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February 26th, 2015

The Fight Over Who Invented siRNA Used for Therapeutic Gene Silencing

from John (I’ve been following this story since the beginning of 2010)

Prequel

The Tuschl II priority application describing the invention of siRNA for therapeutic gene silencing assigned to Max-Planck Institute was filed in the European Patent Office patent application number ‘325 to establish a priority date of the December 1, 2000. This filing date indicates that Thomas Tuschl and his two colleagues, Elbashir and Lendeckel, invented siRNA before that date. The Tuschl I (a second patent family) priority date was March 30, 2000. The Tuschl I interfering RNA invention assigned to Max-Planck, Whitehead Institute, MIT, and UMass   described siRNA vaguely in comparison with the Tuschl II invention which described dsRNA molecules of precise size with the required 3’-overhanging nucleotides. Max-Planck agreed to allow one Tuschl II experiment to be placed in the specification of a Tuschl I application. It was because of negligent management of the Tuschl I invention assignment in early 2000 by the Whitehead Institute that Philip Zamore, one of the four Tuschl I inventors, managed to assign his rights to the invention to the University of Massachusetts (UMass) in April 2000. On the record in court, this mistake led Judge Saris to call the Whitehead Technology Licensing office staff “airheads” in dismissing the assignment issue because, at the time of the initiation of the lawsuit by Max-Planck and Alnylam Pharmaceuticals in 2009, the statutes of limitation had expired on this assignment issue.

The size of the siRNA molecule is important for “best mode” practice of the art of therapeutic gene silencing. Large double-stranded RNA molecules will activate innate immune mechanisms such as the induction of Interferon which will diminish therapeutic potential whereas small siRNA molecules by-pass this adverse side effect.

In 2001 Whitehead Institute requested and received approval from Max-Planck to incorporate aspects of the Tuschl II filings into the specifications of the Tuschl I filings, but not as amended claims. Apparently an understanding (outlined in a 2001 document and an Information Disclosure Statement submitted to the USPTO in 2005) was struck that the rights to the Tuschl II invention would be owned exclusively by Max-Planck. In 2005, according to the complaint filed by Max-Planck and Alnylam in federal district court on July 2, 2009, Whitehead began a secret “scheme” to obtain those Tuschl II rights, essentially by incorporating important features of the Tuschl II invention into the claims of the Tuschl I filings. Alnylam Pharmaceuticals which had been founded by the fourTuschl I inventors – Tuschl, Zamore, Sharp, and Bartel – was supposed to have exclusive rights to Tuschl I (and Tuschl II), but UMass licensed its rights to Tuschl I to Sirna Therapeutics, a direct competitor of Alnylam, in 2003. After acquiring this license Sirna Therapeutics purported licensing of Tuschl II because of the Tuschl II features inappropriately placed in Tuschl I applications. An exhibit regarding this Sirna license (from UMass), “List of Patent Rights,” identified the earlier Tuschl II ’325 priority application as the priority document of the Tuschl I patent family. In 2008, Max-Planck and Alnylam Pharmaceuticals accused Whitehead, MIT, and UMass of taking affirmative steps to effectively gain title to the Tuschl II invention and destroy the property interests of Max-Planck Society and Alnylam in those inventions. Thus, in June 2009 Max-Planck and Alnylam sued Whitehead, MIT, and UMass to win back control of both Tuschl I and Tuschl II in licensing for therapeutic uses of siRNA.

Thomas Tuschl had moved from the Whitehead Institute to Max-Planck in 1999 and teamed up with Sayda Elbashir and Winfried Lendeckel. From late 1999 to the fall of 2000, these three inventors determined that the optimal structure of exogenous interfering RNA in mammalian cells was a 21-23 nucleotide dsRNA with one or two nucleotides at each 3’-strand end unpaired (3’-overhangs) which they synthesized de novo. This is the essence of the Tuschl II invention. These three inventors published this discovery on January 15, 2001 (Elbashir et al) that was submitted for publication on October 25, 2000, and in this paper the authors coined the term “siRNA” for “short interfering RNA.” The authors described 21-23 nucleotide synthetic dsRNAs with 3′-overhangs and demonstrated efficient gene silencing in a drosophila cell lysate and later for the first time in human cells four months later in Nature (Elbashir et al) without further processing of the siRNA molecule.

Here are the authors of the Nature paper (about 10,000 reference citations to date) published on May 25, 2001, left to right: Klaus Weber, Jens Harborth, Thomas Tuschl, Winfried Lendeckel, Sayda Elbashir, and Abdulla Yalcin in the lab at Max-Planck in Goettingen.

Merck bought Sirna Therapeutics for $1.2 billion in 2006 purportedly believing (wink, wink) that it had access to the Tuschl II invention. The lawsuit filed in June 2009 was settled in March 2011 with conditions favoring the Plaintiffs, Max-Planck and Alnylam. In return Merck was given several options to pursue siRNA therapeutics. This competitive situation was ultimately resolved when Merck shut down its RNA interference program and Alnylam was allowed to purchase all of Sirna Therapeutics RNA interference IP from Merck in an amicable agreement.

UUtah Sues Max-Planck, Alnylam, Whitehead, MIT, and UMass Claiming Inventorship of siRNA for Therapeutic Gene Silencing

In the week after settlement of the lawsuit described above in March 2011, UUtah sued all the Plaintiffs and defendants of this first case. UUtah alleged that Professor Brenda Bass invented the Tuschl II subject matter before the defendants’ inventors. UUtah alleged that the defendants “misappropriated” her invention stating that the Tuschl II named inventors (Tuschl, Elbashir, and Lendeckel) intentionally claimed Dr. Bass’s invention as their own. The defendants responded that Dr. Tuschl never discussed any joint research endeavors, or even plans for joint research endeavors, at scientific meetings at Cold Spring Harbor Laboratory and in Upsala Sweden which both he and Dr. Bass attended; and in fact, Dr. Bass and Dr. Tuschl never engaged in any such joint research. By contrast, UUtah alleged that Dr. Bass communicated her alleged conception of the Tuschl II invention to Dr. Tuschl in presentations in both meetings.

Dr. Bass had identified a gene “K12H4.8” in C. elegans (a nematode) that was known to produce an enzyme of a type known as “RNase III” colloquially known as “Dicer”. Unlike the Tuschl II inventors, Dr. Bass knew that Dicer cleaved dsRNA into 21-23 nucleotide pieces. As early as 1993, Dr. Bass understood that Dicer cleaved longer strands of dsRNA into short dsRNA causing staggered cuts that leave 3’ overhangs of about two nucleotides in length well before the RNAi phenomenon (gene silencing) was demonstrated. When RNA interference (RNAi) was first reported in 1998, the discoverers (Nobelists Andrew Fire at Stanford and Craig Mellow at UMass) were unable to describe the mechanism by which it functioned in a cell. When she learned of the RNAi discovery, however, Dr. Bass recognized that Dicer was likely to be involved. In 1998, she began developing experiments to test this conception that was ultimately carried out in her laboratory beginning in 1999. These successful experiments, completed in May 2000, reduced to practice Dr. Bass’s conception that Dicer was responsible for catalyzing RNAi; therefore, she concluded that short interfering dsRNA of about 21-23 nucleotides in length with 3’ overhangs were the mediators of RNAi in living organisms, and these short dsRNAs could be used to accomplish RNAi as a treatment for disease. This, later statement was not actually made in Dr. Bass’ insightful April 28, 2000 mini-review in Cell time.

The Tuschl I patents presented an experiment that indicated that the short fragments were less active than larger dsRNA leaving open the discovery of the best mode for siRNA activity. The Tuschl I paper published on March 31, 2000, suggested that one could affect RNAi by using the short dsRNAs but this paper makes no mention of 3’ overhangs or the length of the overhangs. About that time Dr. Tuschl and the other authors admitted in email communications that they did not know how the short 21-23 nucleotide dsRNAs were produced in the drosophila lysate, and that they did not know the structure of the short dsRNA fragments. Upon reading a pre-publication version of this paper in early March (published on March 31, 2000), Dr. Bass recognized that the K12H4.8 gene she had identified had all the properties necessary for RNAi, and that the resulting short dsRNA fragments would have the 3’ overhang. On March 21, 2000, she began drafting her mini-review, titled “Double-Stranded RNA as a Template for Gene Silencing.” Her draft included information about the Dicer enzyme that cleaves dsRNA into short 21-23 nucleotide dsRNAs with 3’ overhangs.

It has never been clear to me that Dr. Bass ever reduced to practice short siRNA-mediated gene silencing although public speculation can be a problem in prior art. She knew very well what the end-product of an RNase III reaction was, but not what the active best-mode structure of siRNA was for achieving therapeutic intracellular RNA interference. In addition, there was the first-time demonstration in the May 2001 Nature paper that synthetic siRNA worked in human cells using Weber’s and Harroth’s elegant (though non-inventive) indirect immunofluorescence assay (Klaus’ contribution of this assay was communicated to me directly with the added note that they repeated the assay over and over again because he was astonished that gene silencing actually worked in living human cells). It seems to me that if Dr. Bass’ description in 2000 was persuasive and enabling, either Dr. Zamore or Dr. Tuschl or someone else who read her paper or heard her talks would have reduced the invention to practice within a month. Klaus Weber mentioned this later in a videotaped interview of him and Thomas Tuschl. In support of this concern there is that pesky patent Figure 12 in the Tuschl I application that indicated that short RNAi duplexes were far less effective in RNAi than the larger duplexes.

Where the UUtah Case Stands Now

This is Moakley Federal Courthouse in Boston where the case is being litigated. If UUtah and Dr. Bass win this case you can imagine that hundreds of millions in royalties might be claimed (royalties previously earned by the four University assignees). Although this UUtah case was initiated in March of 2011, proceedings have been delayed by multiple amended complaints and jurisdiction appeals. On February 4, 2015, the court reconvened to hear arguments for and against release of 18 “banker boxes” containing 20,000 pages of hard-copy documents to the Defense. UUtah believes that these documents are not responsive to the Defense’s requests for evidence and are not relevant to this case. In making their argument the Defense stated “That’s a small amount of documents – and the burden in producing them – is nothing compared to the hundreds of millions of dollars that they’re seeking in this case.” Apparently the Plaintiff lawyers have reviewed each of these documents. These documents include lab notebooks, descriptions of experimental protocols, recording of ideas for experiments, and possibly commentary about the Tuschl inventions mostly written down after the filing dates of the Tuschl patents in 2000 up to March 22, 2011. Early in the first case UUtah learned that the Defense had revealed a theory that Dr. Bass was the actual inventor of siRNA-mediated gene silencing and proposed a deposition of Dr. Bass.

The Defense would like to focus on whether Dr. Bass ever did any experiments with short siRNAs of the type produced by Dicer cleavage or described in the Tuschl II invention. The Tuschl II patents now number 12 issued patents and over 500 claims. The Defense points out that most, if not all, of Dr. Bass’ experimental research on gene silencing was with large dsRNAs of about 500 base pairs in the nematode model. The Defense asks the question “why did she wait for 10 years before she came forward as the purported inventor?”… and she never filed a patent on her concept of the invention – e.g. preparation and use of siRNAs. The Defense wants to know how Dr. Bass was characterizing the discovery of therapeutic siRNA right up to the filing of its lawsuit.

The Plaintiff’s lawyers insist that they have produced all documents relevant to “short double-stranded RNA molecules”. They pointed out that the reason Dr. Bass did most of her research with long double stranded RNA molecules which in theory become Dicer substrates was because her research was conducted in C. elegans which lacked the innate immune response of mammalian cells. The Plaintiffs further pointed to Bass’ 2000 mini-review that described the action of Dicer to produce the active siRNA entities. UUtah’s lawyers assert that the description of siRNA in the mini-review entitles Dr. Bass to become an inventor. The Defense was offered an opportunity to visit UUtah and review the 20,000 pages of documents on December 2nd, but the Defense elected not to take this opportunity asserting that the Plaintiff had already pre-determined that these documents were irrelevant based on their own criteria and therefore would not turn them over.

At the end of this hearing the Defense revealed that Dr. Bass was to be deposed the following Friday (February 7th) . We shall see how this case proceeds.

February 7th, 2015

Holmeslea Gardens is Where We Will Buy Our Veggies This Coming Season

From John

Holmeslea Gardens website

Click to enlarge

January 22nd, 2015

Rowayton, My Home Town

From John

I lived my first 18 years in Rowayton CT. I’ve attached below an inspiring picture of Tavern Island. This is the harbor and open waters where I took sailing lessons for five years.

In the Picture:

dark green arrow = Hickory Bluff dock, beach, and store.

dark blue arrow = Tavern Island custodian house and dock.

purple arrow = Our house and beach in the 1960s.

red arrow = Shelly T. and the Trubowitz house with beach and canoe.

gray arrow = Fashionable Thomas School for girls where Diane went along with other Rowayton girls.

green arrow = Wilson Point beach where I was lifeguard/beach boy/tennis teacher for two years.

light blue arrow = Where I capsized in Shelly’s canoe in March of 1964 and had to swim the canoe with the current and the wind to the Wilson Point Beach…burrr.

pink arrow= Bell(e) Island where Margo, Laurie, Pam, Bronwyn, Roussie, Linda, and my Aunt and Uncle Charlie and Kate Cornbrooks with Suzie and Nancy lived. No wonder the Island was often called Belle Island.

orange arrow = Bayley Beach around the corner from Bell(e) Island and Roton Point. I spent almost every summer day there playing tennis in the summers. Ran the beach concession for two summers.

source: http://www.norwalkcitizenonline.com/news/article/Island-oasis-for-sale-in-Norwalk-3974742.php#photo-3633268 

also see my brother Peter’s story about lobstering at Tavern Island at http://rowaytonkids.com/

From our terrace looking at Tavern Island at dusk.

January 10th, 2015

Abortion as an Expression of Religious Freedom

From Diane

They say, “Be careful what you wish for. You might get it.” Welcome to the 114th Congress.

First, for those not conversant with our US Constitution, when the First Amendment uses the phrase “an establishment of religion,” it is not talking about building a brick and mortar church. The phrase applies to ideas, some codified in named religions, some promulgated by philosophical constructs, and
some simply held by ordinary people as deep, personal convictions in how Life and the Universe work. However these beliefs come to exist, they, and the people who hold them, are protected by our US Constitution from laws that would prohibit “the free exercise” of those beliefs.

I am amazed at the arrogance and hypocrisy shown when one simultaneously says, “We must follow the Constitution” and then turns right around and says, “Except when it come to MY beliefs. I am RIGHT so MY beliefs trump everyone else’s, never mind that the Constitution expressly forbids me imposing MY beliefs on you.”

So what do the new Republicans in Congress do on their very first day of office? They re-introduce as HR 36 the Pain Capable Unborn Child Protection Act that would criminalize abortions after 20 weeks of “probable” gestation. [BTW, note that the law includes this definition: “UNBORN CHILD- The term `unborn child' means an individual organism of the species homo sapiens, beginning at fertilization, until the point of being born alive as defined in section 8(b) of
title 1.” This definition is completely religious with no scientific basis whatsoever yet this proposed legislation includes this definition as fact.] The idea that a 20-week old embryo “feels” pain has been discredited by many scientists as well as both the AMA and the British Royal College of Obstetricians and Gynecologists. It would seem that what the conservative religious crowd BELIEVES trumps not only what you and I might believe but the
predominant scientific point of view as well. Are there scientists who state that a 20-week old embryo can feel pain? Yes. Are they in the majority? Do they
have peer-reviewed studies to back them up? No.

I can sympathize with those who oppose abortion. If your religion teaches that at the moment of conception, a one-celled zygote is a Human Being, an unborn Child, then clearly, for you and your religion, the premeditated “killing” of that zygote is first degree murder. However, the key phrase here is, “if your
religion.” Not all religions teach that a zygote is a Human Being. There are many different beliefs concerning when an embryo or a fetus becomes a “human
being,” none of which are allowed to be the basis of a law. Our Constitution CLEARLY states that Congress (and by amendment the States) shall not make laws based on religious beliefs. So although YOU sincerely believe that a zygote is a human being, UNDER THE CONSTITUTION you may not impose that belief through law on the rest of us who do not hold your beliefs. It does not matter if you “know” you are right. ALL religions “know” they and they alone are right.

What matters is that you cannot PROVE your beliefs so you take them on faith, the very definition of a religion.

January 7th, 2015

My Life With Influenza

From John

At a regular doctor’s appointment in the fall of 2012, I was approached by a third year medical student who was interning to learn private practice. He asked me if I would like to have the influenza vaccine and said “It’s got three antibodies!” I said no thanks thinking, this guy is going to be a doctor soon and he has no idea what a vaccine is. I think of that experience when I hear someone in a health profession tout the merits of getting the flu vaccine which happens ad nauseam every fall and winter. Scary articles are also published in newspapers by naive reporters predicting the worst for humankind each winter.

My first memory of the scourge of influenza was when I was in high school and my mother took me and my siblings (minus Andy) to Uncle Charlie’s office in Darien to get flu shots. Since I was significantly older and more mature, I was elected to go first to demonstrate that getting a flu shot wasn’t all that bad. Well, Charlie must have hit a nerve because I was racked with pain which shot up my arm and caused me to writhe in agony as I staggered out of Charlie’s office into the waiting room. I remember the horrified look on brother Peter’s face as he Phoebe and David prepared for the worst. It was obvious that I was not faking it ensuring that the experience would be most horrific for my younger siblings :-) .

I never got a flu shot again and have somehow made it to 70. Severe influenza should not be underplayed. I remember the two times I had it in my life – in January 1986 when I huddled in my one room apartment in Palo Alto, and then again in January of 2001 when both Becki and I were flat on our backs together. This disease can be horrible with a fever, extreme muscle soreness, and a hacking cough because our T-cell-mediated immune response in the lungs kills a lot of infected cells. When we were lying there, we both wondered if we were going to survive; so I gave Becki the upside that the virus was killing off cancerous and precancerous cells preferentially as it migrated through our bodies during the course of the infection. This testimony is the evidence that we survived to trudge on through life’s adversities.

I don’t mean to downplay the importance of vaccines like the polio vaccine, the smallpox vaccine, the diphtheria vaccine, and many others which have nearly wiped out these crippling or deadly diseases sparing many human lives. A paper published in November in the New England Journal of Medicine concluded that modern vaccines have prevented more than 100 million cases of severe disease (van Panhuis et al., N. Eng. J. Med. 269(22):2152-2158, 2013) caused by 12 major disease pathogens.

I know something about how these vaccines work having been hired by the FDA division that regulates government licensed vaccines. I also had learned how to grow the virus that causes diphtheria (a lysogenic bacteriophage) and how that disease works in Papenheimer’s lab at Harvard in 1974. I started to pay close attention to flu vaccine campaigns in 1976 when I was at Johns Hopkins in the fall of 1976 after the head of the CDC warned President Ford that the swine flu was coming (the same flu as the Spanish Flu that killed millions in the first quarter of the 20th century). Worried doctors at the hospital trekked across North Wolfe Street to warn us that we all had to get immunized or else… I remember thinking “me thinks not.” But my life changed dramatically for the better because of this national emergency. I had been hovering over the National Institutes of Health in Bethesda MD hoping to latch onto a job, preferably at the Bureau of Biologics which was the Division of the FDA that regulated vaccines and blood products. Then, the CDC’s concern was shared with Congress and, in their imminent wisdom, they voted to give the Bureau of Biologics extra funding to hire people to help deal with the impending swine flu crisis. The Bureau inaugurated a new class of temporary three-five year positions for Staff Fellows and guess who was the first to be hired – moi, as a Senior Staff Fellow no less. This was a wonderful break for me.

The epidemic never happened because the virus never showed up but some vaccinated people developed paralytic Guillain-Barre syndrome…and the head of the CDC was fired for embarrassing President Ford who had gone on nationwide TV to promote vaccination (Presidents giving health advice is a bad idea. Obama should have left promotion of Affordable Healthcare to the Head of NIH or the CDC :-) ). I first learned of this side-effect when I was invited to dinner at a local family’s house in Maryland. At the dinner table the patriarch of the family asked me where I worked. I described the Bureau as the division that regulated vaccines. He became very angry and described his debilitating Guillain-Barre syndrome in his vaccinated arm.

Early on I learned a lot about these viruses and how our immune system works with hands-on research. I persuaded my brother Andy to join me at the Bureau to help me with some experiments to show that we could type flu viruses by the electrophoretic properties flu virus proteins since there was some confusion about the serological identity of the vaccine H1N1 strain (“H1” stands for the haemagluttinin serotype and “N1”stands for the neurominidase serotype, the two surface antigens of the virus that can produce a humoral antibody immune response). In our study we included a strain of the invading H1N1 flu virus, the horrific Russian flu, that was isolated in mainland China that year which was going to wipe us out. Read the rest of this entry »

January 3rd, 2015

Remembering What It Was Like Living in Palo Alto CA

from John

Things were going quite well in my career in 1981 with a tenured civil service position with the FDA at the National Institutes of Health in Bethesda MD but for some reason I felt the need to move on. Twenty-two years ago on January 1, 1982, I loaded up my VW Rabbit with belongings, four immunized mice in a cage, and my liquid nitrogen tank containing all my frozen cell stocks and headed west from Marriottsville MD.

I had spent the previous month in Palo Alto scrutinizing my decision to leave the government, but returned before Christmas to submit my resignation. My colleagues at NIH said I was crazy to shed government security for a high risk position as a senior scientist at the Pauling Institute in Palo Alto which depended to some degree in me winning federal grants to fund my research. I was armed with a novel discovery and wanted to collaborate with a group at Stanford to get the jump on a possible competitor in Japan. My risk turned out well in retrospect. Moving to Palo Alto was like starting a new life on all fronts. No need to talk about the science side because that is a matter of record. This is more about the environment I created for myself in a delightful place to live.

(Click to enlarge map) So I embarked on that cold day, headed west on Route 70, then south at Hagerstown on Route 81 down the Shenandoah Valley to Tennessee and stopped in eastern TN for the night, don’t remember where. In the morning I got on Route 40 near Knoxville and made it to Henryetta OK by evening, a lonely night. The next morning I continued on Route 40 past Albuquerque. I remember looking in my rear view mirror to see the vast lights of Albuquerque on the western slope of the mountain range. I stopped at Grants NM on Route 40 where unknown to me, Becki had lived in a van and caught rattlesnakes for the local college. I was so eager to get to California that the following day I left Grants and drove 19 hours straight through a driving el nino rain storm to Palo Alto ending the trip at 4 AM in the morning in the rear parking lot of the Pauling Institute which was drenched and covered with tree debris. That winter was the wettest of the century for that area, but rainy days always included sections of blue sky in the distance. The hills to the west of Palo Alto were a verdant green, a shade of green that you never saw in the east. The summers were opposite as the open fields surrounding Palo Alto and Stanford turned golden because there was no rain from April to October or November. Except for unusual years the temperature rarely went below 50 degrees and summers were usually in the low 80s and a dry heat. In the Bay Area spring came around the third or fourth week of January with the yellow flowering of the Acacia trees and the popping of bulbs.

I had moved to a heavenly place and never looked back because I was challenged with survival but I survived because of momentum I quickly built through my research as a cell and molecular biologist. I quickly found Larry Kedes lab at Stanford, visited them, and told them that I needed their help in cloning a family of human genes. This was early in gene cloning, especially cloning of human genes. This collaboration moved forward rapidly and by late December I had cloned the human beta-actin gene although it took the better part of 1983 to prove it. At this point I had the ammunition to fund my lab and hire staff, but this story is not about the science.

I found a great coffee house/bookstore, Printers’ Inc. a few blocks away from the Institute which opened a 10 AM, so I would walk from my apartment in central Palo Alto to the coffee house arriving when it opened. There I would read the paper and gather my thoughts for the day. This is where I drafted grants and research papers for publication. I was surrounded by interesting people – writers, composers, and an ocassional Nobel Prize winner like Linus Pauling who I would address as Dr. Pauling. This where I started my coffee habit as well.

Palm Drive, the main entrance to Stanford, was only a few blocks away and I had the run of the campus using the Lane Medical Library and the university’s fields for our softball team, the Pauling Squeeze, which played various Stanford departments. There was also Stanford football, basketball, and top-notch college tennis to attend. One year my eldest daughter, Elizabeth (first marriage), visited and attended a tennis camp held on the campus by the tennis coach. Life was simple in that I walked or biked to work seven days a week working from about 11 AM to 8 or 9 PM each day. My apartment in the early days was a $200 a month single room with four closets – one for a fridge, one for clothes, one for a sink and shower, and one for a toilet. Walking through the neighborhoods was a delightful experience and I marveled that the owners usually had to have a 1st, 2nd, and 3rd mortgage in order to own, betting on their start-up company stock options. I ended up with one too. This was how scientists in the Silicon Valley got rich…that is if the business succeeded.

This was my playground (below). University Ave is the main street of downtown Palo Alto which crosses El Camino Real to Palm Drive, the main entrance to the campus. My small apartment was on Byron. Becki and I met one night at the Class Reunion a block way from the Pauling Institute. We ended up renting two side-by-side houses at the corner of Maureen and Rambow off of Cowper Ave. Mariah was born in October 1988 and we walked her to school a few blocks on East Meadow. The yellow lines are the routes I biked or walked from 1983 through 1995. The area encircled by the purple lines is Stanford Research Park which housed companies like Varian, Wall Street Journal, Xerox, Syntax (first birth control), Alza Corp, Roche, and many other notable companies. Eventually we were joined by Christina, Drew and Elizabeth who visited annually.

December 24th, 2014

Five Years Ago – Eleven Inches at Our House in North Woodstock

GOT PICTS? send them to woodstockctcafe@gmail.com.

We measured 11 inches. Below (1) our house, (2) John wrestling with the snow blower, and Becki pausing from shovelling on Route 197.

house-2.jpgsnow-blower-2.jpgbecki.jpg

December 7th, 2014

New Cell Towers to be Placed at the Fairgrounds

Formerly a Student: I just skimmed the proposal. The “new cell towers being placed” in the title of this article is misleading. To summarize, they’ll be replacing a few wood utility poles in the fairgrounds with steel ones “of equal height,” and adding a battery box and extra antenna (which itself looks like a box) to the poles. The existing antennas will be moved to the top of the poles. No extra access roads, no wetland disturbance, no ground disturbance except for the actual digging of the pole, little aesthetic change, especially from a distance (169).

Sounds good to me on the surface from how they’re presenting the info. But what makes me leery is that they propose that the new antennas will initially be 700 MHz (at 500 mW power). So do they plan on adding more antennas at different frequencies? Adding more poles in the future?

However, the other frequencies only go up — to 2100 MHz. Higher frequencies are lower range, so higher power, so they’re starting off with the best range. For comparison, the Wifi in your house is 2400 or, lately, 5000 MHz frequency but only 70 mW power. Lower MHz travel farther but have more interference (think AM vs. FM radio). Speaking of radio, think of how strong those signals are, compared to the cell towers, which are everywhere and thus have lower range.

Not sure how the numbers play in to health issues, but they say these things are mainly intended for the fairgrounds, and those are usually vacant. It doesn’t seem like the signal will be excessively strong outside the grounds (have a look at the coverage maps).

But again, all this is coming from the big business trying to weasel its way in, so take it with a grain of salt.

PETITION NO. 1119 - Cellco Partnership d/b/a Verizon Wireless petition for a declaratory ruling that no Certificate of Environmental Compatibility and Public Need is required for the proposed construction, maintenance, and operation of three pole-mounted small cell telecommunications facilities on the Woodstock Fairgrounds property located at 281 Route 169, Woodstock, Connecticut.   Field Review.

November 29th, 2014

Woodstock Academy Football 1 and 32 – September 2012 to November 2014 – Subtle Signs of Improvement

Woodstock football is 1-32 since two years and 3 months ago with this week’s loss of 8-41 to 9-1 Windham.

“Several years ago the Academy chose to invest in football with a new stadium and other unneeded athletic fields rather than invest in enhanced academic programs that would help students to develop professional careers.”

The average game score this year is 9 for WA vs 39 for the opponents compared to 7 for WA vs 42 for the opponents last year, and 5 for WA vs 43 for the opponents.

This year the Woodstock Academy football team ranks 156 out of 161 CT high school varsity football teams. The results for this season are:

Windham (9-1) – 41 Woodstock (1-10) – 8

Plainfield (9-1) – 47 Woodstock (1-9) – 7

Woodstock Academy  -   8  to Norwich Free Academy – 44

Woodstock Academy  – 3 to Waterford  – 35

Vinal RVT/East Hampton/Goodwin RVT -  16 to Woodstock Academy  -  13

Griswold   – 34 to Woodstock Academy  – 0

New London – 51 to Woodstock Academy  -  6

Woodstock Academy  – 0 to Montville  – 40

St. Bernard-Norwich RVT – 14 to Woodstock Academy  -  35

Woodstock Academy  – 7 to Bacon Academy -  52

Stonington – 48 to Woodstock Academy  – 7

“Headmaster Foye said that a successful football program would produce college scholarships for Woodstock Academy senior football players” Cafe, July 28, 2008. HERE

“The misguided priorities of the Academy leadership and its ‘track record’ does not bode well for the long term viability of its students’ futures.” Cafe, May 26th, 2008. HERE

By the way, I enjoy football and faithfully support losing programs like the ones at Norwalk High (late 50s to 1960; see the heroic story of Jerry Fishman), Bethany College (1961-1966), the University of Pittsburgh (1966-1972, 16-56)  just before Dan Marino and Tony Dorsett, and currently UConn at 2-7.  I sat virtually alone in driving rain in 1968 watching the lowly Pitt team come back from a 34-0 halftime deficit to beat West Virginia 35-34, the best game I ever saw.

Several years ago the Academy chose to invest in football with a new stadium and other unneeded athletic fields rather than invest in enhanced academic programs that would help students to develop professional careers. This was due to the low-level visionary thinking of Headmaster Foye and the Academy Board of Trustees.

November 26th, 2014

The Latest Developments with Ebola

From John

Yesterday I was interviewed by the Des Moines Register about Merck’s acquisition of NewLink’s Ebola vaccine. This graph shows that there is something different about this Ebola outbreak compared to previous outbreaks. A little bit of immunity caused by the vaccine should have a big impact on the spread of the disease. These numbers provided by the CDC are actual confirmed cases and deaths caused by Ebola. They under report the actual cases and deaths.

November 11th, 2014

In Preparation for the Unusual Cold Spell Coming Our Way – Dealing with Global Warming So We Can Have a Better Ice Age

From John

From National Geographic News: “An instrument near the summit of Mauna Loa in Hawaii has recorded a long-awaited climate milestone: the amount of carbon dioxide in the atmosphere there has exceeded 400 parts per million (ppm) for the first time in 55 years of measurement—and probably more than 3 million years of Earth history.”

The graphics below suggest that we are about 10,000 years into a warm spell on planet Earth. Prior to the last ice age we had about 17,000 years of relative warmth before things started to go down hill. If 17,000 years is about right for our current warm spell, then we have only 7,000 years left in our Garden of Eden. But we are clearly polluting our environment. The big difference now is that in the warm spell that took place between 132,000 and 115,000 years ago there was only a million or so homo sapiens around and no polluting industry. Now we have almost 8 billion modern humans and an industrial society.

It’s clear that whomever coined the term “Global Warming” coined a misnomer because it looks as though our atmosphere was warmer 130,000 years ago. The popular phrase should be “Global Polluting” shouldn’t it? Then the nay-sayers might accept the problem and take some responsibility for it. Otherwise human beings may not be around to have the next ice age.

I’ve added some benchmarks to the graph below which shows the patterns of warming and cooling of the Earth for the last 400,000+ years. The warming and cooling of the Earth is caused by a very subtle movements closer and farther from the Sun in our eliptical orbit. This is not man-made. The last ice age took longer than the three previous ice ages shown in the graph which is based on chemical analysis of core samples from the Vostok ice sheet in Antarctica.  Two benchmarks are the demise of H. erectus and Neanderthals based upon the fossel record. These two species of Homos died off near the ends of two ice ages. Imagine what it would be like for us if the biosphere was 13 degrees colder on average than it is today. Back then their only refuge was a chilly cave or to head south. No wonder humans got their start in Africa.

Our current understanding of human history only came about since 1970 when nucleic acid hybridization became a tool for understanding the divergence of genes among all lifeforms. The rate of hybridization of two strands of DNA is a function of complimentarity of the Watson-Crick double helix.

From the last full cycle it appears that warm spells last about 18,000 years whereas the last ice age lasted about 97,000 years. It looks like archaic Homo sapiens survived two ice ages whereas Neanderthals only survived one. But our human male Y chromosome was passed on from H. erectus while the earliest date of discovery of mitochodrial DNA was during the time that archaic H. sapiens roamed sub-Saharan Africa. The mitochondrial DNA genome is inherited from mothers, not fathers; likewise in plants, chloroplasts are not carried in pollen when the female part of the plant is fertilized.

This is all very mind-boggling to consider. Will scientists have the answers for how to deal with the next ice age? Yup! Will politicians cooperate? We’ll just have to wait and see. ;-)

Graph of CO2 (Green graph), temperature (Blue graph), and dust concentration (Red graph) measured from the Vostok, Antarctica ice core. The shifts between hot and cold periods is thought to be controlled by the the Milankovich cycles:
1. The earth’s orbit changes from being nearly circular to slightly elliptical (eccentricity). This cycle is affected by other planets in the solar system and has a period of around 100,000 years.
2. The angle of tilt of the earth’s axis changes from 22.1° to 24.5° (obliquity). This cycle has a period of 41,000 years.
3. The direction of the tilt of the axis changes (precession) on a cycle of 26,000 years.

CO2 followed temperature change “with a lag of some hundreds of years” amplifies temperature change. Among other factors, CO2 is more soluble in colder than in warmer water. Higher dust levels are believed to be caused by cold, dry periods.

November 4th, 2014

The Vote in Woodstock at 8:30 PM

Governor

Dan Malloy/Wyman (D) – 1254

Tom Foley/Somers (R) – 1637

Representative to Congress

Joe Courtney (D) – 1568

Lori Hopkins-Cavanagh (R) – 1230

State Senator

Tony Guglielmo (R) – 2044

Andrea Penta (WFP) – 370

State Representative

Mike Alberts (R) – 2243

Unopposed

Secretary of State

Denise Merrill (D) – 1193

Peter Lumaj (R) -1609

Treasurer

Denise Napier (D) – 1228

Tim Herbst (R) -1609

Comptroller

Kevin Lembo (D) – 1143

Sharon McLaughlin (R) – 1581

Attorney General

George Jepsen (D) – 1303

Kei Westby (R) – 1436

Judge of Probate

Leah Schad (D) – 1958

Unopposed

Registrar of Voters

Suzanne Woodward (D) -1320

Mary Place (R) – 1485

Constitutional Amendment – Easier to vote

yes – 1196

no – 1417

October 27th, 2014

Explaining the Relevance of Risk Calculation in Choosing a (Chemo)Therapy

Reading Jeff’s explanation of risk calculation below was like taking the Ice Bucket Challenge. My views on that phenomenon are published HERE. This article is very helpful in understanding the nuances and adding perspective to statistical analyses like those published on coffee drinking below. Ultimately one needs to understand the actual biochemical mechanism that explains the benefits of coffee and any other drugs used to treat disease to verify their statistical merits. Until then, I will continue to take my timed-release gram of vitamin C in the morning and pick up a large Dunkin Donuts coffee on my way to work. John Leavitt

From Jeff Gordon, M.D.

Relative Risk is not the same as an actual increase or a decrease in risk.

The Absolute Risk is the risk of developing a disease (such as cancer) over a defined period of time.

The Relative Risk is the risk difference when comparing two groups of people, for example people who smoke cigarettes and people who do not smoke cigarettes. The Hazard Ratio expresses this relative risk difference, but by a different number mechanism.

Let’s say that the risk of developing lung cancer is 80% higher in people who smoke than in people who do not smoke. This means the Relative Risk is an 80% increase. The Hazard Ratio states this as being 1.8. A Hazard Ratio of 1 means the difference between the two groups (smokers and non-smokers) is zero. Numbers higher than 1 mean increased risk. Numbers lower than 1 mean decreased risk. So, 1.8 means the smoking group has an 80% increase of getting lung cancer than does the non-smoking group.

First, this does not mean that the risk of getting lung cancer in the non-smoking group is 0. It just means the risk of getting lung cancer if you smoke is higher than if you do not smoke.

Second, the 80% risk increase may sound like a lot when looking superficially at the number “80%”. But, what is the Absolute Risk increase?

Let’s say the risk in non-smokers of getting lung cancer is 1 in 100,000. For smokers, this risk is increased by 80%, so the risk goes from 1 in 100,000 to 1.8 in 100,000. The absolute difference of 0.8 is very small. If the population were 300 million, then a 1 out of 100,000 risk increasing to a 1.8 out of 100,000 risk would translate into 3,000 cases of lung cancer increasing to 5,400 cases of lung (an increase of just 2,400 cases).

That puts things in perspective.

But, what if the Relative Risk increase is 800%? The Absolute Risk increases from 1 in 100,000 (for non-smokers) to 8 in 100,000 (for smokers). If the population were 300 million, then a 1 out of 100,000 risk increasing to a 8 out of 100,000 risk would translate into 3,000 cases of lung cancer increasing to 24,000 cases of lung (an absolute increase of 21,000 cases).

Even as the Relative Risk goes up, the Absolute Risk increase in this example is not staggeringly high because the baseline risk is not high.

But, what if the risk of getting lung cancer in a non-smoker is 1 out of 100? If the Relative Risk increase is 80% for non-smokers, then given a population of 300 million, as in the example above, then the cases of lung cancer go from 300,000 up to 540,000. This is an absolute increase of 240,000 cases. The increase in total cases goes up more due to the higher baseline Absolute Risk.

If the Relative Risk were 800%, then the number of cases goes from 300,000 to 2,400,000 cases. The increase in total cases is much, much higher because both the baseline Absolute Risk and the Relative Risk are increased.

An example I use daily in my medical practice is explaining the potential risk reduction of dying from a cancer if someone takes a recommended treatment (such as chemo). Look at how the numbers change even if the Relative Risk reduction of dying is the same if the same chemo is used.

· Baseline risk of death is 10%. A 50% Relative Risk reduction by using chemo translates into an Absolute Risk reduction of 5%, so the risk of dying of the breast cancer drops from 10% to 5% after chemo. The risks of having a serious problem from chemo could be 2%, let’s say, so the benefit is larger than the risk of chemo, but not by much.

· Baseline risk of death is 50%. A 50% Relative Risk reduction by using chemo translates into an Absolute Risk reduction of 25%, so the risk of dying of the breast cancer drops from 50% to 25% after chemo. The risks of having a serious problem from chemo could be 2%, let’s say, so the benefit outweighs the risk of chemo.

· Baseline risk of death is 90%. A 50% Relative Risk reduction by using chemo translates into an Absolute Risk reduction of 45%, so the risk of dying of the breast cancer drops from 90% to 45% after chemo. The risks of having a serious problem from chemo could be 2%, let’s say, so the benefit much outweighs the risk of chemo. However, there is still a sizable remaining risk of dying of the cancer even after chemo given the very high baseline risk even with a sizable Relative Risk Reduction.

There are many ways to try to explain this.

Another number worthy of knowing is the Number Needed To Treat (NNT).

Let’s say that chemotherapy has a 50% Relative Risk reduction in the risk of dying of breast cancer. If the Absolute Risk of dying of breast cancer without chemo is 10%, then the Number Needed To Treat with chemo to benefit one person is 20. That means 20 people get chemo so that one person can get the actual benefit. A lot of people would be getting chemo without benefit because the baseline Absolute Risk of death from the breast cancer is low and the Absolute Risk Reduction is low.

But, if the same 50% Relative Risk reduction from chemo is applied to a baseline Absolute Risk of 90% of dying without chemo, then the NNT is 2.2, which means that 2.2 people get treatment so 1 can benefit (which is the same as 22 people getting treatment so 10 can benefit).

Of course, nowadays, we are much better with individualized benefit and risk assessments of breast cancer to minimize people getting treatment that won’t benefit them, thereby focusing on giving treatment to the people who could benefit the most from it.

So, the next time you read a news story trying to wow you with statistics about how great something is, keep these questions in mind:

What is the baseline Absolute Risk of the disease?
What is the Absolute Risk Reduction of a treatment for the disease?
What are the risks of side effects of the treatment?
How many people need to be treated for one person to get benefit?
What is the cost for treating an individual and what are the costs for treating a whole population?

October 25th, 2014

Is Coffee Good or Bad for You?

From John

These are the findings of very recent major meta-analyses of multiple clinical trials, some of which examined >100,000 to >1,000,000 subjects. The arrows point to the data of completely separated studies. I’ve included some tea drinkers and studies on caffeine drinkers, as well. The “relative risk” (risk ratio) is the key measurement. If you are in a group that has a relative risk of 0.80 then you have a 20% lower chance of developing the disease being examined. Likewise if you are in a group with a relative risk of 0.60, 0.40, 0.20, then you have a 40%, 60%, or 80% lower chance of getting the disease being examined, respectively. Over the years I have looked at past meta-analyses and they tell the same story. Rarely has a negative relationship between coffee or tea drinking been found.

Click to enlarge the actual data and its source:

October 21st, 2014

Woodstock Registered Voters Can’t Hide and the Ballot for November 4th

From John

Voter registration lists have always been available. Now CT’s registered voters can be searched by zip code and name (use the Find option when in the list of registered voters for a specific zip code). I looked at my home town of Rowayton and Woodstock. By doing this I can find out who is living in my past houses in my youth right down to their names and phone numbers. For a particular address you might see who lived there in the past also. For example, Andy Rooney’s wife Marge, who passed away a decade ago, is still listed at their former residence in Rowayton. She’s listed as inactive at that address. My sister Phoebe lived with Otis L in Rowayton for several years and voted  from there. Even though she has lived elsewhere for the last seven years, she’s still listed as active. Becki and I are listed in Woodstock. You can hyperlink to a second page which discloses your registered party affiliation and when you voted from 2000 on including referendums. See Connvoters.com for all zips in CT and see the Woodstock CT registered voters. Again, this information has always been available for the savvy.

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