to RNA recognizes and cleaves targeted sequences. The programmable nature of these minimal systems has enabled their repurposing as a versatile technology that is broadly revolutionizing biological and clinical research. However, current CRISPR-Cas technologies are based solely on systems from isolated bacteria, leaving untapped the vast majority of enzymes from organisms that have not been cultured. Metagenomics, the sequencing of DNA extracted from natural microbial communities, provides access to the genetic material of a huge array of uncultivated organisms. Here, using genome-resolved metagenomics, we identified novel CRISPR-Cas systems, including the first reported Cas9 in the archaeal domain of life. This divergent Cas9 protein was found in little-studied nanoarchaea as part of an active CRISPR-Cas system. In bacteria, we discovered two previously unknown systems, CRISPR-CasX and CRISPR-CasY, which are among the most compact systems yet identified. Notably, all required functional components were identified by metagenomics, enabling validation of robust in vivo RNA-guided DNA interference activity in E. coli. Interrogation of environmental microbial communities combined with in vivo experiments allows access to an unprecedented diversity of genomes whose content will expand the repertoire of microbe-based biotechnologies.

The targets and capabilities continue to expand. Stay tuned.

Thursday, December 22, 2016

Progressives, Students and the Academy

After this last election members of the Academy have gone public in their need to reduce the fear and uncertainty in the poor students under their care. Frankly, I do not recall any such during the Vietnam War, but then people were getting killed, even fellow classmates. In this case we have "harmful" words. I gather the levels of harm have dramatically changed.

In the New Republic there is a classic example of this Progressive think that has taken over. Namely the author rebukes one of the NY Times Progressives, a fact in itself which is telling. The author states:

Kristof’s portrayal of campus liberals is just another form of elitist stereotyping, the mirror image of assumptions that every Trump supporter is a narrow-minded racist. By burlesquing progressives in academia, Kristof is making a faux-populist gesture of the very sort that drives the Trump-era right in its contempt for teaching and learning. Trump and his supporters have no regard for knowledge or debate, and thrive on petty caricaturing of political opponents. The right has turned the learning process that is student activism, with all of its inevitable triumphs and miscues, into national news fodder that’s meant to mock and discredit academia, not to bolster freedom of speech or ideological diversity. In this era of virulent anti-intellectualism, we don’t need more caricatures of academic life, especially from the left. We need more public intellectuals, especially progressive ones like Kristof, to stand up for the value of higher education—because without it, our political echo chambers would become that much worse.

One does not need to poke fun at Academia, they do the task so well themselves. It is not the right that turns the student absurdity into what it is, it is the acts themselves. The need to "protect", to deal with such things as micro-aggression, whatever that is. The conversational approach of asking about some students origin is now an overt hostile act. It at one time was a means of starting a friendly conversation. Now it is viewed as real aggression.

Now is it really true that Trump and all his supporters have no regard for knowledge or debate, and thrive on petty caricaturing of political opponents as noted above. What is the basis for that statement? If one were to ask such a question then the absurdity of the Left becomes apparent. In fact in a recent set of interactions I found the opposite may have some basis of fact.

This week in two cab rides I had two drivers. One was from Lebanon and the other from Egypt. Just a few hundred miles distance. The Lebanese was a Trump supporter the Egyptian a Trump hater. The Supporter went through his "on the one hand and o the other" which led to a conclusion. I just listened. The Egyptian was a Trump hater, stating each and every point one would hear on MSNBC. Again I just listened. I wondered which one was better off. I guess the Lebanese fellow, he did not spew forth anything.

As we enter our ninth year, I wonder if this issue will become more dominant. Will it be the focus of an ongoing battle with little benefit to the Country. Who benefits from it? That perhaps is the question.

Wednesday, December 21, 2016

Student Debt

Student debt is still exploding. Is it worth the economic risk? Should everyone have a college education, a college degree? Fifty years ago as we entered the Space Age it was still selective. The Government had programs to fund scientists and engineers. They even had programs to learn Russian. The Government spent money on college students via such things as NASA scholarships. Good students would qualify for financial aid in areas which benefited society and its needs at the time. Made sense. It did not fund liberal arts, literature, fine art. It did not even fund finance majors or law students.

Then what happened. I would argue two things.

First, the Government decided that everyone should get a college education. This led to two results. First it allowed massive numbers to major in subjects that allowed reduced standards and no jobs. Just how many fine arts majors do we need or even how many college educated graphics designers. Second, it motivated many to obtain debts that they ultimately had no economic basis to pay off.

Second, the Government backed massive college debt in direct and indirect manners. This meant two things happened. First students bought into the dream and surrendered to massive debt. Second, and this is the most serious problem, as the Government got more involved it drove up University overhead costs and thus tuition costs, with no appreciable increase in quality. In fact the quality I would argue has seriously suffered.

Thus we have a higher education system infiltrated by Government money and demands and universities responding with profligate spending and acquiescence to Government trends, demands, and dictates. University Presidents now talk as if they were managing some recovery center for orphaned and disadvantaged children. They tend to protect them from the fears of what may be happening in the outside.

In the NY Times, a college president states:

Donald J. Trump has made bold and provocative campaign promises on taxes, trade, immigration and infrastructure. These pledges are all in service of bolstering our economic future. While we hope these initiatives will help our economic prospects, there is one important measure missing from the debate. And it could have an even more immediate and direct impact on economic growth: student debt relief. Student debt now stands at $1.3 trillion. More than half of student borrowers are unable to repay their loans according to the original terms. In a well-intended but poorly executed effort to make college broadly accessible, the government has lent freely to students, with little attention to whether they can repay those loans. The result is millions of young people with debt they cannot afford. As a college president, I frequently hear from students who are anxious about their ability to repay their loans once they graduate. Many let student debt guide their career choices.

I gather that the NY Times mandates some Trump statement, and at least here the author got the demand out of the way in the first sentence. Now back to the facts. More than half the students cannot pay back the $1.3 trillion. Yes, that is a lot of money. But whose fault is it. I suggest the students. Namely they chose studies for which there is no demand. Further they committed funds to schools which may bring little to the job table. So why burden those making money to pay for those who may most likely never do so?

Then we have the authors policy recommendation. She states:

Mr. Trump should scrap debt financing of higher education and make the transition to true income share arrangements. Borrowers would fulfill their obligations to taxpayers by paying a fixed percentage of their income over an extended period of years. Think of this change as a shift in the government’s role from creditor to equity investor. When you lend to a business, it is obligated to pay you back with interest, but with a stock investment, your returns derive from the success of the company.

Yep! Indentured servitude to the Government.  This does not solve or even address the problem. Young people should choose a course of study to get a job. Later on in life they can worry about expanding their horizons if and when the have made enough to do so. This suggestion in my opinion would create a death spiral. Individuals have responsibility to make wise decisions. The young person who enters the military is making a decision to defend their country. A wise and respectable decision. Becoming an engineer, a nurse, a physician, even a banker means contributing to society in an enlightened manner. There is a demand and the investment by the student has a good chance of a return. 

One of the big challenges we face is the ever altruistic hand of big Government. It will destroy the entrepreneurial spirit. That spirit is one that takes risks. Government of the ilk of this author wants Government to burden all to minimize or eliminate risks. The result is the death of the entrepreneur.

Air Traffic Control

I had spent a few years working in the Air Traffic Control, ATC, space decades ago. Some at MIT while working at Lincoln Lab and some with FAA while in DC. Back in 1976, yes forty years ago, I was an Advisor on satellite based ATC systems while in DC. Now some forty years later the ESA announces its intent to really really explore it again.

The ESA states:

ESA recently completed its first flight trials using satellites to help bring Europe closer to its goal of modernising air traffic control. The trials are part of the public–private partnership between ESA and UK satellite operator Inmarsat to deliver high-capacity secure digital data links via satellite for air–ground communications for cockpit crews over European airspace under ESA’s Iris Precursor programme. By 2019, Iris Precursor will provide air–ground communications for initial ‘4D’ flight path control, pinpointing an aircraft in four dimensions: latitude, longitude, altitude and time. This will enable precise tracking of flights and more efficient management of traffic. 

Unfortunately this time the risks may be much greater. Satellites are vulnerable, networks can be hacked, signals can be spoofed, and not by National adversaries but by some less well intentioned individual with a laptop.

Thus what forty years ago was a great idea, in today's world, could cause havoc. Nice try but it is a bit too late.

Tuesday, December 20, 2016

Populism; What is It?

Populism as a term has burst forth on the political landscape. In a recent Nature article, the classic scientific journal turned political commentary sheet for the left, notes:

Right-wing politicians in the crop currently making headlines are populists in that they want the will of the people to be the point of departure for political decision-making. This ‘general will’ should, according to their populist message, be translated as directly as possible into actual political decisions. All institutions, rules and procedures that stand in the way of such a direct expression of the general will are conceived of as liabilities that should be removed as quickly as possible. Minority rights? They hamper the direct expression of the will of the people. Checks and balances? They delay the decision-making process. Political compromises? They lead to the dilution of policy proposals and therefore to a lack of decisiveness. Free media? It only represents the interests of the ‘established order’.

Imagine that, the will of the people is bad. Yes, indeed, when the people voteŠ± if the elite think they are wrong then the will should be disregarded.

This is an example of two extremes. Populism is a rule of the majority; Progressivism is a rule of the "elite" or "smart" minority. Frankly neither of them make any sense. As we have written, the concept of Individualism, in the context of de Tocqueville, is in essence what made this country great. Simply Individualism is respect of each person equally, namely there are no special advantages, there are no minorities, because each is equal under the law.

The challenge going forward will be respect the individual. There are no winners or losers, there is only an amalgam of equally persons under the law. There is no Galbraithian group of great thinkers who we look to for guidance. There really is no great wisdom from Harvard, in fact there may just be a collection of disaffected persons.

Thus is one understand Individualism as not being one of isolation but as one of being equal inclusion then we need not fear the tyrants of the Academy nor the Tyranny of the Majority.

The Nature author continues:

More academics must speak out and warn about where we are heading. Part of this is immediate self-interest. There is no reason to expect that academia will be immune to the kind of populist interferences that we are now seeing in Hungary and Poland. Populist attacks on checks and balances and media freedom might well spill over into attacks on academia as well. After all, populists not only attack political and economic elites; they also target ‘snobby intellectuals’ in academia. In fact, such attacks on academics are happening in Turkey right now. Academics also have a moral obligation to protect liberal democracy. By promoting social and political pluralism, the system produces the circumstances under which researchers can do their jobs and science can flourish. Researchers depend on it.

Perhaps Academic should first listen to the people. Academics truly have no idea about the real world. Over fifty years I have seen this phenomenon become greater. They live is an ever diverging echo chamber. leaving behind reality. Unlike Socrates and the Agora, namely teaching in the market where counter ideas flowed from the people, Academics dictate from their positions of power. There is no room for "what ifs" with the Academy. It is the 21st Century version of a religious cult. The Individual is berated, suppressed, so no wonder it emerges as a revolt of the Populace.

Spin

The recent events surrounding the taking of the US underwater drone is interesting. It was some 60 miles north west of Subic Bay.
That is about about 60 miles north west of the red dots. About a third the way to the upper left hand corner.

Now as China Daily states:

The US drone that China seized in the South China Sea has been successfully returned, China's Defense Ministry said. "After friendly negotiation, the drone was transferred to the US at a location in the South China Sea on Tuesday noon," the ministry said in a press release. The drone was discovered and retrieved by Chinese Navy last Thursday to "prevent danger to the safe navigation of passing ships and personnel", the ministry said. It was operating about 93 kilometers northwest of Subic Bay off the Philippines.

Just a friendly removal of a sea lane obstacle or Act of War?


 Step back a bit, the location is just a small distance off the coast of the Philippines in International waters, a quite a distance from China.

So what are you to believe. The Chinese or your lying eyes?

Science makes an interesting statement:

For ocean scientists who have worked with the U.S. military, today’s news that Chinese forces seized an oceanographic glider launched by an unarmed U.S. Navy research ship working in the South China Sea has a familiar ring. It’s not the first time that Chinese ships have confronted the USNS Bowditch or one of its five sister oceanographic ships, a little-known U.S. Navy fleet operated mostly by civilians that conducts mapping and ocean data collection cruises around the world. In 2001 and 2002, for instance, Chinese Navy frigates dogged the Bowditch as it worked in the Yellow Sea, leading to an exchange of diplomatic complaints. In general, the Chinese object to the U.S. Navy conducting research activities within China’s exclusive economic zone (EEZ), which stretches some 320 kilometers off its coastline. But U.S. officials have long held that the United Nations Convention on the Law of the Sea specifically allows military ships to conduct research cruises within a nation’s EEZ.

One should also remeber for whom ths shipe is named, the great New England navigation expert.

Happy 8th Birthday

This Blog is eight years old today. Over 200,000 visitors from 152 countries. To remind some readers, in 2008 when we started the focus was the economic collapse. The issue was that the world of economists were clueless. We managed to bumble along to where we are now redefining such metrics as unemployment to yield "good" results while at the same time leaving tens of millions out of the labor pool.

We then moved to Health Care and the then emerging ACA. We demonstrated again and again that what was being proposed had fatal flaws. We argued that Health Care should be universal, mandatory, like auto insurance in that it covers a catastrophic event only. If you want full comprehensive with no deductibles then you pay. We also argued no per-existing conditions, no age restraints, and a Government subsidy based on income. Most importantly we argued for individual payment, no Company Plans, and enrollment directly with an Insurer NOT through a Broker. In today's world you can do this on line, why nor to some generally ignorant broker.

We then moved to some key observations. People are fat, smoke, do drugs, and for those choices they should and must pay. If you want top be morbidly obese that is your choice but the cost to be incurred should be from your pocket. Same for smoking. Why should those trying to be health pay. On the other hand if God forbid you get cancer, then you should not be burdened with the added costs.

Then I moved on to Cancer and the progress of understanding and treating it. We will continue this focus.

Finally, this past election cycle has raised a great number of thoughts. As one who spent almost ten years in and out of Russia I perhaps have a different view. But clearly we need better relations, but better from a position of competence, not one driven by neophytes. The next eight years will present challenges never seen before. How they will be dealt with is anyone's guess. Let's just see.

Oh, and one last thing. Let's try to get out of this fear thing that people are all gaffing about. I have been seeing some of the best Universities turning into homes for over sensitive infants. Thus again, grow up.

Saturday, December 10, 2016

When Science Tries to Shingle the Roof in the Fog

There is an old standard from Cape Cod, "Don't shingle the roof in the fog", you run out of roof real soon. But it seems that Nature and the Intellectuals have seen fit to keep on shingling despite the dense fog about them.

Nature especially has taken to this road. As Nature has recently touted:

In the United States, the regions hardest hit by globalization have become more politically extreme, according to a working paper published in September by David Autor, an economist at the Massachusetts Institute of Technology in Cambridge, and his colleagues. They found that these areas elected more hard-line candidates of both stripes to Congress between 2002 and 2010 — Republicans in majority-white communities and Democrats in ethnically and racially mixed areas. A separate, as-yet unpublished analysis by the team suggests that the trend towards extreme candidates favoured Republicans in presidential elections from 2000 to 2016 — perhaps enough to win Trump the White House this year.

Thus one must be "extreme" to vote this way.  If one does not agree with you then one is extreme. The epithets continue without basis.

The author continues:

The Nazis took advantage of the extreme economic hardship that followed the First World War and a global depression, but today’s populist movements are growing powerful in wealthy European countries with strong social programmes. “What brings about a right-wing movement when there are no good reasons for it?”Anheier asks.

Always good to call them Nazis. Especially if you are from across the pond. Try a trip to Munich, I saw that they are still there in places. Not a lot in Iowa.

Then the author continues:

Trump also prevailed in part because the structure of the US electoral college gives outsized influence to Republican-leaning rural areas over Democratic urban centres. And some of his predominantly white supporters voted for President Barack Obama, a Democrat, in past elections.

This is a good one.  You see the Founding Fathers were smart. They did not want New York City and LA to elect the President. They wanted some balance. The Electoral College system does balance a bit. The author may want to read the Federalist Papers. Nice explanations. But it appears that these scientists are devoid of facts.

One should ask in a clinical fashion "why" the election turned out the way it did. I have sat through dinners where the battle back and forth never examined the question. Not for want of trying..

Science deals with facts. Facts and causes and results. Science does not deal with name calling as this piece seems in my opinion to reek with.

Privacy and Secrecy

Some "Novelist" in the NY Times writes about privacy and encryption. I am always amazed when some "writer" takes it upon themselves to opine on topics for which they seem in my opinion to have little if any understanding, at least so far as their presentation of the topic is concerned. But alas, it is the NY Times which has become the perpetual source of anti putative President paper of record. But let us put that aside. As the writer states:

I’ve never been able to fit the concepts of privacy, history and encryption together in a satisfying way, though it continues to seem that I should. Each concept has to do with information; each can be considered to concern the public and the private; and each involves aspects of society, and perhaps particularly digital society. But experience has taught me that all I can hope to do with these three concepts is demonstrate the problems that considering them together causes. Privacy confuses me, beyond my simplest understanding, which is that individuals prefer, to different degrees, that information about them not be freely available to others. I desire privacy myself, and I understand why other individuals want it. But when the entity desiring privacy is a state, a corporation or some other human institution, my understanding of privacy becomes confused. 

 Let's see. First three concepts; privacy, history, encryption. Kind of like; tomato, jumping, and elasticity. Not a single common thread but somehow he tries to get a nexus. I think I get it. Let us consider the seminal work on American privacy. Namely "THE RIGHT TO PRIVACY" by Warren and Brandeis (Originally published in 4 Harvard Law Review 193 (1890)) which states: 

If the invasion of privacy constitutes a legal injuria, the elements for demanding redress exist, since already the value of mental suffering, caused by an act wrongful in itself, is recognized as a basis for compensation. The right of one who has remained a private individual, to prevent his public portraiture, presents the simplest case for such extension; the right to protect one's self from pen portraiture, from a discussion by the press of one's private affairs, would be a more important and far-reaching one. If casual and unimportant statements in a letter, if handiwork, however inartistic and valueless, if possessions of all sorts are protected not only against reproduction, but against description and enumeration, how much more should the acts and sayings of a man in his social and domestic relations be guarded from ruthless publicity. If you may not reproduce a woman's face photographically without her consent, how much less should be tolerated the reproduction of her face, her form, and her actions, by graphic descriptions colored to suit a gross and depraved imagination. The right to privacy, limited as such right must necessarily be, has already found expression in the law of France.

To a degree privacy is a right to be left alone. It goes well beyond the Fourth Amendment. It is a right to live in one's own sphere,  not being attacked and examined by others. Now such a concept is extreme and even if such exists then one rejects it once one places oneself on say the Internet! 

History is what we try to garner about the past by records available, public and private. For example what did FDR think of Churchill, and did JFK almost get the US nuked because of his dalliances? Good for books, possibly for History. Both gotten from private records.

Then there is encryption. Namely the ability that anyone has to take some record of something which has been reduced to a discoverable entity, and protect its discovery, except by some authorized party by some secure encoding. Thus did JFK send secret love letters to his paramours and if so when and what do they say. If encrypted one may never know and thus the impact on the writer of History could be impaired. I think that is what this fellow is trying to say.

They are three distinct topics, like "Charlie" and "in the water". One is a name and the second is a condition. Perhaps.

But the use of news type to present this is questionable at best. The job of the Historian is to reassemble the past from a puzzle like collection of data. Some may be indecipherable, lost, or just wrong. Privacy is what a person has a right to until such time as they give that right away. The pity is that it is now so easy to relinquish that right before anyone even understands what it is.

Missing the Point, As Usual!

The Harvard Economist recommends the post by a CEA member who advocates men take jobs usually performed by women.

The Economist in the article states:

Policy wonks like me have wondered why more lower-skilled men aren’t adapting. Why don’t they take care of their children when they are out of work? Why don’t they take jobs as home health aides? Or sign up for degrees in nursing? One problem is that these occupations conflict with traditional notions of masculinity. They require sitting, caring and communicating, as opposed to working with big machines.

To anyone who has or should have been examining the distribution of labor by segment knows or should have known is that more and more jobs are in Health Care and Education and Government, such as teaching. You see my dear economist friends, all of these jobs are paid from taxes! Yes, surprise, taxes. And these folks want more people to get jobs funded by taxes? Who will pay the taxes? Oh, I forgot, it is the $10 trillion more debt over the past eight years. I would call that funny money.

Frankly I do not know what the incoming President thinks, but I know the numbers. We need jobs that create value not deplete it. Manufacturing may be the name for the jobs creating value and paying taxes. Nurses are wonderful. But they do not create value in a true economic sense, namely we are taxed to pay for them. Ever heard of the ACA or eve Medicare? Yes, Medicare is a tax that for me I have been paying every years since 1965! Likewise for Social Security, guess it will end when I die, and not really, the Government gets one last grab from inheritance tax.

So folks, jobs that create exogenous value are real jobs. Making a wrench, digging a ditch, writing software, installing an outlet. Not one single Government employee creates value. They live off the dole, the taxes paid or to be paid by those who do create value.

The pity is that we have these economists who I believe have never held a job. A real one at least.

Wednesday, December 7, 2016

Remember Pearl Harbor

Since most Millennials have not a clue of Pearl Harbor or most likely where it even is, I thought for the 75th I may provide a bit of context.











It was an important event. As was 9/11. But it ended much more quickly.

Monday, December 5, 2016

A Hearing to Watch

Tomorrow the USPTO will hear the CRISPR patent case. As The Scientist notes:

CRISPR, the gene-editing technology that has taken the scientific community by storm, will have its day in court tomorrow (December 6) as three judges at the United States Patent and Trademark Office (USPTO) hear oral arguments to decide who owns the valuable intellectual property over its use. “The Broad Institute [of MIT and Harvard] is requesting priority based on its patent application filed on December 12, 2012,” ...The University of California, Berkeley, (UCB)/University of Vienna, on the other hand, is asking for its patent applications—filed on May 25, 2012 as well as in 2013 and 2014—to be prioritized. The first patent for the use of CRISPR to edit eukaryotic genomes went to Feng Zhang of the Broad Institute of MIT and Harvard University in spring 2014. However, another group—including Jennifer Doudna of UCB and Emmanuelle Charpentier, formerly of the University of Vienna—had filed a provisional patent application for their CRISPR technology six months earlier. In January, at the request of UCB, the US Patent and Trademark Office (USPTO) declared an “interference” between the two, and the agency now seeks to settle once and for all who has intellectual property rights to the gene-editing technology that has taken the scientific community by storm. Although the USPTO recently changed its rules from prioritizing “first to invent” to giving precedence to “first to file,” the CRISPR patent applications in question predate the rule change.  The interference proceeding, therefore, will be based on the “first to invent” system.

As we have noted before this will likely be a real Cat Fight. The timing and the rules will be most likely the telling fact.

Sunday, December 4, 2016

Carpet Bombing Cancer



The immune system is a powerful attack system. Take the simple example of the common cold. You touch something, or someone coughs and sends particle towards you. The virus enters your nose. Then what? The immune system recognizes this new adversary, the virus, and it sends out warning signals, recruits immediate responders, and at the same time the virus multiplies the immediate immune system releases a volume of cytokines, killer proteins to carpet bomb everything in the path of the virus. The nose starts running, the throat gets sore, the lungs get congested as the battle between the growing virus load is slowly overcome by the ever faster growing immune response. So what makes us feel so bad with a common cold? It may very well be the immune system response rather than the attack.

Now consider working in the garden. Peaceful. Relaxing, at least for some. Then as you dig up weeds, you notice you just unearthed roots that attache to that shiny three leaves plant. Poison Ivy! But no immediate response, you go in and wash your hands, and thinks all is well. No luck. Slowly you start itching and have wheals all over your hands and arms. Again the near immediate response. Your immune system is after that interloper.

These two examples show how this protector of our lives can makes us worse off. It carpet bombs any attacker.

The NY Times notes[1]:

Another recent paper found that 30 percent of patients experienced “interesting, rare or unexpected side effects,” with a quarter of the reactions described as severe, life-threatening or requiring hospitalization. Some patients have died, including five in recent months in clinical trials of a new immunotherapy drug being tested by Juno Therapeutics Inc. The upshot, oncologists and immunologists say, is that the medical field must be more vigilant as these drugs soar in popularity. And they say more research is needed into who is likely to have reactions and how to treat them. “We are playing with fire,” said Dr. John Timmerman, an oncologist and immunotherapy researcher at the University of California, Los Angeles, who recently lost a patient to side effects. The woman’s immunotherapy drugs had successfully “melted away” her cancer, he said, but some weeks later, she got cold and flulike symptoms and died in the emergency room from an inflammatory response that Dr. Timmerman described as “a mass riot, an uprising” of her immune system. “We’ve heard about immunotherapy as God’s gift, the chosen elixir, the cure for cancer,” he said. “We haven’t heard much about the collateral damage.”
 
Unlike chemotherapy, immunotherapy can be long lasting. For example, the CAR-T cells which we have discussed are the patient's cells genetically engineered to recognize cell surface markers and when seen destroy the cancer cell. That would be fine if and only if the cells destroyed are cancer cells. However, there may be unintended consequences. First, there may be other cells which we do not yet fully understand that express the same or similar surface marker. They then also become targets. Second, and this is an issue, is that the process of destruction may have a lot of surrounding cells getting mascaraed, due to the released cytokines. This is collateral damage. Third, the collateral damage must be gotten rid of and this is part of the function of the immune system and this may be some positive feedback loop resulting in a set of catastrophic systemic failures.

Unlike chemotherapy, which is some chemical which kills certain types of cells, say rapidly reproducing ones, thus killing cancers as well as say hair. Immunotherapy may be long lasting if not permanent. You just can't stop administering it. Once started it may last forever, or at least until the patient dies. However, some recent work demonstrates that T cells do get "exhausted".[2]  The authors note:

During cancer or chronic infection, T cells become dysfunctional, eventually acquiring an “exhausted” phenotype. Immunotherapies aim to reverse this state. Using a mouse model of chronic infection, two studies now show that the epigenetic profile of exhausted T cells differs substantially from those of effector and memory T cells, suggesting that exhausted T cells are a distinct lineage (see the Perspective by Turner and Russ). Sen et al. defined specific functional modules of enhancers that are also conserved in exhausted human T cells. Pauken et al. examined the epigenetic profile of exhausted T cells after immunotherapy. Although there was transcriptional rewiring, the cells never acquired a memory T cell phenotype. Thus, epigenetic regulation may limit the success of immunotherapies.

However, there is an explosion of new markers and CAR-T cell targets. Juno Therapeutics lists some of the surface targets which their therapeutics address[3]. They are:

CD19… a cell surface marker for lymphocytes that is present on most B cell malignancies, including acute lymphoblastic leukemia and various subtypes of non-Hodgkin lymphoma, including diffuse large B-cell lymphoma.

WT-1: …high-affinity TCR T cell product candidate targets WT-1, an intracellular protein that is overexpressed in a number of cancers, including adult myeloid leukemia, or AML, and non-small cell lung, breast, pancreatic, ovarian, and colorectal cancers.

CD22…Like CD19, CD22 is a cell surface marker for lymphocytes that is present on most B cell malignancies, including acute lymphoblastic leukemia and various subtypes of non-Hodgkin lymphoma, including diffuse large B-cell lymphoma.  Importantly, CD22 expression has been shown to be maintained in acute lymphoblastic leukemia that has lost CD19, making anti-CD22 CAR T cells a potential combination or follow on therapy for CD19 CAR T cells.

L1-CAM…also known as CD171, is a cell-surface adhesion molecule that plays an important role in the development of a normal nervous system. It is overexpressed in neuroblastoma, and there is increasing evidence of aberrant expression in a variety of solid organ tumors, including glioblastoma and lung, pancreatic, and ovarian cancers. Our L1CAM product candidate was originally developed at SCRI.

MUC-16 / IL-12…a protein overexpressed in the majority of ovarian cancers, but not on the surface of normal ovary cells. CA-125 is a protein found in the blood of ovarian cancer patients that results from the cleavage of MUC-16. CA-125 levels in the blood are a common test for ovarian cancer progression because they correlate with cancer progression. Our MUC-16/IL-12 product candidate, which was originally developed at MSK, has a binding domain that recognizes an extracellular domain of MUC-16 that remains following cleavage of CA-125.  Our MUC-16/IL-12 product candidate is our first development candidate that uses our “armored” CAR technology.

ROR-1…a protein expressed in the formation of embryos, but in normal adult cells its surface expression is predominantly found at low levels on adipocytes, or fat cells, and briefly on precursors to B cells, or pre-B cells, during normal B cell maturation. ROR-1 is overexpressed on a wide variety of cancers including a subset of non-small cell lung cancer, triple negative breast cancer, pancreatic cancer, prostate cancer, and ALL. It is expressed universally on B cell chronic lymphocytic leukemia and mantle cell lymphoma. Our ROR-1 product candidate was originally developed at FHCRC.

One major concern is that of targeting the right cell. We assume that we can identify a specific cell by its unique surface marker. We design a specific immune targeting mechanism that goes after that cell. But if we believe in the stem cell theory of cancer, we more than likely have not targeted the stem cell. We have targeted some of it proliferations but not control elements. In fact, I would be willing to bet we have not targeted the stem cell. Thus, any immunotherapy may just make cancer a chronic illness but would not be curative. One then would be concerned by the continuing mutations.

Immunotherapy is a derived or indirect therapy. It is derived from examining how cancer cells are different, based upon surface markers. It is indirect because it deals with a secondary effect of the failing cell. It does not care what the problem is inside the cell but just that it has a different cell marker. In contrast the pathway methods whereby we know what pathway element is defective addresses a specific direct defect. This is a directed therapy.

Immunotherapy has a wealth of tools. T cells, NK cells, CAR-T cells Mabs, IL variations and the likes. To a degree, they are all a step up from chemotherapy but do not necessarily represent a panacea. There are two things we must do. First identify the stem cell and its characteristics. Second, eliminate the stem cell or fix the genetic fault. Until then we will always have the unintended consequences.